Abstract
Background: Although the NWTSG and SIOP studies have included the largest number of patients, several individual institutions have made likewise important contributions to the optimization of Wilms' tumor therapy. The purpose of this study is to present our personal experience obtained in the last 42 years by treating Wilms' tumor in childhood. Patients and Methods: Throughout the period 1965-2006, 65 children with histological confirmation of Wilms' tumour were treated in the Department of Urology, University of Erlangen Medical Centre. The records of all patients presenting to our institution with Wilms' tumour were examined. Results: The results obtained by this study group indicate that prognosis according to age demonstrated no significance, but prognosis according to tumor size, lymph node involvement and distant metastasis was significant. After a 10-year follow-up, our data revealed an 89.4% survival rate. Furthermore, the statistical evaluation performed in order to evaluate the significance of surgical complications following neoadjuvant therapy in comparison to non adjuvant therapy, indicates that there is a significant increase in complications in patients who are not treated with neoadjuvant therapy. Discussion: Although clinicians in the U.S.A. and Europe have different philosophies on preoperative chemotherapy, most patients with Wilms' tumor survive long term, regardless of the sequence of therapeutic interventions. In the absence of a clear choice between up-front nephrectomy and preoperative chemotherapy, it is reasonable to base the timing of resection on factors such as tumor size, the patient's clinical condition, and the experience of the surgeon.
In 1899, surgeon Max Wilms (1867-1918) described seven children suffering from nephroblastoma in a monograph on mixed tumors (1). Nowadays, Wilms' tumor represents approximately 6% of all childhood cancer cases in Europe and the United States and is the most common primary malignant renal tumor of childhood. Wilms' tumor was the first solid malignancy in which the value of adjuvant chemotherapy was established. Together with the discovery of the tumor's radiosensitivity, there has been a significant improvement in outcome from approximately 30% in the 1930s to more than 85% in the modern era (2). Currently, management emphasizes reducing the morbidity of treatment for low-risk patients and reserving more intensive treatment for selected high-risk patients for whom survival remains poor. Since the National Wilms Tumor Study Group (NWTSG) and International Society of Paediatric Oncology (SIOP) nephroblastoma studies began more than three decades ago, there has been a difference of opinion on the therapeutic management of Wilms' tumor. Their philosophy might differ regarding the merits of preoperative chemotherapy, but outcomes of patients treated with either up-front nephrectomy or preoperative chemotherapy have been excellent. Although the NWTSG and SIOP studies have included the largest number of patients, several individual institutions have made likewise important contributions to the optimization of Wilms' tumor therapy. The purpose of this study is to present our personal experience obtained in the last 42 years by treating Wilms' tumor in childhood.
Patients and Methods
Throughout the period 1965-2004, children with histological confirmation of Wilms' tumour have been treated in the Department of Urology, University of Erlangen Medical Center. All children underwent open surgery with regional lymph node dissection performed in 62. The records of all patients presenting to our institution with Wilms' tumour were examined. The mode of presentation, clinical and radiological findings, blood count, blood chemistry, urine analysis results, operative findings as well as histological findings of the affected kidney, associated Wilms' tumor syndromes and genitourinary anomalies were recorded.
Log-rank test comparing the survival between patients under and older than 2 years. There was no significance in comparison between genders (p=0.427).
Staging was preformed according to the NWTSG staging system. As for a therapeutic approach, the NWTSG protocol was performed up to 1972 and the SIOP protocol up to the present time were used individually, so primary chemotherapy regardless of extent of disease was not performed in all cases. Regardless of the protocol used, patients younger than 6 months never received primary chemotherapy, since congenital mesoblastic nephroma is the most common solid renal tumor of the newborn period. Nephrectomy alone is the adequate treatment for infants aged less than 6 months (3).
Statistical analysis was performed with SPSS version 15.0. The 10-year prognosis was analysed with the Kaplan-Meier curve. Statistical significance was evaluated with the log-rank test and was performed in order to analyze the prognostic factors according to age, tumor size, lymph node involvement and distant metastasis. Additionally, a statistical evaluation was performed in order to evaluate the significance of surgical complications following neoadjuvant therapy in comparison to non-adjuvant therapy. A p-value under 0.05 was considered significant.
