Treatment

Historical perspective

Dramatic improvements in survival have occurred as the result of advances in anesthetic and surgical management, irradiation and chemotherapy. The role of chemotherapy in treating Wilms' tumors is unquestioned. The activity of dactinomycin and vincristine against Wilms' tumor was shown in the 1950s and 1960s, and these drugs have served as the cornerstone of Wilms' tumor therapy ever since. Doxorubicin was added to the Wilms' tumor treatment armamentarium in the 1970s. Today treatments are based on several multicenter trials and studies conducted by the International Society of Paediatric Oncology (SIOP) in Europe and the National Wilms Tumor Study Group [NWTSG] (nowadays Childrens Oncology Group (COG)) in North America. This multidisciplinary management of Wilms' tumour has resulted in a striking improvement in survival from 30% in the 1930s to more than 90 % nowadays and has become a paradigm for successful cancer therapy. Main objectives of these trials and studies are to treat patients according to well-defined risk groups in order to achieve highest cure rates, to decrease the frequency and intensity of acute and late toxicity and to minimize the cost of therapy.

There is a different approach in the treatment of nephroblastoma between SIOP and COG (NWTS) in that the COG believes it is necessary to identify accurate tumour staging by immediate surgery whereas the SIOP trials and studies largely focus on the issue of preoperative therapy. The SIOP strategy of giving preoperative chemotherapy is based on the premise that preoperative therapy reduces the risk of tumor rupture during surgery, thereby reducing the likelihood of local and distant recurrence. Postoperative treatment in both groups is mainly stratified according to the tumour stage and the histology after surgery. Through successive NWTS, SIOP and UK trials, the combination, length, and mode of administration of chemotherapy have been refined to optimize survival rates while minimizing acute and long-term toxicities. Radiation therapy, although still an important component of Wilms' tumor therapy, is restricted to treatment of stage III or IV disease.

Both approaches (SIOP, NWTS) result in similar tumour control rates but a different overall burden of treatment. In NWTS approximately 30% of patients have stage I tumours compared to 60 % in SIOP after downstaging by preoperative chemotherapy. Approximately 50% of children in SIOP studies receive an anthracycline but only 17% receive radiotherapy, compared to approximately 35% receiving both therapies in NWTS studies. In metastatic disease SIOP uses a response adapted risk stratification so that two thirds of children with stage IV disease whose lung metastases resolve during the preoperative chemotherapy phase are not given pulmonary radiotherapy.

Today the primary objective of clinical trials on WT is to reduce treatment for children with low-risk tumours and to increase treatment intensity for patients with high risk tumours. By this approach unwanted long-term side-effects will be minimized without compromising the excellent cure rates and novel strategies for patients with high risk tumours will hopefully improve outcome.

Primary surgery versus preoperative chemotherapy

In the NWTSG and upcoming COG studies, primary surgical resection of the tumor is the initial treatment in most children. This approach ensures that children with non-malignant conditions, as well as children with clear-cell sarcoma (CCSK) and rhabdoid tumours of the kidney (RTK) are not given inappropriate cytotoxic treatment. Only primary surgery allows to determinate virgin histopathological and stage variables, uncorrupted by preoperative chemotherapy. On the other hand the SIOP trials and studies largely focus on the issue of preoperative therapy. The complete surgical removal of a shrunken tumor is facilitated, mutilation caused by surgical procedures is minimized or avoided and micrometastases, not visible at diagnosis, are treated as early as possible. Besides that, response to treatment can be measured individually by tumor volume reduction and / or percentage of therapy induced necrosis at the time of surgery in the histological specimen. This gives an early individual prognostic parameter and can be used for further stratifying and more individualizing postoperative treatment.

Risk of preoperative chemotherapy without histological proven Wilms? tumor

There is a risk of up to 1.5 % that chemotherapy will be administered to a benign tumor during the preoperative phase. This is rare in the SIOP series and well-balanced by the low incidence of tumor ruptures and the high number of stage I tumors after preoperative chemotherapy. In addition, the preoperative chemotherapy is well tolerated and without long-term toxicity. Acute toxicity is restricted to temporarily moderately disturbed liver functions in less than 8 % of patients and in low platelet counts in 4 % of patients.

