Radiotherapy may improve overall survival of patients with T3/T4 transitional cell carcinoma of the renal pelvis or ureter and delay bladder tumour relapse.

Abstract

Since transitional cell carcinoma (TCC) of the upper urinary tract is a relatively uncommon malignancy, the role of adjuvant radiotherapy is unknown.
We treated 133 patients with TCC of the renal pelvis or ureter at our institution between 1998 and 2008. The 67 patients who received external beam radiotherapy (EBRT) following surgery were assigned to the radiation group (RT). The clinical target volume included the renal fossa, the course of the ureter to the entire bladder, and the paracaval and para-aortic lymph nodes, which were at risk of harbouring metastatic disease in 53 patients. The tumour bed or residual tumour was targeted in 14 patients. The median radiation dose administered was 50 Gy. The 66 patients who received intravesical chemotherapy were assigned to the non-radiation group (non-RT).
The overall survival rates for the RT and non-RT groups were not significantly different (p = 0.198). However, there was a significant difference between the survival rates for these groups based on patients with T3/T4 stage cancer. A significant difference was observed in the bladder tumour relapse rate between the irradiated and non-irradiated bladder groups (p = 0.004). Multivariate analysis indicated that improved overall survival was associated with age < 60 years, T1 or T2 stage, absence of synchronous LN metastases, and EBRT. Acute gastrointestinal and bladder reactions were the most common symptoms, but mild non-severe (> grade 3) hematologic symptoms also occurred.
EBRT may improve overall survival for patients with T3/T4 cancer of the renal pelvis or ureter and delay bladder tumour recurrence in all patients.

Full text

Page 1

RESEARCH ARTICLEOpen Access
Radiotherapy may improve overall survival of
patients with T3/T4 transitional cell carcinoma of
the renal pelvis or ureter and delay bladder
tumour relapse
Bing Chen1, Zhao-Chong Zeng1*, Guo-Min Wang2, Li Zhang2, Zong-Ming Lin2, Li-An Sun2, Tong-Yu Zhu2,
Li-Li Wu1, Jian-Ying Zhang1and Yuan Ji3
Abstract
Background: Since transitional cell carcinoma (TCC) of the upper urinary tract is a relatively uncommon
malignancy, the role of adjuvant radiotherapy is unknown.
Methods: We treated 133 patients with TCC of the renal pelvis or ureter at our institution between 1998 and 2008.
The 67 patients who received external beam radiotherapy (EBRT) following surgery were assigned to the radiation
group (RT). The clinical target volume included the renal fossa, the course of the ureter to the entire bladder, and
