Primary nephrectomy and intraoperative tumor spill: Report from the Children's Oncology Group (COG) renal tumors

committee
Kenneth W. Gowa, Douglas C. Barnhart, Thomas E. Hamilton
Journal of Pediatric Surgery (2013) 48, 3438

Introduction

COG protocol
Children with suspected unilateral renal malignancy,Children's Oncology Group (COG) protocols recommend : primary nephroureterectomy with lymph node sampling .

Rationale : provides adequate tissue for definitive diagnosis and accurate staging.

Intraoperative spill
A known risk of primary nephrectomy is intraoperative tumor rupture or spill (IOS). Increases the risk of local recurrence

Added short- and long-term morbidity.

Significance of the study

A rigorous evaluation of factors that may predispose to IOS has not yet been performed

Purpose of the study

To determine the rate of IOS and to identify those pre-surgical factors that may predispose to IOS

Materials and methods

Study population
Drawn from the AREN03B2 renal tumor classification, biology and banking study of the Childrens Oncology Group.

Pts enrolled from 204 institutions .

All participating institutions had institutional review board approval of the study protocol

Study period

February 2006 to December 2010

Eligible for the study

All children with a first time occurrence of a renal mass

Data collection
At the time of enrollment, the institution was required to submit the following for central review:
Operative notes, Pathology specimens, Computed tomography (CT) scan chest Contrast - enhanced CT abdomen/pelvis Magnetic resonance imaging (MRI) abd/pelvis

Central review
FIRST CENTRAL RADIOLOGICAL REVIEW:
assesses the presence of lung metastasis, liver metastasis, tumor size, and bilateral renal lesions.

REVIEW OF PATHOLOGY SPECIMENS

for histological diagnosis and assignment of a pathological Stage of I-III.

REVIEW OF OPERATIVE NOTES

for rationale for surgical approach, tumor extent, and protocol compliance

Surgeon combines the review of the operative reports with the radiological and pathological review to assign a local and overall disease stage. Pediatric oncologist then collates the data from the discipline reviews to determine an overall initial risk classification and therapeutic protocol eligibility.

Included in the study

Eligible patients with unilateral Wilms' tumor (WT) undergoing primary nephrectomy and having favorable histology among the first 2,000 patients enrolled on AREN03B2 To minimize confounding issues with biology, only favorable WT were included in analysis

Patients classified as IOS only if spill occurred from the primary tumor or renal vein

Excluded from the study

All other locations and types of tumor spill

So ultimately

There were 1131 primary nephrectomies for unilateral WT

Data Analysis & Results

Rates of IOS
Rates of IOS from the primary tumor and the renal vein calculated both separately and combined

Results : Rates of IOS

In total 135/1131(11.9%)

Due to primary tumour 110/1131(9.7%)

During renal vein thrombectomy 20/1131(1.8%)

Both 5/1131(0.4%)

Chi -square test

To examine with laterality (left the vs. right) and relationship between maximum tumor IOS diameter (<12 cm (positive vs. vs. 12 cm). negative)

Results (p<0.05 statistically significant)

a statistically with maximum diameter (p<0.0001) significant association right-sided tumors between (p=0.0414) IOS

Logistic regression models

to determine if the following were predictive of IOS:
Maximum tumor diameter Tumor weight Laterality , maximum diameter (with 12 cm cutoff), and weight together

Results of Simple logistic regression

IOS increased 2.7% with each 1 cm increase in diameter (3-21 cm), 15cm was the diameter with maximum risk

4.7% with each 100 g increase in weight (80 1800 g)

Results of Multiple logistic regression

laterality [right p=0.048] and weight [p=0.03] were predictive of IOS WHEN DIAMETER INCLUDED AS A CONTINUOUS VARIABLE

The odds of IOS were OR 1.45 for patients with right as compared with left tumor. In this model, the risk of an IOS increased by 3.9% with each 100 g increase in weight.

Results of Multiple logistic regression

Diameter as a binary variable of 12 cm was highly prognostic of IOS (p=0.0002), while laterality and weight were not significant

The odds of IOS were 2.183 times greater for patients with maximum tumor diameter 12 cm as compared with <12 cm.

Discussion

Soilage
Contamination d/t tumor spill may occur
PREOPERATIVE RUPTURE (spontaneous or traumatic), BIOPSY (needle or open), INTRAOPERATIVE from either the tumor (rupture of capsule or removal of the tumor in more than one piece) or by transection of involved structures (lymph nodes, vein, or ureter).

Earlier reported soilage in National Wilms' Tumor Study Group (NWTSG) studies

Bundled together to include

preoperative and intraoperative biopsy preoperative rupture and intraoperative spill.

So not possible to determine earlier rates for specific causes such as intraoperative spill.

COG
Clear published criteria defining circumstances when it is more appropriate to do an upfront biopsy and prenephrectomy chemotherapy:
(1) tumor thrombus above the level of the hepatic veins (2)pulmonary compromise from a massive tumor or extensive pulmonary metastases (3) resection requiring removal of contiguous structures (other than adrenal gland) (4)surgeon's judgment that attempting nephrectomy would result in significant morbidity, tumor spill, or residual tumor.

