Is Post Operative Radiotherapy Justified for Completely Resected Locally Advanced Renal Cell Cancers?

doi:10.4236/jct.2013.49170

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Journal of Cancer Therapy, 2013, 4, 1429-1434

Published Online November 2013 (http://www.scirp.org/journal/jct)

http://dx.doi.org/10.4236/jct.2013.49170

Open Access JCT

1429

Is Post Operative Radiotherapy Justified for Completely

Resected Locally Advanced Renal Cell Cancers?

Reham Abdulmoniem1,2, Tarek Haikal3, Hossam Darwiesh3

1Radiation Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt; 2Comprehensive Cancer Center, King

Fahad Medical City, Riyadh, Saudi Arabia; 3Medical Oncology Department, Damietta Cancer Institute, Ministry of Health, Damietta,

Egypt.

Email: [email protected]

Received September 9th, 2013; revised October 8th, 2013; accepted October 16th, 2013

License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Background: There is an underutilization of postoperative radiation therapy (PORT) in renal cell carcinoma (RCC) fol-

lowing radical nephrectomy (RN). The main reason for that is the lack of strong evidence and the contradictory data in

the literature regarding its benefit. We aimed to evaluate the efficacy of PORT in locally advanced patients with RCC

following complete resection. Materials and Methods: The patients had RN and at least two of the poor prognostic

factors like lymph nodes involvement (LN+), renal vein invasion (RVI), inferior vena cava invasion (IVCI) and renal

capsule infiltration (RCI) were included in the study. Ninety-four patients were retrospectively evaluated; 56 patient

received PORT 50Gy/25 fractions/5 weeks and 38 patients who did not receive PORT were compared. The LN+, RVI,

IVCI and RCI were documented in 63 (67%), 46 (49%), 30 (32%) and 71 (76%) patients respectively. Results: Eight

patients (14%) in PORT arm developed local recurrence (LR) are compared with 10 patients (26%) for non-PORT arm.

Five-year overall survival (OS) rates were 78% and 70% for PORT and non-PORT arms respectively (p = 0.3), while 5-

year locoregional control (LRC) rates were 88% for PORT arm and 70% for the non-PORT arm (p = 0.05). The IVCI

and LN+ affected OS significantly (p values 0.007 and 0.009) respectively. The RCI and LN+ only affected the LRC

with p values 0.03, 0.04 respectively. Two out of 56 patients (3.5%) received PORT developed intestinal obstruction

which was treated surgically. Conclusion: The PORT decreased the LR rate in high risk locally advanced RCC patients

significantly. The high incidence of distant metastasis offsets this improvement at the level of overall survival.

Keywords: Renal Cell Carcinoma; Locally Advanced; Postoperative Radiation Therapy; Outcomes

1. Introduction

The incidence of RCC, which accounts for 3% of all

adult malignancies, is gradually increasing and consid-

ered as the most lethal carcinoma of the genitourinary

tumors, with >40% of patients dying from their tumor

[1,2]. Seventy percent of patients presented by locally

advanced disease are still potentially curable by RN;

however, LR rate is high for such group of patients [3,4].

The lymph node involvement, renal capsule invasion,

renal vein involvement and inferior venal cava thrombo-

sis are well-known bad prognostic indicators specially if

the patients had 2 or more of these factors [5,6]. Some

retrospective studies showed survival benefit for adju-

vant post-operative radiation therapy [7-10]. However,

this has not been confirmed in prospective randomized

trials, mostly because these trials were performed during

the era of conventional irradiation using old radiotherapy

techniques [11,12]. Theoretically, PORT would improve

the local control in patients with high-risk features. The

use of targeted therapy following RN as adjuvant treat-

ment had improved the survival, and hence the local re-

currence became a real problem especially in patients

with high risk features for local recurrence.

The purpose of the present study was to evaluate the

value of post-operative radiotherapy on local control and

survival in high risk RCC patients for local recurrence

following RN.