the paracaval and para-aortic lymph nodes, which were at risk of harbouring metastatic disease in 53 patients. The
tumour bed or residual tumour was targeted in 14 patients. The median radiation dose administered was 50 Gy.
The 66 patients who received intravesical chemotherapy were assigned to the non-radiation group (non-RT).
Results: The overall survival rates for the RT and non-RT groups were not significantly different (p = 0.198).
However, there was a significant difference between the survival rates for these groups based on patients with T3/
T4 stage cancer. A significant difference was observed in the bladder tumour relapse rate between the irradiated
and non-irradiated bladder groups (p = 0.004). Multivariate analysis indicated that improved overall survival was
associated with age < 60 years, T1 or T2 stage, absence of synchronous LN metastases, and EBRT. Acute
gastrointestinal and bladder reactions were the most common symptoms, but mild non-severe (> grade 3)
hematologic symptoms also occurred.
Conclusion: EBRT may improve overall survival for patients with T3/T4 cancer of the renal pelvis or ureter and
delay bladder tumour recurrence in all patients.
Background
Transitional cell carcinoma (TCC) of the renal pelvis
and ureter is a relatively uncommon malignancy; it is
estimated to account for 7% of all renal neoplasms and
5% of all urothelial malignancies in the United States
[1]. Upper urinary tract carcinoma is often a multifocal
process, meaning that patients with cancer localised to
the upper urinary tract are at greater risk of developing
transitional tumours elsewhere. Approximately 20-50%
of patients with an upper urinary tract tumour will
develop bladder cancer [2-4].
Radical nephroureterectomy is a routine initial therapy
for most patients with TCC of the renal pelvis or ureter.
Surgery alone provides sufficient loco-regional control
for the majority of patients that present with early stage
disease; however, the overall 5-year survival rate after
surgery ranges from 0-34% for patients with locally
advanced TCC of the renal pelvis and ureter. The rate of
local failure is reported to be between 30 and 50%, and
this is the major cause of mortality in TCC patients [2-5].
The role of adjuvant external beam radiotherapy
(EBRT) in the treatment of patients with TCC of the
* Correspondence: zeng.zhaochong@zs-hospital.sh.cn
1Department of Radiation Oncology of Zhongshan hospital, Fudan
University, 136 Yi Xue Yuan Road, Shanghai 200032, China
Full list of author information is available at the end of the article
Chen et al. BMC Cancer 2011, 11:297
http://www.biomedcentral.com/1471-2407/11/297
© 2011 Chen et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.

