Gemcitabine Based Hypofractionated Chemoradiation in Treatment of Muscle Invasive Bladder Carcinoma
Abdelmalik NA¹*, Tareq salah², and Diaa Hameed³
1Department of Radiotherapy and Nuclear Medicine, Assiut University, Egypt
2Department of Clinical oncology, Assuit University, Egypt
3Urology department, Assuit University, Egypt
Noha Ali Abdelmalik, MD, Lecturer of Radiation
oncology, SECI, Assuit University, Egypt, Email: email@example.com
Submitted: 19 February 2019; Accepted: 19 April 2019; Published: 22 April 2019
Cite this article:
Abdelmalik NA, Salah T, Hameed D (2019) Gemcitabine Based
Hypofractionated Chemoradiation in Treatment of Muscle Invasive Bladder Carcinoma. JSM Radiol Radiat Ther 3: 5.
Introduction: Bladder cancer is a global health problem worldwide and the ninth most common cancer. The most appropriate
treatment algorithm for muscle-invading disease remains controversial. Although radical cystectomy has been the mainstay for treatment
for decades, organ preserving regimens using predominantly multiple modality therapy are emerging as viable proven alternatives in a
subset of patients. The RTOG 95-06 study, examining the combination of hypo fractionation with chemotherapy, showed a 67% complete
response rate and a 3-year survival rate of 83 %.
Objectives: This prospective study aimed at evaluation the efficacy and toxicity of a modified hypo fractionated chemo radiotherapy
protocol for patients with muscle invasive bladder cancer.
Patient and methods: This prospective study was conducted during the period from April 2012 to end of 2016 in the radiotherapy
department, South Egypt Cancer Institute, clinical oncology department, Assiut University Hospital and urology hospital Assiut University.
Forty-five patients, 37-79 years old, transitional cell carcinoma, stage 57.8% T2, 40%T3, N0, M0 after transurethral resection [24.4%
complete TUR and 75.6% incomplete TUR] and magnetic resonance imaging, were recruited. Patients were treated with hypo fractionated
radiotherapy [RT] schedule that delivered 52.5 Gy in 20 fractions with weekly Gemcitabine 100mg/m².
Results: The majority of patients achieved complete response (CR) up to 86.7% and 13.3% with partial response. Three patients only
(6.7%) suffered from G3 acute bladder toxicity but no G3 proctitis. The 2-year overall survival [OS] rate recorded 93.3%and progression
free survival [PFS] (82.8%)in favor of hypofractinated radiation schedule regarding standard conventional one. The multivariate analysis
showed TUR as the only factor affecting OS [0.002] and PFS [0.38] significantly.
Conclusion: The hypo fractionated radiation proved to be of higher CR rate and survival rate with the favorable toxicity profile than
that of conventionally fractionated radiation schedule given concurrently with Gemcitabine. Also, the schedule is tolerable and cost effective as well.
Bladder cancer represents a health problem worldwide as it
is the ninth common cancer in both males & females. It is the most
common malignant disease involving the urinary system and
the second most common genitourinary cancer. Bladder cancer
accounts for approximately two-thirds of all urinary tract cancers
in United States. The estimated annual incidence in the United
States of 68,810 cases, accounting for 5% of all newly diagnosed
cancers. In Egypt, the situation of bladder cancer is very special.
It has been the most frequent malignancy among male. Liver and bladder cancers represented approximately 44% of cancer in
males. Bladder cancer ranked next to liver cancer in Lower Egypt
(8. 8%).In Upper Egypt, liver cancer was still the most common
cancer, with a small difference from bladder cancer (12.6%).
Bladder cancer ranked second in males [1,2].
The main risk factor for bladder cancer in Egypt was urinary
Schistosomiasis which was more frequent in Upper Egypt and its
prevalence decreased when going north. The age-standardized
rates are 16.9/100,000 (more developed) and 5.3/100,000 (less
developed) compared to 21.1/100,000 in Egypt .
Primary cystectomy is considered the main treatment but,
it carries significant physical, sexual, psychological morbidity.
Also, quality of life can be impaired, even with neobladder
reconstruction . Therefore, increasing interest in using bladder
preservation approaches in selected patients, which provide
equivalent tumor control and to minimize treatment-related
Maximal transurethral resection of bladder tumor (TURBT)
followed by irradiation with concurrent chemotherapy has
emerged as viable proven alternatives in a subset of patients.