2. Materials and Methods

2.1. Inclusion Criteria

The medical records of 230 patients with RCC treated at

Damietta Cancer Institute (DCI) from 1998 to 2006 were

Is Post Operative Radiotherapy Justified for Completely Resected Locally Advanced Renal Cell Cancers?

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reviewed. One hundred thirty six patients were excluded

for the following reasons: incomplete hospital records,

early stage disease, second malignancy, incomplete re-

section and distant metastasis at diagnosis.

High risk patient for local recurrence were only se-

lected for analysis. High risk patients were defined as

patients with stage III or IV and having two factors of

following of poor prognostic factors; 1) lymph node in-

volvement, 2) renal capsule invasion, 3) renal vein in-

volvement and 4) inferior venal cava thrombosis. Total

94 patients met the criteria and were evaluated for the

purpose of this study.

2.2. Radiation Therapy Details

The PORT patients were treated as per Institutional pro-

tocol. The patients treated in supine position using verti-

cal, transverse and lateral laser beams for alignment. All

patients were simulated using Philips AcQsim RT CT-

Simulator, with multiple slices taken. The target volume

was limited to the renal bed and para-aortic lymph nodes.

The radiation was delivered with anteroposterior/poste-

roanterior portals to a total dose of 50.4 Gy with a daily

fraction of 1.8 Gy five times per week. After 45Gy spinal

cord was protected by using lead shielding. In right sided

tumors, part of the liver was shielded after 30 Gy. The

mean dose to the small bowel was kept below 45 Gy and

0% of the volume was not allowed above 55 Gy. The

dose was prescribed at the patient’s midplane at the field

central axis. No attempt was done to include the entire

surgical scar in the treated fields. MULTIDATA plan-

ning system was used for dose calculation. Radiotherapy

was administered with megavoltage Elekta Linear accel-

erator machine dual energy using photon beams 6 and 10

MV. Acute and late toxic effects were graded according

to EORTC/RTOG scale.

2.3. Follow-Up

The follow up protocol included physical examination

every 3 - 4 months during the first 2 years, every 4 - 6

months during the following 3 years and once yearly

thereafter. Annual CT chest and abdomen was done dur-

ing follow up or as per patient complaints.

Information about the disease and survival status was

obtained from the clinical records. For any uncertainty,

phone calls were made to patients by the cancer registry

department at our institute; otherwise patients were con-

sidered lost to follow-up and censored at the date of their

last visit for survival calculations.

2.4. Statistical Analysis

The duration of local control was measured from day 1

of treatment to the date of LR or last contact with the

patient. Overall survival was measured from day 1 of

diagnosis till death or the last follow up date.

Statistical package software system for windows was

used for evaluation of the data. Descriptive statistics in-

cluded values and percentages for quantitative data. Sur-

vival curves were obtained with the Kaplan-Meier me-

thod. The log-rank test was used to compare LR-FS and

OS between groups, and a p value of ≥0.05 was con-

sidered statistically significant. Univariate analyses of the

prognostic features were realized. Factors chosen for the

final model for multivariable analysis were based on the

elimination of non-significant factors on Univariate ana-

lysis. Multivariable regression analyses were performed

to assess the independent impact of factors on the out-

comes.

3. Results

The pathology reports showed that 89% of the patients

were renal cell carcinoma and 11% were clear cell car-

cinoma and granular subtypes. Excised tumor sizes ran-

ged from 7 to 23 cm in greatest diameter, with a median

of 10 cm. The pathological grade was G III and IV in

82% of patients. Fifty-five patients had right-sided tumor,

and 39 patients had left-sided tumors. The follow up pe-

riod ranges from 8 to 74 months with 59 months median

value. Fifty six (60%) patient who had received post-

operative radiotherapy (PORT arm) compared to 38

(40%) patients who did not receive PORT (non-PORT

arm). Table 1 shows patients’ characteristics with dif-

ferent prognostic factors in each group of patients. Sixty

patients were male, and 34 patients were females. The

age of the patients ranges from 29 to 71 years with me-

dian age 50 years (52-year in PORT arm and 45-year in

non-PORT arm). Seventy one (75%) patients had RCI

(43 patients in PORT arm and 28 in non-PORT arms).

