Purpose: Adjuvant radiation therapy could reduce loco regional failure, but currently has no defined role because of previously reported morbidity. NCI-Cairo routine work is to give adjuvant PORT for locally advanced bladder carcinoma patients. The aim of this work is to re-evaluate this protocol regarding its effect on prognosis and complications. Patients and Method: A retrospective study included 208 patients with pathologically proven bladder cancer who presented to the NCI, Cairo University from 2007-2011. All of them underwent RC with bilateral PLND followed by conventional post-operative radiotherapy in 2 - 6 weeks after surgery for 5000 cGy in 25 fractions, over 5 weeks using 2D technique. Analysis of data from their files was done for the treatment results, prognostic factors and complications. Results: Three years overall survival (OS) and disease free survival (DFS) for the whole group was ~60%, and 54% respectively in favour of the female gender, non-smokers, Squamous cell carcinoma patients, low grade tumours (grade 1 and 2) negative margins, N0, pT2b and early stage group showed the best prognoses. The 3 years metastases free survival (MFS) was ~71%. Only four factors showed a significant relation with the MFS which were the grade, LN status, T-stage and group staging. The local recurrence rate (LRC) at 2 years for the whole group was ~95% and 94% at 3 years. Only surgical margin status and extent of LN dissection had a significant impact on the LRC. Conclusions: Adjuvant radiotherapy shows sustained improvement in the loco regional control, and should be recommended for patients with locally advanced disease especially those with less than 10 dissected lymph nodes and those with positive margins.
More than 350,000 new cases of bladder cancer are diagnosed worldwide each year; the vast majority (>90%) of these are transitional cell carcinomas (TCC) [
A meta-analysis of randomized controlled trials with or without platinum-based chemotherapy following local therapy (usually RC) showed that 25.6% of patients with chemotherapy had locoregional recurrence as a first event with or without synchronous distant metastasis [
In an attempt to increase locoregional control, the use of postoperative radiotherapy (PORT) was explored decades ago and demonstrated robust local control [
Improvements in targeting radiation and the increasingly recognized local-regional failure as a more significant problem than was previously appreciated have rekindled interest in adjuvant RT for high-risk patients [
Postoperative radiotherapy has the advantage of dealing with microscopic cells that are easier to sterilize. It allows better identification of the group of patients that may benefit from such adjuvant therapy.
Previous results of our own centre showed significant improvement in local control using PORT for locally advanced bladder carcinoma patients [
This retrospective study included 208 patients with pathologically proven bladder cancer who presented to the radiotherapy department, NCI, CU from January 2007 till December 2011. All of them underwent RC with bilateral PLND followed by adjuvant external beam radiotherapy. All of the 208 patients, included in the analysis completed their course of radiation.
The treatment volume included the urinary bladder bed and pelvic lymph nodes.
・ Upper margin: either at the level between sacral vertebra one and two (83 patients) or between lumbar vertebra five and the first sacral vertebra (125 patients).
・ Lower margin: at the inferior border of obturator foramena. In cases of prostatic invasion, the inferior border extended downwards to the lower border of the ischium.
・ Lateral border: lies 1.5 cm outside the bony pelvic brim.
・ The anterior border of the lateral field lies just in front of the symphysis pubis.
・ The posterior border stops at the junction of anterior one third and posterior two thirds of the rectal circumference or the junction of the first and second sacral vertebrae.
・ Field arrangement: All patients were treated isocenterically through three fields (one anterior and two lateral wedged fields) or four fields (box technique).
・ A homogenous distribution to the treatment volume with maximum deviation of +7% and −5% and a minimum dose to the rectum have to be insured.
・ Treatment was given on a 6 MV Linear accelerator.
