Introduction
Gastric cancer is one of common and lethal cancer
worldwide, with more than 1 million people new cases
reported each year.[] Despite the global decline in incidence
and mortality and also recent development in treatment of gastric cancer in the past five decades, the
prognosis is still poor, and it remains the third leading
cause of cancer-related death.[] The curative management
of gastric cancer is difficult unless it is found
at an early stage. Primary curative therapy for gastric
cancer is surgical intervention with lymph node dissection, but overall 5-year survival rates remain low
after resection, particularly in patients with T3-T4 or
metastasis.[] After the intergroup-0116 trial, adjuvant
chemoradiation (chemoradiotherapy [CRT]) has
become the standard of care for high-risk patients with
gastric cancer as an additional treatment that prolongs
survival and reduces local recurrence rates.[] However,
long-term toxicity associated with treatment
with CRT still remains a significant problem. The kidneys
are radiosensitive organs and thus are dose-limiting
structures for abdominal radiotherapy (RT) in
gastrointestinal cancers; late effects of renal irritation
may develop depending on dose and volume.[] The
incidence of RT-related kidney damage may probably
not be reported due to the long delay time, and late
renal dysfunction due to RT may often be attributed
to other more common causes.[] Despite advances
in RT techniques, dose-related reductions in renal
function have been reported in patients with abdominal
malignancies from 6 months up to 10 years after
irradiation.[] However, the pathophysiology of radiation-
related nephropathy in gastric cancer is poorly
understood. To date, few studies have been conducted
the effects of RT on renal function through creatinine
clearance (Ccr) and renal parenchymal (RPR) volume,
which are used as an indicator of impaired renal
function overtime, and the relationship between these
parameters and the dose-volume histogram (DVH).
[,,] However, their results were inconclusive. Besides,
some studies examined radiation-induced renal
damage have short follow-up times and use of nephrotoxic
chemotherapy regimens.
The aim of this study is to evaluate the long-term
impact of adjuvant CRT on renal function through the
Ccr and RPR volume and to compare the results with
DVH parameters in gastric cancer patients treated with
CRT using a non-nephrotoxic chemotherapy agent.
Methods
The study was designed as a single-center retrospective
study and was carried out from 2013 to 2014 in
the Department of Radiation Oncology, Faculty of
Medicine, Bulent Ecevit University, Zonguldak, Turkey.
A total of 34 patients diagnosed with Stage 2-3 gastric
cancer (T2-4, N0-3, and M0) who received post-operative
CRT were included the study. All patients underwent
D2 dissection and were histologically proven to
have gastric adenocarcinoma. Patients were included in
this study if they received RCT and three-dimensional
conformal abdominal RT (3D-CRT) or intensitymodulated RT (IMRT); had laboratory data, imaging
studies, and dosimetric parameters available for evaluation;
had no history kidney disease before RCT; and
had at least one kidney included in the RT treatment
fields. At least 4 years of follow-up were required for
eligibility. Patients with systemic diseases which could
have influenced renal function, metastasis, a history of
kidney disease (glomerular filtration rate [GFR] <55
mL/min/1.73 m²), and positive surgical margin were
excluded from the study. All research procedures were
evaluated and accepted by the Clinical Research Ethics
Committee of Bulent Ecevit University (No: 2018-118-
11/04) and were conducted in agreement with the ethical
standards specified in the Declaration of Helsinki.
As a retrospective design, written informed consent
from patients was disclaimed.
RT and Chemotherapy
All patients were treated according to the INT-0116
trial and received concurrent CRT.[4] One cycle of 425
mg/m2 per day of 5-fluorouracil (FU) and 20 mg/m2
per day folinic acid (FA) chemotherapy was given for
5 days before CRT. A second course of chemotherapy
comprised 5-FU (400 mg/m2/day) and FA (20 mg/m2/
day) during the first 4 and last 3 days of RT. After completion
of RT, two additional cycles of chemotherapy
were administered. Patients received RT by 3D-CRT
or IMRT with linear accelerators using 6 or 15 MV
photon beams in a total dose of 45 Gy in 25 fractions
of 1.8 Gy in 5 weeks. Computed tomography-based
treatment planning was managed using Eclipse treatment
planning system (Varian Medical Services, CA,
USA). 3D-CRT plans were generated in seven patients
with three (gantry angels: 0°, 90°, and 270°) or four
fields (gantry angels: 0°, 90°, 180°, and 270°), whereas
IMRT plans were designed in 27 patients with seven
fields (gantry angels: 25°, 75°, 135°, 180°, 225°, 280°,
and 325°). The design of the radiation treatment field
was individualized depending on the extent and location
of the primary tumor and involved lymph nodes.