Forty six (49%) had RVI (31 patients in PORT arm and

15 patients in non-PORT arm). Thirty patients (32%) had

IVCI (19 patients in PORT arm and 11 in non-PORT

arms). Sixty three (67%) patients had LN+ disease (40

patients in PORT arm and 23 in non-PORT arm). As

shown in Table 2, 18 patients (19%) developed LR and

30 patients (32%) developed DM. Nine patients had both

LR and DM. The LR documented in 10 (26%) patients in

non-PORT arm and in 8 (14%) patients in PORT arm. At

the time of analysis, 70 patients (74%) were alive and 55

patients (59%) were disease free.

Using the Kaplan Meier estimate, the 5y-OS and 5y-

LR-FS for all patients were 75% ± 10% and 82% ± 9%

respectively. The prognostic factors studied include RCI,

RVI, IVCI and LN+ in addition to PORT.

3.1. Local Recurrence Free Survival

The 5-year local recurrence free survival rate for PORT

arm was 88% ± 7% compared to 70% ± 11% for the non-

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Table 1. Patients characteristics.

Prognostic Factor Surgery +

PORT

(N = 56)

Surgery

(N = 38) All

(N = 94)

Age in years

(median value) 52 45 50 NS

Sex

Male

Female

39 (70%)

17 (30%)

21 (55%)

17 (45%)

60 (64%)

34 (36%)

Renal Capsule

Invasion

No invasion

43 (77%)

13 (23%)

28 (74%)

10 (26%)

71 (75%)

23 (25%)

Renal Vein

Invasion

No invasion

31 (55%)

25 (45%)

15 (40%)

23 (60%)

46 (49%)

48 (51%)

IVC

Thrombus

No thrombus

19 (34%)

37 (66%)

11 (29%)

27 (71%)

30 (32%)

64 (68%)

Positive

Negative

40 (71%)

16 (29%)

23 (61%)

15 (39%)

63 (67%)

31 (33%)

Pathological Type

Renal cell ca

Clear cell carcinoma

Granular cell ca

53 (95%)

2 (3.5%)

1 (1.5%)

31 (82%)

4 (10%)

3 (8%)

84 (89%)

6 (6%)

4 (4%)

Pathological grade

G I, II

GIII, IV

7 (12%)

49 (88%)

10 (26%)

28 (74%)

17 (18%)

71 (82%)

Table 2. Effect of post-operative radiotherapy on disease

and survival status.

Patient groups

Outcome Total No

Surgery + PORT Surgery alone

Local Control

Recurrence

No Recurrence

8 (14%)

48 (86%)

10 (26%)

28 (74%)

Distant Metastasis

Metastasis

No Metastasis

16 (29%)

40 (71%)

14 (36%)

24 (64%)

Overall Survival

Alive

Dead

44 (79%)

12 (21%)

26 (68%)

12 (32%)

PORT arm with signiﬁcant difference; p value 0.05 (Fig-

ure 1).

The following parameters had a statistically signiﬁcant

inﬂuence on 5y LR-FS: renal capsule invasion and lymph

node involvement. The probability of 5-year LR-FS in

case of renal capsule invasion were 71% ± 11% compa-

red to 88% ± 8% for patients without RCI (p value 0.03).

The 5y LR-FS for LN+ patients was 73% ± 8% and for

node negative patients were 90% ± 12%; p value 0.04.

The 5y-LR-FS was 78 ± 8% in patients with IVCI vs.

83 ± 10% in patients free from IVCI (p value 0.1). The

renal vein invasion affected the 5y-LR-FS none signi-

ficantly. The 5y LR-FS was 75% ± 9% for patients with

RVI vs. 85% ± 13% for patients without RVI (p value

0.1).

Figure 1. Local recurrence free survival difference in pa-

tients received post nephrectomy radiotherapy compared to

patients performed surgery alone.