Results
Patient age and gender, clinical presentation, neoadjuvant therapy, type of surgical approach, surgical complications, lymph node status, adjuvant therapy, stage, histological subtypes, tumor recurrence, isolated genitourinary anomalies and associated syndromes are summarized in Table I. Statistical significance of prognostic factors according to age, tumor size, lymph node involvement and distant metastasis are summarized in Figures 1, 2, 3 and 4. Figure 1 demonstrates the survival comparison between patients under and older than 2 years, Figure 2 demonstrates the survival comparison between patients with a tumor size smaller and larger than 10 cm, Figure 3 demonstrates the survival comparison between patients with positive and negative lymph nodes and Figure 4 the survival comparison between patients with distant metastasis and no metastasis. The 10-year prognosis, as well as the significance of surgical complications following neoadjuvant therapy in comparison to non adjuvant therapy are also summarized.
Log-rank test comparing the survival between patients with a tumor size smaller and larger than 10 cm.
The age of the patients at operation was 3.38±2.55 years, 52% of the patients were male and 48% female. Clinical symptoms were noted in 98.5% of patients and included weight loss in 9%, a palpable smooth abdominal mass in 80%, hematuria in 18.5%, fever in 24.5%, anemia in 18.5%, hepatomegaly in 4.5%, hypertension in 3% and fatigue, constipation and/or ileus in 3% of the patients. The surgical approach mostly performed was a radical nephrectomy in 95% of patients. Lymph node dissection was performed in 95% and were disease-involved in 11% of patients. Surgical complications were noted in 15% of patients, but in only 3% was tumor rupture evident. All complications were associated with a tumor size over 5 cm or with patients who were not handled with primary chemotherapy. Neoadjuvant therapy was performed in 46% of cases and included vincristin and actinomycin D. Adjuvant therapy was performed in 95% of cases. Chemotherapy was performed in 40% of cases and included vincristin, actinomycin D plus cyclophosphamide, adriamycin and ifosfamide, while radiochemotherapy was performed in 55.5% of patients. Patients with stage II, III, or IV diffuse anaplasia received abdominal irradiation and a chemotherapy regimen consisting of vincristine, doxorubicin, and cyclophosphamide alternating with cyclophosphamide and etoposide. Patients with stage II–IV focal anaplasia were treated with abdominal irradiation, vincristine, doxorubicin, and dactinomycin.
Log-rank test comparing the survival between patients with positive and negative lymph nodes.
Staging was preformed according to the system of the NWTSG and exhibited 58% as stage I, 11% as stage II, 8% as stage III, 20% as stage IV, and 3% as stage V. Histological subtypes were: well-differentiated in 14%, moderately differentiated in 45%, poorly differentiated in 29% and anaplastic tumor in 12% of patients. Distant metastasis was noted in the lungs in 15% of cases and liver in 3% of cases. Furthermore, 9% of patients exhibited isolated genitourinary anomalies, while 4.5% demonstrated associated Wilms' tumor syndromes.
Prognosis according to age demonstrated no significance (p=0.243), but was significant according to tumor size (p=0.0817), lymph node involvement (p=<0.01) and distant metastasis (p≤0.05). After a 10-year follow-up our data revealed an 89.4% survival rate, while 10.6% had tumor-related deaths. The statistical evaluation performed in order to examine the significance of surgical complications following neoadjuvant therapy in comparison to non adjuvant therapy exhibited a significant increase in complications in patients who were not treated with neoadjuvant therapy.
Log-rank test comparing the survival between patients with distant metastasis and no metastasis.
Complications after adjuvant therapy such as fertility, muscle atrophy, scoliosis, chronic nephritis etc. were also noted but are not in the scope of this study.
Discussion
Treatment regimens for Wilms' tumor are selected based on an individual's risk of recurrence, which is defined by clinical, histological, and biological prognostic factors. Assignment of tumor stage is based on intraoperative and pathological findings. Surgical procedures for Wilms tumor must include complete inspection of abdominal cavity, lymph node sampling and tumor resection. The presence of metastasis may not be detected even when using highly sophisticated investigative techniques such as computed tomography (CT) and magnetic resurance imaging (MRI), so a sufficient abdominal exploration is a rule. A transabdominal incision is recommended to permit inspection of sites of involvement, lymph node dissection and to facilitate biopsy of suspicious sites. An NWTSG review of surgical factors that predict recurrence demonstrated that failure to sample the lymph nodes was an adverse prognostic feature, even in comparison with documented tumor invasion of the lymph nodes. Presumably, a subset of patients who did not undergo lymph node sampling was undertreated (6).