[] DVHs were generated for kidneys, planning target
volume (PTV), and liver in all patients. During
planning and evaluation of DVHs, the dose delivered
to target volume was intended to cover at least 95%
of PTV in 3D-CRT plans and also to achieve D2 and
D98 values as recommended in ICRU-83 in IMRT
plans.[] In addition, mean kidney dose (MKD) and
also the renal volume that received more than 10 Gy
(V10), 15 Gy (V15), 20 Gy (V20), 25 Gy (V25), 28 Gy
(V28), and 30 Gy (V30) were calculated for the left,
right, and both kidneys.
Follow-up
Patients were followed every 3 months after CRT during
the first 2 years and at 6 months intervals thereafter.
During the follow-up period, demographic and clinical
parameters including age, gender, height, weight, body
mass index, comorbidities, treatment features, and results
of basal, the 2nd and 4th year biochemical parameters
were obtained. To evaluate renal function, Ccr was
calculated using the Cockcroft-Gault formula before
RT (but after CT), 24 and 48 months after RT.[]
Ccr= ((140-age) * body weight in kilograms)/72 *
serum creatinine
This value was adjusted for females by multiplying
by 0.85.[] The ratio of Ccr was calculated by the formula:
Post-RT Ccr divided by pre-RT Ccr. In addition,
RPR volume was calculated by contouring the kidneys
except the calyx in each tomographic slice, and the results
were evaluated by computed tomography before
and 48 months after RT. Volumes were expressed as a
percentage of the volume in CT before RT.
Statistical Analysis
All statistical analyses were performed using the SPSS
software version 16.0 (SPSS Inc., Chicago, IL). Patients
and treatment characteristics were given as percentage.
Kidney parenchymal volume, kidney dose, and DVH
values were reported as mean and standard deviation.
Ccr was demonstrated as median and range. The categorical
data were compared by means of Chi-square
test. The comparisons of the groups were assessed using
the Student's t-test for normally distributed continuous
variables. The Mann-Whitney U-test was utilized
for non-normally distributed continuous variables.
Statistical significance was defined as p<0.05.
Results
A total of 34 patients with gastric cancer who received
CRT were included retrospectively in the study. The median
of the patients was 60 years (range: 42-79) and most
of them were male (n=26; 76.5%). In pathological examinations,
all patients were diagnosed with gastric adenocarcinoma.
Fifteen patients (44.1%) had Stage 2 and 19
had (55.9%) Stage 3. Because of the stomach position,
the irradiation doses of the left kidneys were higher than
the right kidney doses (10.2 vs. 15.58 Gy, respectively).
During the follow-up period, Grade 2 renal toxicity was
observed in five patients, while none of the patients had
Grade 3 toxicity. However, no patients had renal failure
or requiring hemodialysis. Demographic and treatment
characteristics of patients are shown in Table 1.
Table 1: Demographic and treatment characteristics of
patients (n=34)
Median of Ccr before RT was 82.8 mL/min (range:
41-130). Following RT, Ccr decreased to 78.4 mL/min
(range: 39-130) 24 months after RT and to 75.3 mL/
min (38-123) 48 months after completion of treatment
(Table 2). There was statistically significant difference in
terms of Ccr before and 48 months after RT (p=0.034).
The number of patients with a Ccr value >90 mL/min
decreased from 14 to 10 at the 24th month and to 8 at
the 48th month. In addition, the number of patients
with Ccr 60-89 mL/min increased from 18 to 21 at
24 months and increased to 23 at 48 months. The left
and right RPR volumes were significantly decreased in
4 years after RT (from 143.4 to 126.1 cm³ and 141.9-
126.9 cm³, respectively, both p=0.001) (Table 2).