・ Dose: conventional post-operative radiotherapy in 2 - 6 weeks after surgery for 5000 cGy in 25 fractions, over 5 weeks using 2D technique (
・ Toxicity Reporting: The RTOG/EORTC Radiation Toxicity Grading was used to score acute radiation (≤90 days) toxicities while toxicities appearing or persisting beyond 90 days from start of RT were documented as late radiation toxicities [
・ Overall survival (OS): the period started from the date of diagnosis until patient death or time of last follow up.
・ Disease free survival (DFS): the period started from the date of cystectomy until the first appearance of relapse, whether this relapse was local or systemic or the last date of follow up.
・ Local control period is the time started from the date of cystetomy until appearance of locoregional recurrence, or the day of reporting. Patients who developed distant metastasis without local recurrence considered censored.
・ Distant metastasis-free survival time in the period from cystectomy until first appearance of dissemination or time of last follow up in those who did not develop distant metastasis. Patients who developed local recurrence without systemic dissemination are considered censored.
Data was analyzed using IBM SPSS advanced statistics version 20 (SPSS Inc., Chicago, IL). Survival analysis was done using Kaplan-Meier method and comparison between two survival curves was done using log-rank test. All tests were two-tailed. A p-value < 0.05 was considered significant [
Out of the 208 eligible bladder cancer patient, 158 were males (76%) and 50 females (24%), with a male to female ratio of 3:1. The mean age was 56 ± 7.4 years (range: 26 - 77 years). Patient’s characteristics are shown in
Transitional cell carcinoma constitutes about 52.4% of cases while the remaining is SCC. Low grade tumours (grade 1 and 2) were more common (65.4%) than high grade tumours (34.6%). About 82% of SCC patients had low grade tumours compared to 50% in the TCC group of patients. Only 20% in the SCC group were LN positive compared to 32% of TCC patients (
The pathological p3b stage represented the majority of cases (56.3%). Seventy four percent of patients have negative LN status while the rest (26%) had positive node. The surgical margin was positive in 15 patients only (7.2%).
・ Lower GI symptoms
One hundred forty eight patients (~71%) had lower GI symptoms. Eighty one patients (~55%) complained of grade 1 symptom and 63 patients (~43%) complained of grade 2 symptoms (
・ Skin reactions
Nine patients (~4%) experienced skin toxicity. Grade 1 reactions were present in 2 patients while grade 2 reactions were present in 7 patients (
・ Relation of the upper field border with acute toxicity
One hundred and twenty five patients were treated with an upper border of L5-S1 while the rest (83 patients) treated with S1-S2. The lower GI symptoms were present in 91 patients (~73%) treated with L5-S1 as an upper border. Grade 1 constituted 56% of cases while grade 2 was 44%. On the other hand 57 patients out of 83 (~69%) treated with S1-S2 as an upper border complained of GI symptoms with grade 1 and 2 of 57% and 43% respectively. These results were not found to be statistically significant.