Page 2

renal pelvis and ureter is unknown. Some studies report
that EBRT is not effective; therefore, EBRT is not
recommended for use as a prophylactic postoperative
therapy [6,7]. In contrast, other studies report that
EBRT may improve the treatment outcome when it is
concurrently administered with chemotherapy in
patients with resected, locally advanced, upper tract
urothelial malignancies. The ability of EBRT to improve
the treatment outcome for patients with locally
advanced renal pelvis or ureter cancer has been assessed
[8,9], but the studies included a small patient population
and were not detailed enough to draw any conclusions.
In this study, we report on a relatively large group of
patients with TCC of the renal pelvis and ureter who
were treated with postoperative radiotherapy and intra-
vesical chemotherapy. Therefore, this study provides a
detailed evaluation of the efficacy of adjuvant radiother-
apy in patients with TCC of the renal pelvis and ureter.
Methods
Patients and staging evaluation
To evaluate the outcome of external beam radiation
therapy (EBRT) in patients with TCC of the renal pelvis
or ureter, we analysed data collected prospectively for
patients treated at the Department of Urology at Zhong-
shan Hospital, Fudan University between September
1998 and April 2008. The study was approved by the
Fudan University Zhongshan Hospital Ethics Commit-
tee. A total of 133 patients were included in this study.
The patients had nephroureterectomy without distant
metastases, and were pathologically re-staged according
to the sixth American Joint Committee on Cancer
(AJCC) staging manual [10]. Patients who died within
the peri-operation period (6 weeks) or who developed
ureteral cancer from bladder cancer or bladder tumour
recurrence within 3 months following nephroureterect-
omy were excluded. Due to conflict among urologists
regarding the outcome of adjuvant post-operative EBRT
for treating TCC of the renal pelvis or ureter, the deci-
sion of whether a patient should receive radiation ther-
apy was based on the physician’s preference and the
patient’s consent. Since this factor could have potentially
contributed a significant bias to our study, we compared
the demographic and clinical factors of patients who did
and did not receive radiation therapy (Table 1).
Therapies
Surgical resection: Before surgical resection, all patients
were required to undergo computed tomography (CT)
and/or magnetic resonance imaging (MRI) of the abdo-
men and pelvis, and an intravenous excretory urogram
or retrograde pyelogram. Of the 133 patients in the
study, 108 were treated with the standard approach of
radical nephroureterectomy, including removal of the
contents of Gerota’s fascia with the ipsilateral ureter and
the cuff of the bladder at its distal extent. Open
nephron-sparing surgery for upper-tract TCC was used
in patients with a large renal pelvic tumour in a single
kidney. A partial ureterectomy or distal ureterectomy
with reimplantation is a reasonable treatment alternative
for patients who underwent palliative resection (R2,
macroscopic residual) or had poor kidney function.
Twenty-five patients underwent local resection surgery,
including nine patients with gross lymph node metas-
tases or accompanying cancers, for which palliative
resection was subsequently performed. There were five
patients over 80 years of age, four patients with poor
kidney function or an absent contralateral kidney, two
patients mistakenly diagnosed with renal cell cancer and
underwent radical nephrectomy, two patients mistakenly
diagnosed with urolithiasis but were subsequently found
Table 1 Patient characteristics
n Non-RTRT
p value
Age (average)
< 60 years
≥60 years
Sex
Female
Male
Tumor location
Renal pelvis
Ureter
Tumor lesions
Solitary
Multiple nodules
Pathologic T stage
T1
T2
T3
T4
Synchronous LN
-
+
Resection modality
Local resection
Nephroureterectomy
Residual Disease
R0
R1
R2
Histological grade
I
II
III
IV
68.5 ± 1.430
14(21.2%)
52(78.8%)
66.2 ± 1.208
17(25.4%)
50(74.6%)
0.074
0.57031
102
50
83
28(42.4%)
38(57.6%)
22(32.8%)
45(67.2%)
0.254
42
91
26(39.4%)
40(60.6%)
16(23.9%)
51(76.1%)
0.054
117
16
61(92.4%)
5(7.6%)
56(83.6%)
11(16.4%)
0.117
21
60
33
19
12(18.2%)
30(45.5%)
11(16.7%)
13(19.7%)
9(13.4%)
30(44.8%)
22(32.8%)
6(9.0%)
0.083
124
9
61(92.4%)
5(7.6%)
63(94.0%)
4(6.0%)
0.712
22
111
17(25.8%)
49(74.2%)
5(7.5%)
62(92.5%)
0.004
108
11
14
53(80.3%)
5(7.6%)
8(12.1%)
55(82.1%)
6(9.0%)
6(9.0%)
0.816
6
73
51
3
5(7.6%)
38(57.6%)
21(31.8%)
2(3.0%)
1(1.5%)
35(52.2%)
30(44.8%)
1(1.5%)
0.195
RT: Radiation Therapy, LN: Lymph Node
Chen et al. BMC Cancer 2011, 11:297
http://www.biomedcentral.com/1471-2407/11/297
Page 2 of 10