Patient, disease and treatment characteristics.
Histological characteristics are the most powerful prognostic indicators for Wilms' tumor. Histological classification defined by the NWTSG and SIOP studies differs because the SIOP protocols use preoperative chemotherapy. Hence, the SIOP histological classification reflects chemotherapy-induced changes, including regressive changes or cell differentiation, whereas the NWTSG classifies Wilms' tumors based on the presence or absence of anaplasia (4, 5).
In the NWTSG studies, primary surgical resection of the tumor is the initial treatment of most children. One of the main challenges for surgeons is to avoid tumor spillage, which increases the risk of local abdominal relapse and subsequent poor outcome (6). Preoperative chemotherapy is recommended only under certain circumstances, including the occurrence of Wilms' tumor in a solitary kidney, bilateral Wilms' tumor, tumor in a horseshoe kidney, tumor thrombus in the inferior vena cava above the level of the hepatic veins, and respiratory distress resulting from the presence of extensive metastatic tumor (7). In contrast, SIOP recommends the administration of chemotherapy for 4 weeks before surgery. The SIOP strategy of giving preoperative chemotherapy is based on the premise that preoperative therapy reduces tumor size, induces a pseudocapsule and decreases the incidence of tumor rupture in Wilms tumor (8). By comparing the therapeutic protocols provided by these two large groups, one can see that the primary strength of the NWTSG approach is that up-front resection allows an accurate assessment of histological diagnosis and tumor extent. On SIOP 93-01, approximately 5% of lesions in patients treated with chemotherapy were ultimately shown not to be Wilms' tumor and included 1.8% that were benign (4). Within the SIOP protocol, tumor biopsy is not recommended because of possible tumor spread following needle biopsy. Indeed there are studies that present recurrence in the abdominal wall after needle biopsy (9-10). Furthermore, a research benefit of removing the tumor before chemotherapy is that it enables the collection of untreated tumor for biological studies and provides an unadulterated view of the tumor's molecular biology. The primary strength of the SIOP approach is that preoperative chemotherapy usually reduces the tumor volume, thereby decreasing the likelihood of spillage and “downstaging” the tumor (11). As a result, fewer patients received local irradiation on SIOP-9 than on NWTS-5, although slightly more of the SIOP-9 patients received anthracycline (12).
Another difference between the NWTSG and SIOP studies is in the management of lung metastases. In the most recent NWTSG studies, CT scan and chest x-ray were performed to determine the presence of lung metastases. If the two imaging modalities yielded discordant results, the disease stage was ultimately designated by the treating physician. Any patient deemed to have lung metastases was given whole-lung irradiation. The 2-year relapse-free survival estimate for patients with stage IV disease treated on NWTS-4 was 81% (13). In the SIOP studies, only chest x-ray was used to evaluate lung metastasis. If lung metastases completely disappeared with chemotherapy patients did not receive lung irradiation. With this approach, SIOP reported a 4-year prognosis of 83% (14). In contrast, the first Wilms' tumor study by the United Kingdom Children's Cancer Study Group reported a survival rate of only 65% when radiation therapy was not given to patients with lung metastases (15).
Although the NWTSG and SIOP studies have included the largest number of patients, several individual institutions have made likewise important contributions to the optimization of Wilms' tumor therapy. As seen in this article the therapeutic approach used by our study group was both the NWTSG as well as the SIOP protocols, so primary chemotherapy regardless of extent of disease was not performed in all cases. The truth is that although clinicians in North America and Europe have different philosophies on preoperative chemotherapy, most patients with Wilms' tumor survive long term, regardless of the sequence of therapeutic interventions. In the absence of a clear choice between up-front nephrectomy and preoperative chemotherapy, it is reasonable to base the timing of resection on factors such as tumor size, the patient's clinical condition, and the experience of the surgeon.
The results obtained by this study group indicate that prognosis according to age demonstrated no significance, but according to tumor size, lymph node involvement and distant metastasis were significant. After a 10-year follow-up, our data revealed an 89.4% survival rate. Furthermore, the statistical evaluation performed in order to evaluate the significance of surgical complications following neoadjuvant therapy in comparison to non adjuvant therapy exhibited a significant increase in complications in patients who were not treated with neoadjuvant therapy.
Footnotes
- Received August 19, 2009.
- Revision received March 23, 2010.
- Accepted March 23, 2010.
- Copyright© 2010 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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