Table 2: Changes in Ccr and kidney parenchymal volume
after radiotherapy overtime
Radiation therapy was given as a MKD of 13.5±4.3
Gy. We found that the mean left kidney dose was 15.5±8.1 Gy, and also the mean right kidney dose was
10.2±6.7 Gy (Table 3). While 13 of 17 patients (76.5%)
with a MKD >14 Gy had decreased Ccr, only three of
19 patients (19.8%) with a MKD of ?14 Gy showed
Ccr reduction, and this difference was statistically significant
(p=0.001). The Ccr reduction percentage at
48 months after RT was 9%, which showed a significant
correlation with the total dose of renal radiation
(p=0.008) (data not shown). The total kidney dose,
bilateral kidney V20, bilateral kidney V25, and right
kidney V20 doses were significantly higher in patients
with decreased Ccr more than 10 mL/min at 48 months
after RT than those who did not decrease (p=0.003,
p=0.037, p=0.029, and p=0.013, respectively) (Table
3). In correlation analysis, we found no correlation between
not only the changes in RPR volume and Ccr but
also the changes in RPR volume and renal mean doses
in the study group (data not shown).
Table 3: Radiation treatment characteristics
Discussion
The study was aimed to assess the prolonged effects of
adjuvant CRT on renal function and to compare the
results with DVH parameters in gastric cancer patients
treated with CRT. We found decreased Ccr and kidney
parenchymal volume in follow-up period after treatment.
These changes demonstrate that parameters associated
with renal functions tended to decrease with
CRT overtime. We showed a correlation between Ccr
reduction and the renal radiation dose in the followup
period. We also revealed the relationships decreased
Ccr and bilateral kidney V20, bilateral kidney V25, and
right kidney V20.
Adjuvant post-operative chemotherapy and abdominal
RT have been used in the management of locally
advanced gastric cancer to improve local control and
survival rates. Radiation-associated renal toxicity has
been recognized as one of the most important dose-limiting
factors in abdominal RT.[] Acute toxicity may
occur between 6 and 12 months after RT and is usually
subclinical.[] The late kidney damage emerges after
18 months, with a longer period may be required for the
development of symptomatic nephropathy. In our study,
Grade 2 renal toxicity was developed in five patients,
during the 48 months follow-up period, while none of
the patients had renal failure or requiring hemodialysis.
Human studies on kidney toxicity of adjuvant CRT
in gastric cancer are limited and these studies also have
relatively short follow-up period. Yavas et al.[] demonstrated
in 12 months of follow-up period that MKD
>1500 cGy and basal GFR <90 mL/min/1.73 m2 were associated with an increased risk of decreased GFR at
12 months in 59 gastric cancer patients who underwent
post-operative CRT. Inaba et al.[] showed in 38 patients
with primary gastric diffuse large B-cell lymphoma
treated with CRT that Ccr and kidney parenchymal volumes
decreased 4 years after CRT. They found the mean
Ccr values to be 82.7 mL/min before treatment and 70.4
mL/min 4 years after CRT. They also demonstrated 12%
reduction of RPR volumes in the same period. These results
were consistent with our study. To show the possible
toxicity, we followed all patients for at least 4 years in
our study. We found similar reduction of Ccr and RPR
volume in our patient group. This indicates that a progressive
decline in renal function may occur in gastric
cancer patients after adjuvant post-operative CRT. However,
we could not observe these declines in clinically.
None of the patients had symptomatic nephropathy. It
may have been due to the compensatory response of the
other kidney or asymptomatic course of renal damage.
Other cofactors and comorbidities including diabetes
and hypertension may also complicate the course of
renal failure of RT. However, none of the patients had
diabetes and hypertension in our study.
The use of nephrotoxic chemotherapeutic agents,
such as cisplatin, with abdominal RT in the adjuvant
treatment of gastric cancer can reduce renal tolerance
and lead to renal toxicity. Welz et al.[] showed in 27
gastric cancer patients with treated cisplatin before and
after simultaneous FU and RT in 26 months of followup
period that Ccr tended to worsen overtime. Therefore,
all patients in our study received only 5-FU-based
chemotherapy, which was safer and had fewer renal
side effects.