Page 3

to have TCC, and two patients with tumour invasion to
psoas.
Intravesical chemotherapy: All patients underwent a 8-
week induction regimen followed by a once-monthly
maintenance regimen for 12 months. The induction
regimen consisted of intravesical administration of mito-
mycin C (20 mg) or epirubicin (50 mg) dissolved in 50
ml saline, which was retained for 60 minutes and
drained once a week for 8 weeks. This procedure was
followed by the maintenance regimen, which used the
same dose of mitomycin or epirubicin once a month for
12 months.
Post-operative radiotherapy: Each patient provided
written or oral informed consent regarding their treat-
ment course. The median and average interval between
nephroureterectomy or ureterectomy and EBRT was 23
and 26 days (range, 12-76 days, standard error, 1.55
days) respectively. Patients received limited-field EBRT
using a linear accelerator with 15-MV photons. Immobi-
lization devices for patients with intra-abdominal
tumours usually included the thorax and pelvis. Radia-
tion doses of 46 to 50 Gy at 2 Gy per day were routinely
used to treat subclinical disease. For R1 (microscopic
positive margins) or R2 (macroscopic residual margins)
resections, a boost of 6 to 10 Gy at 2 Gy per fraction
was considered. The median dose of EBRT administered
to patients in this study was 50 Gy (range, 36-60 Gy).
Multiple-field arrangements, including oblique and lat-
eral fields with field reductions, were important to mini-
mise the toxicity to surrounding normal tissues. The
clinical target volume covered the ipsilateral renal fossa
and the course of the ureter, the whole bladder, and the
paracaval and para-aortic lymph nodes, which were at
risk of harbouring metastatic disease in 53 patients. In
addition, the tumour bed and regional draining lymph
nodes were targeted in 14 patients, including six
patients who underwent R1 or R2 resection and eight
patients by request. A coverage area of 90.0% of the
planned treatment volume as defined by the 95% iso-
dose line was required. Figure 1 shows the designated
irradiation fields, including the renal fossa, ureter, whole
bladder, and the at-risk lymph nodes.
Assessment of toxicity
Patients were monitored weekly by radiation oncologists
for symptoms of toxicity resulting from their radiation
therapy. Radiation toxicity was evaluated according to
the guidelines established by the Radiation Therapy
Oncology Group (RTOG; version 2.0) [11].
Follow-up
Patients were advised of the need for an initial follow-up
examination at the sixth week after completion of EBRT.
Patients were monitored every 3 to 6 months thereafter.
Follow-up information was obtained primarily through
telephone interview and follow-up was stopped on
March 15, 2009. The overall survival time was defined
as the interval between the date of surgery and either
the date of death or the date of the last follow-up
(censored).
Statistical analysis
The primary endpoint measures of the study were
safety, loco-regional failure or the occurrence of distant
metastasis, and overall survival. These were defined as
the time from the date of nephroureterectomy. Data
were censored at the date of the last visit or the date of
death. The characteristics of the patients, loco-regional
failure or metastasis rates, and overall survival rates
were compared between patients in the RT and non-RT
groups. The chi-square test was used for comparison
between groups. Survival curves were calculated by the
Kaplan-Meier method and compared using the log-rank
test. The Cox proportional hazards model was used to
determine the independent factors affecting endpoints,
based on the variables selected by the univariate analy-
sis. Statistical analyses were performed by SPSS 13.0 for
Windows (SPSS Inc., Chicago, IL). P values < 0.05 were
considered to be statistically significant.
Results
Among the 133 total subjects, 53 died during follow-up,
four were lost during follow-up, and the remaining 76
were censored at the end of the follow-up period on 3/
15/2009. The interval between surgery and initiation of
RT was 26.4 days on average with a 95% confidence
interval of ± 3.14 days. The median follow-up time was
26.6 months. The age of the patients ranged from 34 to
91 years, and the mean age was 67.8 years. A similar
proportion of patients with similar clinical symptoms
were included in the radiation (RT) and non-radiation
(non-RT) groups (Table 1).
We scheduled the full postoperative adjuvant radiation
dose as 46-50 Gy, but this dosage was subject to change
based on unpredicted situations that arose during the
course of EBRT and indicated the need for a reduced
dose, such as adverse side effects and the emergence of
distant metastases. The dosage was increased to between
54 and 60 Gy for patients who underwent R1 or R2
resection (12 patients). Three patients presented with
distant metastases during radiation, and four patients
developed ≥ grade 2 anorexia; the radiation dose was
reduced to < 46 Gy in these seven cases.
Survival analyses and prognostic factors
The median survival period was 55.0 months (range, 2.8-
118.6). The overall 1-, 3-, and 5-year survival rates were
82.2%, 58.8%, and 47.1%, respectively. Of the 133 patients,
Chen et al. BMC Cancer 2011, 11:297
http://www.biomedcentral.com/1471-2407/11/297
Page 3 of 10