Two important tumor characteristics that guide surgeon decision-making

size

location

To date, a comprehensive review of factors that may influence the risk of IOS not been undertaken.

The current study to determine contemporary rates and possible risk factors associated with IOS.

Rates of IOS
Overall 11.9%(COG)
d/t primary tumor alone 9.4% d/t tumor thrombus spilling from renal vein 1.8% both 0.4%

NWTSG-5
Tumor spill : 253 /1305 IOS MC type : 139/1305 (55%) Calculated IOS rate : 10.7%(139/1305)

IOS rates appear comparable

One change made between the two studies:

All biopsies would be considered Stage III disease from the outset regardless of the indication or the manner by which this was done.

Tumour size

NWTS-2 : tumor size did not influence the outcome

NWTS-4:a tumor diameter 10 cm increased risk

COG: risk of IOS tumor significant at 12 cm and peaked at 15 cm

Difficulties in large sized tumours

Limited operative field Difficult dissection from surrounding structures More difficult to handle the tumor Difficult isolation of renal vasculature Thinner tumor capsule due to outgrowing blood supply

Laterality : Rt sided tumours

Rt sided tumors a risk factor for IOS, explained by anatomic differences between the two sides :

Right kidney in close proximity to the liver -> less space for dissection Anatomic differences in the renal vasculature, dissection difficult More congenital anomalous variants of the right renal arteries and veins Close proximity of the right renal vein to the IVC About half the length compared to left renal vein

Stage III
Tumor spill as the sole reason for Stage III: 108/860 (12.6%)
Tumor rupture significantly increases local relapse Relapses difficult to treat and survival drops from over 90% to as low as 43% Entails additional chemotherapy (doxorubicin) and radiation therapy with its own late effects

Limitations of the study

Does not assess judgment, skill level, or surgeon experience, all factors potentially affecting the risk of spill. Spill rates of individual surgeons were not assessed or compared

Prenephrectomy chemotherapy

surgical resection easier d/t:

tumor shrinkage less vascularity, firm to handle less extrarenal extension

SIOP
Long used by the Socit Internationale d'Oncologie Pdiatrique (SIOP) to reduce IOS Published SIOP studies: lower IOS rate of 2.86%.

COG
COG Renal Tumors Committee feels
staging (i.e. lymph node status) and pathological data critical to accurate determination of appropriate risk-based therapy. Prenephrectomy chemotherapy not routinely recommended in COG therapeutic studies for unilateral Wilms' tumor.

CONCLUSIONS
IOS on COG renal tumor trials : one in ten cases

Surgeons must exercise caution when attempting to primarily resect right-sided and/or large (12 cm) renal tumors Presence of multiple risk factors for spill analogous to higher risk group such as WT with intravascular tumor extension where preoperative chemotherapy significantly reduces surgical morbidity without sacrificing survival

REFERENCES

Wilms tumor: preoperative risk factors identified for intraoperative tumor spill.
Barber TD, Derinkuyu BE, Wickiser J, Joglar J, Koral K, Baker LA J Urol. 2011 Apr; 185(4):1414-8

Retrospective review : Jan 2000 August 2008

67 pts undergoing unilateral nephrectomy 26 excluded : CT / pathology reports unavailable IOS: 6/41 (15%)

PREOPERATIVE TUMOR VOLUME significantly greater in patients with tumor spill, risk of spill being greater in patients with tumors >1000g

NO RADIOGRAPHIC FINDINGS predicted an increased likelihood of tumor spill

NO PATIENT UNDERGOING NEOADJUVANT CHEMOTHERAPY had tumor spill PREOPERATIVE TUMOR BIOPSY, shown in prior studies to be a significant risk factor for intraoperative spillage, was NOT FOUND TO BE SIGNIFICANT in this study

Predictors of surgical outcome in Wilms' tumor: a single-institution comparative experience.

Hall G, Grant R, Weitzman S, Maze R, Greenberg M, Gerstle JT. J Pediatr Surg. 2006 May;41(5):966-71

1985 to 2003: 161pts (114 preoperative chemotherapy & 46 primary nephrectomy)

Tumor spill :6 (5.3%) of 114 PC and 2 (4.3%) of 46 PN Tumor inhomogeneity, tumor size, and IVC compression/clot at diagnosis did not affect incidence of spill. Failure of the tumor to shrink in size with PC significantly associated with increase in spillage Preoperative chemotherapy and PN had equal rates of surgical complications.

Clinicopathologic Findings Predictive of Relapse in Children With Stage III Favorable-Histology Wilms Tumor
Peter F. Ehrlich, James R. Anderson, Michael L. Ritchey Journal of the American Society of Clinical Oncology, 2013

Criteria for stage III designation in NWTSG-5: LN involvement (38%),microscopic residual disease alone (20%), microscopic residual disease and LN involvement (14%), and spill or soilage alone (9%)

LN involvement and microscopic residual ds : highly predictive of event free survival and overall survival for patients with stage III FHWT
It is possible that in future studies, patients with different stage III criteria may receive different therapies.

Thank you