Staging, tumor ruptures and radiotherapy

In the SIOP trials and studies preoperative chemotherapy consisting of 4-weeks vincristine and actinomycin D for localized Wilms? tumors induces a favorable stage distribution and prevents tumor ruptures. Combining all trial patients of studies SIOP 5, 6 and 9, who did receive the same preoperative chemotherapy, 55.5 % of this population (1076 patients) achieved stage I disease after surgery. 26.8 % were diagnosed having stage II N0 disease and only 17.7 % had a stage II with positive lymphnodes or stage III. Altogether 47 ruptures did occur in these 1076 patients. The significantly poorer stage distribution and higher rupture rate of primarily operated children is independent of the tumor volume at the time of surgery. In 114 GPOH patients registered in SIOP 9 and SIOP 93-01, who were primarily operated, the mean tumor volume was 200 ml at the time of surgery and statistically not different to a pretreated group of 411 GPOH patients with a mean tumor volume of 226 ml at the time of surgery. Nevertheless only 44.7 % of the primarily operated children experienced stage I disease and 37.7 % had stage III. The message is, that a small tumor volume is no guarantee in preventing tumor ruptures and giving a favorable postoperative stage distribution. It has been argued that preoperative chemotherapy results in understaging patients in the SIOP studies. Patients staged as I or II N0, however, have the same prognosis for cure as do NWTS stage I and II patients, if treated according to the SIOP regimens for those SIOP stages.

Because of the favorable stage distribution after preoperative chemotherapy and the risk adapted postoperative treatment radiotherapy was subsequently successfully replaced with chemotherapy. Today less than 18 % of children with unilateral non-metastatic disease are irradiated in the SIOP studies. This is less than the number of children irradiated in the NWTS studies. The concept of replacing radiotherapy with chemotherapy is expanded to children with pulmonary metastases. Only those children with stage IV disease and not in a complete remission after preoperative chemotherapy and surgery receive a lung irradiation. Results are encouraging. This significant benefit decreases late sequelae caused by a lower percentage of irradiated children. In the NWTS series all patients with lung metastases are irradiated up to NWTS 5.

A transabdominal, transperitoneal incision is recommended to permit inspection of sites of involvement 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.

The benefit of tumor volume reduction after preoperative chemotherapy is also seen in a low total surgical complication rate of 8 % in SIOP 9 patients (45). The most frequent event was small-bowel occlusion (3.7%). This contrasts with the reported surgical complication rate in NWTS-3, in which small bowel obstruction was reported in 6.9 % of the registered patients. Surgical complications observed in the fourth National Wilms' Tumor Study (NWTS-4) were bowel obstruction (5.1%), extensive hemorrhage and wound infection (1.9% each), extensive vascular injuries (1.4%), and injuries to other visceral organs (1%). Risk factors for surgical complications included intravascular extension into the inferior vena cava, the atrium, or both; a flank or paramedian surgical approach; and a tumor diameter greater than 10 cm. Interestingly, nephrectomy performed by a general surgeon carried a higher risk of complications (odds ratio, 9.0; 95% confidence interval, 1.3-65; p = .03) than that performed by a pediatric surgeon (reference group; odds ratio, 1.0) or a pediatric urologist (odds ratio, 0.7; 95% confidence interval, 0.3-1.8).

To determine if patients receiving preoperative chemotherapy with vincristine and actinomycin D for non-metastatic Wilms' tumour have a more advantageous stage distribution and need less treatment without adversely affecting outcome, a randomised trial was carried out by the UK Children's Cancer Study Group (UKW 3). Between 1991 and 2001, a total of 205 patients with newly diagnosed non-metastatic renal tumours, of which 186 had Wilms' histologies, were randomly assigned either to immediate nephrectomy or to 6 weeks preoperative chemotherapy and then delayed surgery. Postoperatively both groups of children received chemotherapy according to tumour stage and histology determined at the time of nephrectomy. There was a significant improvement in the stage distribution for patients with Wilms' histologies receiving delayed surgery compared to those having immediate nephrectomy. This improvement resulted in 20% fewer children receiving radiotherapy or doxorubicin. The event-free and overall survivals at 5 years were similar in the two groups. The results suggest that all children with non-metastatic Wilms' tumour should receive chemotherapy prior to tumour resection. The NWTSG has recommended preoperative chemotherapy 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.