Refining the treatment choice by maximizing the quality of life
without compromising survival rates is the goal . Combined
modality therapy achieves a CR and preserves the native bladder in roughly two-thirds of patients, while offering long-term
survival rates comparable to contemporary radical cystectomy
series for patients of similar clinical stage. Altered radiotherapy
fractionation has been intensely investigated during the past 20
years. A reduction of the overall treatment time (acceleration)
has shown some improvement in radiotherapy efficacy in headand-
neck and lung cancer . The effectively applied high dose
radiotherapy fractions have been in clinical practice with 5-year
local control rates of 20% to 30%. The RTOG 95-06 study, showed
a 67% complete response rate and a 3-year survival rate of 83
%in the combination of hypo fractionation with chemotherapy .
This study is the first study to be conducted in our locality
to revise these data in our patients as this beside added clinical
benefit may help to decrease the overload on our fully loaded
radiotherapy machines hoping to shorten waiting lists.
This single arm, phase II prospective study was conducted
during the period from April 2012 to end of 2016 in the
radiotherapy department, South Egypt Cancer Institute, clinical
oncology department, Assiut University Hospital, Assiut University
and urology hospital, faculty of medicine, Assiut University.
Informed consent was obtained from all recruited patients with
Institutional Review Board approval for the protocol. Patients
with cT1-3, N0, M0 bladder cancer who underwent maximum
TURBT were eligible for the study. Baseline evaluation of each
patient included chest radiograph, abdomen-pelvic magnetic
resonance imaging (MRI)/computed tomography (CT), bone
scan (if ≥T3 , bone pain or elevated alkaline phosphatase), full
blood picture, kidney and liver function tests, performance status
≤ 2 according to ECOG scoring system , hemoglobin ≥ 10 mg/dl,
an absolute neutrophil count of ≥1500/ml, a platelet count of >
100,000/mm3, a serum creatinine of 1.5 mg% or less, a serum
bilirubin less than or equal to 1.3 time of Upper limit of normal,
were included in current study. Patients with previous pelvic
radiation therapy, patients with node positive disease, evidence
of distant metastasis (M1) were excluded from study. All patients
in this study underwent maximum transurethral resection of
All patients were planned through CT simulator-based
planning with isocentric technique. Patients received hypo
fractionated radiation schedule in form of 5250 cGy/20 fractions
by 262.5 cGy per fraction, over 4 weeks with weekly concurrent
gemcitabine 100 mg/m2. Clinical target volume (CTV) had
included the whole bladder + 1.5cm margins all around.
Assessment of response to treatment
Response to treatment was evaluated 3 months after
completion of treatment by MRI scans of the abdomen and
pelvis together with cystoscopy under general anesthesia with
biopsy from any suspicious lesion. Additional cystoscopy was
performed at 7 and 12 months and every 6 months thereafter.
Repeat MRI scans were undertaken at 12 months and 24 months. Complete response was defined as the absence of visible tumor
endoscopically and the absence of histologic evidence of disease.
Acute treatment related toxicity was assessed weekly during
treatment and on the final day of treatment. After completion of
treatment, acute toxicity was scored for additional 6 weeks and
it was expressed by using the RTOG/EORTC Radiation Toxicity
Late treatment related toxicity was assessed monthly up
to one year starting from 6 weeks from end of chemoradiation
course and then every 6 months with time of cystoscopy and
imaging evaluation. Patients were assessed based on RTOG/
EORTC Radiation Toxicity Grading.
If any grade 3 hematological toxicity develops, chemo
radiotherapy should be discontinued for one week. For a grade
3 in field (radiation-related) toxicity during any treatment week
(such as radiation cystitis, acute colitis), chemotherapy and
radiation therapy should be delayed until resolution of toxicity
to grade 2 or less. If the delay to resume treatment is greater
than three weeks, the patient should be considered intolerant to
protocol therapy and considered off-protocol and will be referred
to radical cystectomy.
Overall survival was defined as the time from diagnosis till
death or last follow up visit at time of analysis.
Progression free survival was defined as the time from
diagnosis till time of clinical, radiological progression OR death.
The mean age of patients was 58 years (range 37 - 79 years),
93% (42 patients) were males. History of bilharzial infestation
was noted in 73.3 % (n=33) of patients. Three quarters (34
patients) presented with hematuria (75%). T staging showed
that 2%, 58%, and 40%of patients presented with T1, T2andT3
disease respectively. The majority of patients (75.6%) presented
with high grade tumors (34 patients).All patients underwent
maximal TURBT, but complete TUR was achieved in 34 % of
patients. Pathological report documented pure TCC in 76%
(n=34), transitional cell carcinoma with squamous differentiation
was noted in 11 patients (24%) (Table 1).
39 patients (86.7%) had CR, and 6 patients had partial
response (PR); of them 3 patients showed muscle invasive
bladder cancer (MIBC) and were shifted to radical cystectomy, 2
patients had non MIBC and shifted to intravesical instillation of
BCG (Figure 1). Only one patient has progressed and discovered
to have bone metastasis at the end of chemoradiation (Table 2).