3.2. Overall Survival Results

The 5-year actuarial survival rate for PORT arm was

78% ± 7% compared to 70% ± 10% for the non-PORT

arm. There was no significant difference observed in

terms of 5-year overall survival between the groups with

and without post-operative radiotherapy; p value 0.3

(Figure 2). As shown in Table 3, IVCI showed signifi-

cant lower 5y-OS 50% ± 14% in comparison to 80% ±

9% in patients with no inferior vena cava thrombosis; p

value 0.007. The LN+ was also highly predictive prog-

nostic factor for OS (79% ± 8% in LN negative and 63%

± 12% in LN positive); p value 0.009. On the other hand,

RCI was not affecting 5y-OS significantly with p value

0.6. Also, 5y-OS in the group of patients having RVI

(69% ± 11%) was not significantly different compared to

78% ± 7% in patients without RVI; p value 0.08. In mul-

tivariate analysis, none of the prognostic factors affected

the 5y LR-FS significantly as shown in Table 3. The p

value for the PORT is 0.07 with hazard ratio 0.8 and

confidence interval ranges from 0.7 to 1.0. Analyzing the

factors affecting overall survival, multivariate analysis

showed that both IVCI and LN+ significantly affected 5y

OS with p value 0.2 and 0.1 respectively.

The acute treatment-related toxicities such as abdomi-

nal pain, nausea, vomiting and diarrhea were seen during

radiotherapy. However generally, PORT was well toler-

ated. The serious events related to radiation were only in

the form of intestinal obstruction which was in 2 patients

out of 56 received PORT (3.5%). Only 1 patient required

surgical interference.

4. Discussion

We believe that OS in locally advanced RCC patients

following RN is going to increase with the advent of tar-

geted therapy in next decade, and we are going to see

more loco-regional recurrences and for such patients

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Table 3. The effect of different prognostic factors on the 5-year local recurrence free survival and 5-year overall survival.

Overall survival Local recurrence free survival

Prognostic factor 5y-OS

% ±S D

Univariate analysis

P value

Multivariate analysis

P value/HR (CI)

5y-LR-FS

% ± SD

Univariate analysis

P value

Multivariate analysis

P value/HR (CI)

Radiotherapy

Yes

78% ± 7%

70% ± 10%

0.3

88% ± 7%

70% ± 11%

0.05

P = 0.07

HR = 0.8

(0.7 - 1.0)

Renal Capsule

Invasion

No invasion

70% ± 10%

77% ± 11%

0.6

71% ± 11%

88 ± 8%

0.03

IVC

Thrombus

No thrombus

50% ± 14%

80% ± 9%

0.007

P = 0.02

HR = 0.66

(0.02 - 1.4)

78% ± 8%

83% ± 10%

0.1

Renal Vein

Invasion

No invasion

69% ± 11%

78% ± 7%

0.08

75% ± 9%

85% ± 13%

0.1

Positive

Negative

63% ± 12%

79% ± 8%

0.009

P = 0.01

HR = 0.3

(0.1 - 1.2)

73% ± 8%

90% ± 12%

0.04

All patients 75% ± 10% 75% ± 10%

Figure 2. Local recurrence free survival difference in pa-

tients received post nephrectomy radiotherapy compared to

patients performed surgery alone.

PORT would be beneficial [13]. The retrospective trials

have shown that radiotherapy improve the local control

following radical nephrectomy. Cuneyt et al., retrospec-

tively reviewed 40 patients [14]. Five-year OS rates were

found 70% in the PORT group and 20% in the non-

PORT group (P = 0.1) and five-year DFS rates were

found 66% in the PORT group and 16% in non-PORT

and difference in both univariate and multivariate analy-

ses (P = 0.045 and P = 0.0007, respectively).

Rafla et al. reported the results of two retrospective

studies, which showed that OS and DFS rates were better

in patients who received PORT [15,16]. Stein et al.,

studied 56 patients with better OS and DFS in the group

of patients received PORT. Five-year OS rates 50% in

PORT and 40% in non-PORT groups respectively [8].

Safwat et al., reviewed 136 patients who underwent RN.