Page 4

67 were in the RT group and 66 were in the non-RT
group. The overall survival rates for these two groups at 1,
3, and 5 years were 98.8% vs. 75.5%, 61.1% vs. 53.6%, and
49.6% vs. 44.7%, respectively. The median survival periods
were 55.0 months vs. 52.4 months, respectively. There was
no significant difference between the overall survival for
the RT and non-RT groups (p = 0.198; Figure 2A).
When we subdivided the groups based on the tumour
stage of the patients, we found a significant difference
between the RT and non-RT groups for patients who
had a T3 or T4 tumour stage. The median survival
times of these two groups were 29.9 months vs. 11.4
months (p = 0.006) for the RT and non-RT groups,
respectively (Figure 2B, C).
A
C
B
D
EF
50 Gy
47 Gy
40 Gy
38 Gy
30 Gy
Figure 1 Dose distribution of a patient with renal pelvis cancer and beam arrangements of 0°, 129°, and 229° gantry: (A) renal fossa;
(B, C) course of ureter; and (D) bladder. Digitally reconstructed radiograph for views of (E) 0° gantry and (F) 90° gantry. Internal pink and
yellow lines represent the CTV50 and CTV40 respectively.
Chen et al. BMC Cancer 2011, 11:297
http://www.biomedcentral.com/1471-2407/11/297
Page 4 of 10

Page 5

Univariate analysis indicated that an increased overall
survival rate was significantly associated with age < 60
years, a T1 or T2 tumour stage, no synchronous LN
metastases, nephroureterectomy, a R0 resection, and a
lower histological grade (Table 2).
Using multivariate analysis, we identified several favour-
able predictors associated with an improved overall survival,
which included age < 60 years, a T1 or T2 tumour stage,
absence of synchronous LN metastases, and EBRT. The his-
tological grade factor was determined to be significantly dif-
ferent using univariate analysis but not significantly different
based on multivariate analysis. This result is due to multicol-
linearity, which arises because many of the evaluated risk
factors correlate with histological grade. In this study, the
histological grade correlated with the tumour stage, resec-
tion models, and presence of residual disease (Table 2).
Failure patterns
In this study, 38 (28.6%) patients experienced bladder
tumour relapse. Table 3 shows the univariate and multi-
variate analysis for patients with and without bladder
tumour relapse. The favourable predictors were associated
renal pelvic TCC and irradiation of bladder. Bladder
tumour relapse rates in the non-RT and RT groups were
34.8% (23/66) vs. 22.4% (15/67), respectively; however, this
difference was not statistically significant (p = 0.112). Of
the 67 patients who received EBRT, 14 patients did not
undergo bladder irradiation; their radiation treatment
focused only on the tumour bed due to either R1 or R2
resection or the patient’s request. When we sub-divided
the 133 patients based on bladder irradiation, a significant
difference was observed in the rate of bladder tumour
relapse between the two groups [38.7% (31/80) without
irradiation vs. 13.2% with irradiation (7/53) (chi-square
test, p = 0.001), respectively]. Figure 3 provides the bladder
tumour relapse-free survival curves. The curves stabilised
to approximately 50.0% after 32.8 months in patients who
had not received bladder irradiation and to approximately
69.1% after 44.1 months in patients who had received
bladder irradiation. There was a significant difference
between the two groups (p = 0.002).
Table 4 provides the failure patterns for the two
groups. EBRT significantly reduced the rate of loco-
regional relapse, including anatomic/tumour bed recur-
rence and lymph node metastases, in patients who
underwent nephroureterectomy.
Adverse effects
Acute gastrointestinal reactions occurred in most
patients with RTOG grade 1 and were uncommon in
patients with grade 2. The most common side effect was
bladder spasms with mild symptoms not requiring inter-
vention. There were no cases of gastrointestinal bleeding
or perforation, and there were no severe cases (> grade 3)
of haematologic symptoms (Table 5).
Causes of death
Table 6 lists the causes of patient death. The most com-
mon cause of death was distant metastases; however,
A
B
C
Log-rank p=0.198
Log-rank p=0.764
Log-rank p=0.006
Figure 2 Survival curves of external beam radiotherapy (EBRT)
and non-EBRT groups based on (A) all tumour stages; (B) T1/
T2 stage; and (C) T3/T4 stage.
Chen et al. BMC Cancer 2011, 11:297
http://www.biomedcentral.com/1471-2407/11/297
Page 5 of 10