Late Toxicity:
From a total of 208 patients, 50 patients (24%) suffered from late reactions: 20 patients (40%) complained of bilateral lower limb oedema, 21 patients (42%) presented by ureteric stricture, 3 patients (6%) complained of scrotal swelling and 6 patients (12%) suffered from intestinal obstruction necessitating surgical referral (Two
Characteristics | Number | Percentage (%) | |
---|---|---|---|
Total | 208 | 208 | |
Age group | < 60 | 128 | 61.5 |
≥ 60 | 80 | 38.5 | |
Gender | Males | 158 | 76 |
Females | 50 | 24 | |
Smoking | Yes | 92 | 55.8 |
No | 116 | 44.2 | |
PS | 1 | 144 | 69.2 |
2 | 59 | 28.4 | |
3 | 5 | 2.4 | |
Pathology | SQ | 99 | 47.6 |
TCC | 109 | 52.4 | |
Grade | 1 | 10 | 4.8 |
2 | 126 | 60.6 | |
3 | 72 | 34.6 | |
SM | Positive | 15 | 7.2 |
Negative | 193 | 92.8 | |
LN dissection | <10 | 71 | 34.1 |
≥10 | 137 | 65.9 | |
LN | Negative | 153 | 74 |
Positive | 55 | 26 | |
T-stage | 2b | 54 | 26 |
3a | 16 | 7.7 | |
3b | 117 | 56.3 | |
4a | 21 | 10.1 | |
N-stage | N0 | 153 | 73.6 |
N1 | 21 | 10.1 | |
N2 | 34 | 16.4 | |
Stage | 2 | 46 | 22.1 |
3 | 106 | 51 | |
4 | 56 | 26.9 |
No. | LN +ve | LN −ve | Low grade | High grade | |
---|---|---|---|---|---|
TCC | 109 | 35 (32.1%) | 74 | 55 (50.4%) | 54 (49.5%) |
SCC | 99 | 20 (20.2%) | 79 | 81 (81.8%) | 18 (18.2%) |
patients were treated conservatively, 2 patients underwent surgical exploration, 1 patient died and 1 patient had lost follow up) (
・ Relation of the upper field border with late toxicity
Patients with L5-S1 as an upper border had higher late complications than those with S1-S2 as an upper border. In the L5-S1 group, 30/125 patients (24%) had late complications which was represented by lower limb edema in 12 patients, ureteric stricture in 14 patients and intestinal obstruction in 4 patients. As for the S1-S2 group, 20/83 patients (24%) had late complications which was represented by lower limb oedema in 8 patients, ureteric stricture in 7 patients, ureteric stricture in 3 patients and intestinal obstruction in 2 patients only. None of this relation proved to be statistically significant (
The median follow up period was 22 months, ranging from 8 months to 7 years and 3 months.
1) Overall Survival
The 2-year OS for the whole group was ~69% and the 3-year OS was ~60% (
All factors were statistically significant except age, performance status and number of lymph node dissected (
2) Disease Free Survival
The DFS among all 208 patients was ~65% at 2 years and ~54% at 3 years. Patients’ age, performance status and number of LN dissection had no significant impact on DFS (
3) Metastasis Free Survival (MFS)
The 2-year MFS for all treated patients was~78% and the 3 years MFS was ~71%. Only four factors showed a significant relation with the MFS which are the grade, LN status, T-stage and group staging (