Total renal radiation dose has an important impact
on renal function, and several studies have shown a
relationship between renal radiation dose and renal
function. A comprehensive review of 12 studies revealed
that the total dose was the only significant variable
associated with increased renal toxicity after total
body irradiation in adults.[] Inaba et al.[] showed
that kidney D30% <19 Gy and V20Gy <26.6% should be
obtained to achieve safe dose constraints for a lower
Ccr reduction. May et al.[] showed in 164 patients
with gastrointestinal malignancies who were treated
with CRT that V10 and mean kidney radiation dose
were found to be related to Ccr reduction 1 year after
treatment. Jansen et al.[] demonstrated renal
function by renography in 44 gastric cancer patients
treated with post-operative CRT and observed a progressive
decrease in left kidney function during the 18-
28 month follow-up, as well as a relationship between
the mean left kidney dose and left kidney V20 and decreased
kidney function. Kaydihan et al.[] revealed
in 22 gastric cancer patients that V5 and V10 of the left
and bilateral kidneys were related with GFR decline.
Diavolitsis et al.[] observed a significant correlation
between decreased Ccr and all DVH parameters
including V5, V10, V20, and absolute volume of kidney
in 125 patients with gastrointestinal malignancies
treated with RT, with a median follow-up of 2.4 years
and MKD of 16.2 Gy. In our study, we examined Ccr,
kidney parenchymal volume, and DVH to demonstrate
the late effects of adjuvant CRT. We showed a relationship
between total renal dose and reductions of Ccr.
This indicates that the onset and extent of renal failure
are dose dependent in gastric cancer patients after CRT.
We also found that the patients with Ccr reduction of
>10% had significantly higher total renal dose, higher
V20, V25, and right kidney V20 values. Although no
statistically significant difference was found except
V20 in our study, the right kidney DVH parameters
tended to be higher in patients with >10% Ccr reduction.
Therefore, it can postulate that the right kidney"s
V20 value may affect the compensatory response of
the right kidney. It also indicates that the irradiated or
low dose irradiated kidney has an important, compensatory
response feature after contralateral, whole volume,
and high-dose irradiation.
Abdominal RT is commonly delivered using CTbased
treatment planning including 3D-CRT or IMRT.
The standard target dose of 45 Gy limits the ability to
deliver higher doses, exceeding the tolerance of some
critical normal tissues. Studies have shown that fewer
side effects can be achieved with IMRT due to lower kidney and other surrounding tissue doses.[] IMRT
may allow higher doses to increase control and reduce
acute toxicity by limiting the dose to normal structures.
[] Wieland et al.[] showed that median renal dose
can be reduced by >50% with IMRT compared with 3D
planning. Minn et al.[] demonstrated a comparison
of IMRT and 3D-CRT as adjuvant therapy for gastric
cancer and found similar survival rates and Grade >2
acute gastrointestinal toxicity, indifferent serum creatinine
levels between two groups. In addition, Chopra
et al.[] compared 3D-CRT and IMRT in 51 patients
with gastric cancer patients and found no difference
between 3D-CRT and IMRT in terms of gastrointestinal,
hematological or renal toxicity, as well as local relapse
and overall survival. In our study, 3D-CRT was
generated in seven patients and IMRT was designed in
27 patients. Since the number of patients treated with
3D-CRT is low, we did not compare the effect of 3DCRT
and IMRT on kidney function.
The study has some limitations. First, because of the
nature of retrospective study design, our analyses did
not include the homogeneous data. Second, the study
involved the small patient numbers and relatively short
follow-up. Third, we did not compare 3D-RT and IMRT
in our study group. Third, we examined on the patients
with similar ethnicity (Turkish population). Thus, the
results may not be representative of the general population
of gastric cancer treated with post-operative CRT.
Conclusion
We observed long-term progressive renal toxicity with
both functional and imaging tests after post-operative
adjuvant CRT in locally advanced gastric cancer. We
also demonstrated that decline in renal function was
associated with bilateral and compensatory kidney radiation
dose and volume. For RT planning, bilateral
and compensatory kidney radiation dose and volume
might be evaluated for safe dose constraints and may
be useful for predicting late kidney toxicity.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved by
the Bulent Ecevit University Clinical Research Ethics Committee
and were conducted in agreement with the ethical
standards specified in the Declaration of Helsinki (No: 2018-
118-11/04, Date: 11/04/2018).
Financial Support: None declared.
Authorship contributions: Concept - Ö.E., B.H.B.; Design
- Ö.E., B.H.B.; Supervision - Ö.E., B.H.B.; Funding - Ö.E.;
Materials - Ö.E.; Data collection and/or processing - Ö.E.;
Data analysis and/or interpretation - Ö.E.; Literature search
- Ö.E.; Writing - Ö.E.; Critical review - Ö.E.
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