Histological subtyping and response to treatment

It has been questioned whether detection of unfavorable histology is still possible after prenephrectomy chemotherapy. In the SIOP 1, 2 and 5 studies, necrotic changes were more frequently seen in patients pretreated with radiotherapy than in those pretreated with chemotherapy. Analysis of the post-treatment histology in these studies as well as that of 83 patients who underwent prenephrectomy chemotherapy in NWTS 3 showed no evidence that the prenephrectomy therapy alters the detection of anaplastic histology. Comparing the histological subtypes between primarily operated and pretreated tumors a change in the distribution pattern of the different subtypes can be found. In the registered patients of the GPOH subgroup of SIOP 9 and SIOP 93-01 28.5 % of pretreated tumors show significant amounts of necrosis. On the other hand the percentage of blastemal predominant tumors goes down from 34 % to 9.1 % after preoperative chemotherapy. Children with the blastemal predominant tumors after preoperative chemotherapy have a poorer outcome in this analysis than all other histological subtypes of the intermediate risk group (79 % 5-year event free survival, compared to more than 90 % for all other subtypes regardless of stage). It can be concluded that the blastemal predominant subtype after preoperative chemotherapy is more chemoresistant and that this tumor has to be treated more intensively. Analysizing comparative genomic hybridization findings in primary Wilms tumors of blastemal type, there were significant differences in the cytogenetic constitution tumors between those primarily operated and those receiving preoperative chemotherapy. As a trend, tumors in the preop-CT group had fewer changes (mean, 2.7) than those in the non-preop-CT group (mean, 3.8), and the frequencies of imbalances at 7p or +7q, respectively, were significantly lower compared to tumors in the non-preop-CT group (2/19 vs. 10/22, p = 0.019; 1/19 vs. 9/22, p = 0.011). In contrast, +1q was common in both the preop-CT group (10/19) and the non-preop-CT group (7/22). The results suggest that Wilms tumor clones with +1q prevail after CT, while cytogenetically more complex clones with +7q and/or imbalances at 7p appear to be more responsive and are more likely to be eliminated by chemotherapeutic treatment. This and the significantly higher reduction of tumor volume in intermediate risk than in high risk tumors shows that response to preoperative therapy is of prognostic value.

Surgery only

Nephrectomy without adjuvant therapy was suggested to be adequate treatment for a subset of patients with highly favorable clinical features in the 1970s. Green and Jaffe suggested that nephrectomy only might be adequate therapy for patients less than 24 months of age with tumors weighing less than 550 grams. This hypothesis was supported by the results of a small, prospective study of eight such children treated with only nephrectomy. A review of children treated on National Wilms' Tumor Studies (NWTS) -1, -2, and -3 supported the hypothesis that changes in the NWTS regimens had not improved on the excellent prognosis of this group of children, suggesting that nephrectomy alone was sufficient therapy. Based on these findings, NWTS-5 prospectively treated 75 children younger than 24 months with small (<550 g) stage I favorable histology tumors with nephrectomy only. The study closed early according to predefined stopping rules because the risk of relapse at 2 years was 13.5%; however, all patients were successfully salvaged with standard therapy. In light of the high OS rate achieved, the COG is re-evaluating the benefit of nephrectomy-only in this selected group of patients.

Kidney sparing surgery

Partial nephrectomy as a primary tumour resection strategy remains controversial and is probably not indicated in routine treatment of Wilms' tumour. After successful inauguration of parenchymal sparing surgery in children with bilateral WT, recent reports emphasize conservative surgery for children with unilateral WT. A study of the feasibility of partial nephrectomy in treating nonmetastatic, unilateral Wilms' tumors found that only 4.7% of patients would be eligible for this procedure. A recent published study presented bench surgery with autotransplantation as another new surgical technique. However, most of the studies concerning PN in unilateral WT are limited to a small number of patients. One larger series of 37 partial nephrectomies from GPOH showed that there is no difference in outcome, if partial nephrectomy is done only if the tumor involves one pole and less than one third of the kidney, if the patient has a functioning kidney, if the collecting system or renal vein had no tumor involvement, and if clear margins existed between the tumor and surrounding structures. Because the rate of renal failure in patients with unilateral Wilms' tumor is less than 1%, kidney-sparing resection is not generally recommended and should be restricted to few experienced surgical centers.

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