4) Loco Regional Control (LRC)
The LRC at 2 years for the whole group was ~95% and 94% at 3 years. Only surgical margin status and extent of LN dissection had a significant impact on the LRC (
No. | Cum survival at 2 yrs % | Cum survival at 3 yrs % | 5 yrs | P-value | |
---|---|---|---|---|---|
Whole group | 208 | 69.1 | 59.5 | 50.9 | |
Age group | |||||
<60 | 128 | 71.5 | 62.9 | 54.8 | 0.371 |
≥60 | 80 | 66 | 55 | 45.6 | |
Sex | |||||
Males | 158 | 63.8 | 53.3 | 43 | 0.002 |
Females | 50 | 86.4 | 79.1 | 75.4 | |
Smoking | |||||
Yes | 92 | 65.3 | 52.8 | 38.8 | 0.042 |
No | 116 | 71.9 | 64.8 | 61.2 | |
PS | |||||
1 | 144 | 71.4 | 64.8 | 55.2 | 0.197 |
2 & 3 | 64 | 63.3 | 49.9 | 40.6 | |
Pathology | |||||
SQ | 99 | 77.7 | 68.2 | 62.6 | 0.020 |
TCC | 109 | 61.5 | 51.6 | 39.5 | |
Grade | |||||
Low (1 & 2) | 136 | 75.9 | 66.4 | 59.2 | 0.003 |
High (3) | 72 | 56 | 46.1 | 34.4 | |
SM | |||||
Positive | 15 | 51.1 | 38.4 | 0 | 0.014 |
Negative | 193 | 70.3 | 60.9 | 53.8 | |
LN dissection | |||||
<10 | 71 | 68.3 | 57.4 | 48.2 | 0.668 |
≥10 | 137 | 69.6 | 60.6 | 52.3 | |
LN | |||||
+ve | 55 | 52.2 | 40.7 | 36.2 | 0.005 |
−ve | 153 | 74.6 | 66.5 | 55.5 | |
T-stage | |||||
pT2b | 54 | 80.2 | 73 | 73 | 0.011 |
pT3a | 16 | 80.8 | 61.2 | 32.6 | |
pT3b | 117 | 65.4 | 57.6 | 48 | |
T4a | 21 | 47.2 | 28.3 | 18.9 | |
N-stage | |||||
N0 | 153 | 74.6 | 65.4 | 55.5 | 0.02 |
N1 | 21 | 51 | 44.6 | 35.7 | |
N2 | 34 | 52.6 | 36.1 | 36.1 | |
Stage | |||||
2 | 46 | 85.2 | 81.3 | 81.3 | 0.001 |
3 | 106 | 69.9 | 60.2 | 45.3 | |
4 | 56 | 53.6 | 42.6 | 38.4 |
No. | Cum survival at 2 yrs % | Cum survival at 3 yrs % | 5 yrs % | P-value | |
---|---|---|---|---|---|
Whole group | 208 | 65.2 | 53.9 | 52.9 | |
Age group | |||||
<60 | 128 | 70 | 56.7 | 56.7 | 0.455 |
≥60 | 80 | 58.9 | 50.6 | 47.6 | |
Sex | |||||
Males | 158 | 59.2 | 46.6 | 45.1 | 0.001 |
Females | 50 | 84.8 | 77.4 | 77.4 | |
Smoking | |||||
Yes | 92 | 59.7 | 44.1 | 41.7 | 0.049 |
No | 116 | 69.4 | 61.8 | 61.8 | |
PS | |||||
1 | 144 | 68.9 | 57.8 | 57.8 | 0.116 |
2 & 3 | 64 | 55.8 | 44.5 | 41.1 | |
Pathology | |||||
SQ | 99 | 72.9 | 64.1 | 64.1 | 0.019 |
TCC | 109 | 58.3 | 44.6 | 42 | |
Grade | |||||
Low | 136 | 72.7 | 61.7 | 60.2 | 0.002 |
High | 72 | 50.4 | 38.7 | 38.7 | |
SM | |||||
Positive | 15 | 48.5 | 0 | 0 | 0.005 |
Negative | 193 | 66.4 | 56.4 | 55.3 | |
LN dissection | |||||
<10 | 71 | 62.1 | 56.2 | 52.7 | 0.657 |
≥10 | 137 | 66.7 | 53.3 | 53.3 | |
LN | |||||
Positive | 55 | 55.9 | 39.5 | 39.5 | 0.025 |
Negative | 153 | 68.6 | 58.6 | 57.2 | |
T-stage | |||||
pT2b | 54 | 78.6 | 74.7 | 74.7 | 0.009 |
pT3a | 16 | 72.7 | 42.4 | 28.3 | |
pT3b | 117 | 61.4 | 51.3 | 51.3 | |
T4a | 21 | 42.7 | 21.4 | 21.4 | |
N-stage | |||||
N0 | 153 | 68.6 | 58.6 | 58.6 | 0.074 |
N1 | 21 | 51.9 | 37.9 | 37.9 | |
N2 | 34 | 59.1 | 40.5 | 40.5 | |
Stage | |||||
2 | 46 | 83.3 | 83.3 | 83.3 | 0.003 |
3 | 106 | 62.1 | 48.3 | 46.5 | |
4 | 56 | 57.4 | 41.8 | 41.8 |