DFS improved significantly by PORT in Univariate and

multivariate analysis. Five-year cumulative risk of LR

reduced from 38% to 22% (p value 0.014). However, in

this study there was no difference in OS by adding PORT

[7].

Makarewicz et al. also showed that the PORT reduced

the LR rates from 15.8% to 8.8% in 114 patients with

T3N0 RCC, but there was no significant effect on the OS

rate [17]. However, Gez et al., retrospectively showed

that PORT did not improve the LRC and was accompa-

nied by mild to moderate adverse effects [18].

The prospective randomized trials which that tested

the value of PORT and did not demonstrate an advantage

in receiving radiotherapy were published by Finney [19]

and Kjaer [11,12]. Finney et al. reported five-year OS

rates of 36% in the PORT group and 47% in the non-

PORT group. The LR rates were 7% for both groups.

The Copenhagen Renal Cancer Study Group (CRCSG)

compared PORT 50Gy and non-PORT in patients having

stage II or III renal cancer. There was no significant dif-

ference in DFS rates between the two groups. Forty four

percent of the patients in the PORT group had radia-

tion-related gastrointestinal and hepatic complications

[12].

The contradictory data in the literature between the

retrospective and prospective studies regarding PORT

was realized by recently published meta-analysis by

Tunio et al. which included 7 randomized trials [13].

Seven hundred and thirty five patients were analyzed

with pooled results from these trials showed a significant

reduction of LR in patients treated with PORT (P value

0.0001). However, there was no difference in OS (P =

0.29) and DFS (P = 0.14).

WE strongly believe that tailoring PORT for RCC pa-

tients may show a real benefit especially in patients with

poor prognostic factors. In our study, we chose high risk

patients (those with more than one poor prognostic factor;

Is Post Operative Radiotherapy Justified for Completely Resected Locally Advanced Renal Cell Cancers? 1433

RVI, IVCI, LN+ and RCI) for evaluation of PORT ret-

rospectively. Five-year LRC in our study is 82% ± 9%

which is higher than that reported by Safwat et al. [7]

and similar to Aref series [4] and Gez et al. [18]. This is

mainly due to better case selection in our series (inclu-

sion of patients who underwent RN with lymphadenec-

tomy and exclusion of patients with positive surgical

margin or gross residual following surgery). The radio-

therapy improved the local recurrence rate (26% in non-

PORT arm and 14% in PORT arm) however the DM was

29% and 39% in PORT and non-PORT patients respec-

tively. These data is nearly similar to Aref and Maka-

rewicz data. The isolated LRR were observed in 9 (10%)

patients only; six of them in the non-RT arm. Five-year

LRC was worst in the group of patients having RCI and

LN+ with P values 0.03, and 0.04 respectively. These

findings are comparable to studies by Stein, Rafla and

Finney data [8,16,19].

The radiotherapy did not improve OS rates in our

study and this is comparable to all retrospective and pro-

spective studies [12-18]. Five-year OS in PORT arm was

78% as compared to 70% in non-PORT arm (p = 0.3).

The univariate analysis showed that IVCI and LN+

affected the OS with p values 0.007 and 0.009 respec-

tively. These findings were confirmed by multivariate

analysis with p value 0.02 for the IVCI and 0.01 for LN+.

These results are comparable to the studies of Maka-

rewicz et al. [17] and Safwat et al. [7]. The exclusion of

the pathological types and the pathology grade was main-

ly due to unequal distribution of cases between the two

treatment groups.

5. Conclusion and Recommendation

Our study showed the benefit of PORT in reducing local

recurrence in locally advanced RCC. The overall survival

was also better in irradiated patients, but the difference

did not reach statistical significance. The high DM rate

could justify the need for use of adjuvant targeted ther-

apy in such high risk patients. As there are conflicting

data in the literature regarding the value of PORT, multi-

institutional prospective randomized trials using modern

radiotherapy techniques in addition to targeted therapy

are necessary to evaluate the real role of PORT and im-

prove survival in locally advanced RCC patients.

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