Median progression free survival was 12 months (Figure 2) and
median overall survival was 18 months (Figure 3).
Hypo fractionation chemoradiation protocol was well
tolerated for majority of patients with mild to moderate
complains, that improved with supportive medical treatment.
Three patients (6.7%) had suffered from G3 cystitis, 67% (30
patients) developed G2 cystitis, and 15% (7 patients) had
enteritis. During follow up, only one patient was reported changes
in bladder capacity with increased frequency of micturition.
All symptomatic patients responded to medical treatment and completed the full planned course of chemoradiation.
After time of analysis, Table (3). Univariate analysis of factors
that might influence OS and PFS in patients showed that TUR
adequacy was the only factor that affected OS (P =0.001) (Figure 1).
Hypo fractionated radiation therapy can provide many
advantages to both cancer patients and health care providers
(radiotherapy departments). It could be considered as possible
alternative to conventional radiotherapy schedules. Two
published UK-based randomized controlled trials allowed the
use of conventional (6400 cGy/ 32 fr.) and Hypo fractionated
Radiotherapy (5250 cGy / 20 fr.)[10,11]. Neither study showed
difference in outcome based on dose and fractionation. Many
reported studies showed favorable treatment outcome and
tolerable toxicity profiles of hypofractionated radiotherapy
protocols [6,7,8,9,10]. Analysis of our study showed high response
rate with 86.7% (n=39) complete response and 4.4% (2 patients)
have got partial response with non-muscle invasive disease so
treated conservative maneuver. The OS in hypofractionated
radiation protocol was 93.3% which is comparable OS to
that documented in conventional chemoradiation protocols of bladder cancer management. These results are confirmed
by previously published series including phase II study of
conformal hypofractionated radiotherapy with gemcitabine
in which 88% of patients achieved complete response, 3-year
overall survival was 75% and disease specific survival was
82% . Another published study by Christe group who had
studied hypofractinated radiotherapy alone in treatment of 60
selected patients, had demonstrated 75% complete response
rate and 61% overall survival . Radiation Therapy Oncology
Group 95-06 had studied combination of hypofractionation
with cisplatin and showed 67% complete response rate, 3-year
survival rate 83% . Regarding to the factors affecting outcome,
current study analysis showed that complete TURBT is the only
significant factor affecting overall survival (P=0.001) with a trend
towards improving relapse free survival (0.06) (Table 3). Median
progression free survival was 12 months (Figure 2) and median
overall survival was 18 months (Figure 3).
As early toxicity is considered dose limiting in altered
fractionation radiotherapy, conformal radiotherapy emerged as
bright way to spare early reacting normal tissue. Bowel sparing
technique would not only reduce treatment toxicity, but also would
enhance the surgeon’s ability to create continent diversions after
pelvic radiation if salvage surgery was needed. It was approved
in studying patients with bladder cancer used concomitant boost
technique with small pelvic field was planned to increase dose
to bladder gross. That technique reduced acute bowel toxicity
(G2) to 14% but had similar response to conventional dose series
. So, to irradiate bladder only with margins as modeling study
documented that the choice of margins was as important as the
choice of fractionation in term of intestine, rectum dose volume
histogram data and normal tissue control probability predictions
. Our study can confirm that bladder only radiation is as
effective as pelvic radiation in disease relapse survival. Similar
results were published by single institutional study that
compared bladder only concurrent chemoradiation (BO-CCRT)
vs. whole pelvis (WP-CCRT) in lymph node negative invasive
bladder cancer. In reported study, WP-CCRT was associated with
a 5-year disease-free survival of 47.1% compared with 46.9% in
patients treated with BO-CCRT. The bladder preservation rates
were 58.9%and 57.1% in WP-CCRT and BO-CCRT, respectively
and the 5-year overall survival rates were 52.9% for WP-CCRT
and 51% for BO-CCRT (p= 0.8). In WPCCRT group, 42.9% had regional lymphadenopathy recurrence . German study of
a combined modality treatment for locally advanced bladder
cancer 415patients with bladder cancer (high-risk T1or T2-4)
received radiotherapy or chemoradiotherapy after TURBT. A CR
was achieved in 72% of the patients. The 10-year disease-specific
survival rate was 42%, and more than80% of survivors had their
bladder preserved . Our study showed comparable bladder
preservation rate 77.8%. Patients in hypofractionated schedule
had no significant changes in sexual function and associated with
statistically significant less acute bladder toxicity and small bowel
toxicity (G2). Only3 patients (6.7%) have experienced radiation
cystitis G3. Hematologic toxicity was minimal. Our study can
demonstrate significant benefit of hypofractionation schedule
in bladder cancer management and better toxicity profile than
conventional chemoradiation schedule.