No. | Cum survival at 2 yrs % | Cum survival at 3 yrs % | 5 yrs % | P-value | |
---|---|---|---|---|---|
Whole group | 208 | 78.2 | 70.7 | 70.7 | |
Age group | |||||
<60 | 128 | 77.5 | 70.4 | 70.4 | 0.591 |
≥60 | 80 | 79.9 | 71.5 | 71.5 | |
Sex | |||||
Males | 158 | 74.6 | 65.5 | 65.5 | 0.29 |
Females | 50 | 89.5 | 85.6 | 85.6 | |
Smoking | |||||
Yes | 92 | 72.4 | 59.9 | 59.9 | 0.072 |
No | 116 | 82.5 | 78.5 | 78.5 | |
PS | |||||
1 | 144 | 80 | 71.3 | 71.3 | 0.506 |
2 & 3 | 64 | 73.8 | 69.4 | 69.4 | |
Pathology | |||||
SQ | 99 | 80.1 | 76.1 | 76.1 | 0.278 |
TCC | 109 | 76.3 | 64.5 | 64.5 | |
Grade | |||||
Low | 136 | 83.8 | 79.5 | 79.5 | 0.002 |
High | 72 | 66.3 | 50.9 | 50.9 | |
SM | |||||
Positive | 15 | 77.1 | 77.1 | 77.1 | 0.504 |
Negative | 193 | 78.7 | 70.8 | 70.8 | |
LN dissection | |||||
<10 | 71 | 77 | 72.9 | 72.9 | 0.852 |
≥10 | 137 | 78.6 | 70 | 70 | |
LN | |||||
+ve | 55 | 70.8 | 60.3 | 60.3 | 0.053 |
−ve | 153 | 80.9 | 74 | 74 | |
T-stage | |||||
pT2b, pT3a | 70 | 92.7 | 89.3 | 89.3 | 0.0005 |
pT3b, T4 | 138 | 70 | 60.6 | 60.6 | |
Stage | |||||
2 | 46 | 91.2 | 91.2 | 91.2 | 0.019 |
3 | 106 | 76 | 66 | 66 | |
4 | 56 | 72 | 62 | 62 | |
N-stage | |||||
N0 | 153 | 80.9 | 74 | 74 | 0.154 |
N1 | 21 | 69.5 | 57.9 | 57.9 | |
N2 | 34 | 72.4 | 62 | 62 |
No. | Cum survival at 2 yrs% | Cum survival at 3 yrs % | 5 yrs | P-value | |
---|---|---|---|---|---|
Whole group | 208 | 94.7 | 93.5 | 93.5 | |
Age group | |||||
<60 | 128 | 94.3 | 92.4 | 92.4 | 0.492 |
≥60 | 80 | 95.3 | 95.3 | 95.3 | |
Sex | |||||
Males | 158 | 95.2 | 93.3 | 93.3 | 0.735 |
Females | 50 | 93 | 93 | 93 | |
Smoking | |||||
Yes | 92 | 97.6 | 97.6 | 97.6 | 0.125 |
No | 116 | 92.4 | 90.5 | 90.5 | |
PS | |||||
1 | 144 | 94.2 | 94.2 | 94.2 | 0.899 |
2 & 3 | 64 | 95.9 | 90.9 | 90.9 | |
Pathology | |||||
SQ | 99 | 95 | 95 | 95 | 0.628 |
TCC | 109 | 94.4 | 91.8 | 91.8 | |
Grade | |||||
Low | 136 | 95.4 | 93.8 | 93.8 | 0.590 |
High | 72 | 93.3 | 93.3 | 93.3 | |
SM | |||||
Positive | 15 | 76.6 | 76.6 | 76.6 | 0.001 |
Negative | 193 | 96.1 | 94.8 | 94.8 | |
LN dissection | |||||
<10 | 71 | 89.5 | 89.5 | 89.5 | 0.052 |
≥10 | 137 | 97.3 | 95.5 | 95.5 | |
LN | |||||
+ve | 55 | 92.6 | 92.6 | 92.6 | 0.658 |
−ve | 153 | 95.3 | 93.8 | 93.8 | |
Stage | |||||
2 | 46 | 94.9 | 94.9 | 94.9 | 0.924 |
3 | 106 | 95.3 | 93 | 93 | |
4 | 56 | 92.8 | 92.8 | 92.8 | |
T-stage | |||||
2b, 3a | 70 | 96.7 | 93.7 | 93.7 | 0.677 |
3b, 4 | 138 | 93.4 | 93.4 | 93.4 | |
Upper Border | |||||
L5-S1 | 125 | 93.9 | 92 | 92 | 0.480 |
S1-S2 | 83 | 95.8 | 95.8 | 95.8 |
Bladder cancer is one of the commonest malignancies in Egypt [
Bladder cancer is more common in males than in females with a 3:1 ratio. This was affirmed in our study with males representing 76% of cases. Bladder cancer occurs mainly in older people. About 9 out of 10 people with this cancer are over the age of 55. The average age at the time of diagnosis is 73 [
Transitional cell carcinoma represents 90% of bladder cancer with low incidence of SCC and adenocarcinoma. A time trend retrospective analysis on 9843 patients treated by cystectomy at NCI, Cairo during the years 1970- 2007 was reported. Bilharzial association dropped from 82% to 55%. There was a significant rise of transitional cell carcinomas (TCC) from 16% to 66% becoming at present the most common tumour type, with a significant decrease in SCC from 76% to 28% [
The effect of patients’ sex on survival is controversial. A study by Tracey et al. 2009 [
A study of 460 patients who underwent RC between the years of 1991-2011 was analysed retrospectively. The 5 years DFS rates were 58% in the TCC and 39% in the SCC group. Although the DFS among TCC cases was better than in SCC, both pathologic types had almost similar prognosis when compared stage by stage. Also, SCC cases were diagnosed at advanced stages of the disease. The incidence of organ-confined, extra vesical, lymph node-positive disease in TCC vs. SCC cases was 49% vs. 32%, 29% vs. 32%, 22% vs. 36%, respectively [
The beneficial effect of PORT was proved in a large prospective randomized trial at NCI Cairo, including 236 patients, for locally advanced bladder cancer patients. The 5 year LC rates were 87% ± 4% and 93% ± 3% for hyperfractionated (HF) and conventional (CF) PORT compared to 50% ± 6% for the cystectomy alone group. This effect was consistent across all tumour types, grades and pathologic stages whether or not the lymph nodes were involved. The 5-year LC rates for pT3a, pT3b and pT4a were 96%, 91% and 74% respectively [
A study of 442 patients performed to assess the factors affecting local failure after RC (130 patients out of 442 received adjuvant/neoadjuvant chemotherapy) proved that SM status and the extent of lymph node dissection strongly affected the LC rates with 5year LC rate of 86% vs. 58% for negative and positive SM respectively. As for the extent of LN dissection, the 5 year LC rate was 86% for ≥10 nodes vs. 69% for <10 nodes dissection [
With reference to the T stage, the current study demonstrated more inferior OS associated with more advanced T stage with 5 year OS of 73% with pT2b, 40% with pT3 and 19% with pT4a patients. This data was in accordance with Zaghloul et al. 2010 [
Post-operative radiotherapy in bladder cancer remains unpopular owing to the fear of late intestinal complications. Warning results were published by Reisinger et al. 1992 [
This study supports that postoperative radiotherapy for selected group of patients, significantly improves local control with tolerable toxicities. With the modern radiotherapy techniques and improved normal tissue sparing, we recommend more investigation with adjuvant radiotherapy following RC with the addition of chemotherapy.
Azza M.Nasr,Magda ElMongi,MamdouhHagag,Manar M.Moneer,Hisham ElHossieny,AzzaTaher,SherifMagdy, (2015) Postoperative Radiotherapy in Bladder Cancer Patients: 5-Year Institutional Experience of National Cancer Institute, Cairo University. Journal of Cancer Therapy,06,579-593. doi: 10.4236/jct.2015.67063