Surgery Only for the Treatment of Patients With Stage I (Cassady) Wilms’ Tumor Eric Larsen, MD, Antonio Perez-Atayde, MD, Daniel M. Green, MD, Alan Retik, MD, Luis A. Clavell, MD, and Stephen E. Sallan, MD

A prospective pilot study was undertaken to examine the outcome of patients with Stage I (Cassady) Wilms’ tumor treated with nephrectomy only. Eight consecutive patients fulfilling the criteria for Stage I (Cassady) Wilms’ tumor (age < 2 years with unilateral, nonmetastatic, favorable histopathologic type, and tumor weight < 550 g) underwent nephrectomy with no further therapy. All eight patients were alive and free of disease with a mean follow-up period of 5 years. There was one tumor recurrence that involved a metachronously occurring bilateral tumor. Overall survival (100%) and event-free survival (88%) were comparable with clinical trials in which patients received adjuvant therapy. Patients with Stage I (Cassady) Wilms’ tumor can be successfully treated with nephrectomy alone, thereby eliminating the toxicity of adjuvant therapy. Cancer 66264-266,1990.

ILMS’ TUMOR is the most common malignant W neoplasm of the kidney in infants and children. Nephrectomy has been an essential component of treat- ment for patients with Wilms’ tumor. Before the routine use of adjuvant therapy, the survival rate of children with Wilms’ tumor after nephrectomy only was 36970.’ The subsequent addition of irradiation and chemotherapy re- sulted in striking increases in survival. However, the ef- ficacy of those modalities were not rigorously evaluated in controlled trials.

The National Wilms’ Tumor Studies (NWTS) have re- cently demonstrated that certain subsets of patients with Wilms’ tumor can be effectively treated with less therapy. Specifically, postoperative tumor bed irradiation was not necessary for patients with Stage I and I1 favorable his-

From the Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Division of Hematology/Oncology, and the Departments of Pathology and Urology of The Children’s Hospital, Boston, Massachusetts; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts; and the Department of Pediatric On- cology, University of Puerto Rico, San Juan, Puerto Rico.

Support in part by Grant #52T32 HL07574 from the National Insti- tutes of Health.

The authors thank the surgeons who treated these patients, Drs. Enrique Marques, Amary Capella, Arnold Colody, Raphael Levey, and Joseph Vacanti. The authors also thank Sharon Thornhill for assistance with the manuscript.

Address for reprints: Stephen E. Sallan, MD, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 021 15.

Accepted for publication January 19, 1990.

tologic type turn or^.^,^ At this time the NWTS recommend combination chemotherapy for all patients.

A review of the hospital records of all previously un- treated children with Wilms’ tumor referred to The Chil- dren’s Hospital in Boston suggested that the prognosis for patients younger than 24 months at diagnosis with Stage I (Ca~sady)~ tumors was excellent. Stage I (Cassady) tu- mors were unilateral, nonmetastatic, small (< 550 g total tumor and kidney specimen weight), and had favorable histopathologic t ~ p e . ~ . ~ No beneficial effect of local irra- diation or chemotherapy on the relapse-free survival of this group of children was apparent.6

These findings and the results of the first NWTS, which showed excellent disease-free survival among nonirra- diated children younger than 24 months with Group I tumors,’ suggested that there was a group of young pa- tients with Wilms’ tumor whose therapy could be limited to nephrectomy only. We report the results of a prospec- tive pilot study in which young patients with Stage I fa- vorable histologic type Wilms’ tumor were treated with nephrectomy only.

Patients and Methods

Between January 1982 and June 1989,69 children were diagnosed with Wilms’ tumor at The Children’s Hospital and Dana-Farber Cancer Institute in Boston and the Uni- versity of Puerto Rico in San Juan. Eight patients were younger than 24 months and had tumors which satisfied

264

No. 2 SURGERY ONLY IN WILMS’ TUMOR Lavsen et al. 265

the criteria for Stage I (Ca~sady).~ The preoperative eval- uation in all patients consisted of a history, physical ex- amination, abdominal ultrasound, and computed to- mography of the abdomen and lungs. All patients under- went unilateral nephrectomy, six at The Children’s Hospital/Dana-Farber Cancer Institute and two at the University of Puerto Rico in San Juan. Postoperative evaluation consisted of monthly physical examination and chest radiograph, and abdominal ultrasound every 1 to 2 months for 1 year. These examinations were subsequently performed at increasing intervals. Other patient charac- teristics and outcome are summarized in Table 1.

Pathologic Techniques

Multiple histologic slides (6 to 21; mean, 12) from the tumor and adjacent renal parenchyma were reviewed in all cases. Each tumor was carefully evaluated for the pres- ence of cellular anaplasia (as defined by the NWTS)’ or cellular atypia not meeting the complete criteria of ana- plasia (hyperchromatism and nuclear enlargement of at least two-fold). The histologic evaluation included the presence or absence of capsular invasion, inflammatory pseudocapsule, invasion of the renal sinus, vascular in- vasion, and lymph node metastases. The number of mi- toses per I0 high-power fields and the relative amount of necrosis were also estimated.

None of the tumors had evidence of cellular anaplasia, atypia, or positive lymph nodes. One tumor (from Patient 8) had focal areas of inflammatory pseudocapsule. In an- other nephrectomy specimen (from Patient 7) there was focal invasion of the renal sinus by tumor, and in one tumor (from Patient 2) there was evidence of intrarenal vascular involvement. The number of mitoses vaned from 3 to 42 per 10 high-power fields (mean, 21).

Results

As of January 1990, all eight patients were alive and free of disease. The mean follow-up was more than 5 years (range, 3 to 7.5 years). Seven patients had been contin-

uously disease-free. One patient, who also had congenital hypospadias, developed a metachronously occurring bi- lateral Wilms’ tumor 3 months from the time of his initial presentation. The recurrence was successfully treated with partial nephrectomy after the tumor had failed to respond to chemotherapy (vincristine, dactinomycin, cyclophos- phamide) and local irradiation (1 500 cGy to the whole kidney).

Discussion

Major advances in the treatment of Wilms’ tumor have been made in the last 70 years. The development of im- proved surgical and anesthetic techniques coupled with the use of postoperative irradiation and chemotherapy have resulted in a dramatic increase in overall survival from less than 10% in 1915 to 90% in 1985.8 There re- mains a small group of patients with Wilms’ tumor with poor prognosis, such as those with unfavorable histologic type, metastatic disease, or bilateral tumors who might benefit from more intensive forms of therapy. However, the majority of patients enjoy a good prognosis and are successfully treated with relatively little therapy after sur- gery.

The NWTS has shown that certain patients with fa- vorable histologic type, Stage I or I1 Wilms’ tumor can be effectively treated with a reduction of chemotherapy and elimination of irradiation. This therapeutic strategy achieves the same overall result with less t~xici ty .~ Ra- diation therapy results in significant morbidity and mor- tality in young patients with Wilms’ tumor.’ Chemother- apy can also cause toxicity in children treated for Wilms’ tumor. In reviewing the toxic deaths in the second NWTS, Jones and co-workers found that of 47 patients younger than 12 months with Group I or I1 disease, four (8.5%) had toxic deaths.” When drug doses were reduced by 5070, mortality was eliminated and morbidity reduced signifi- cantly.’ ’

The current study explored treatment with nephrec- tomy alone in patients younger than 24 months with Stage

TABLE 1. Patient Characteristics and Outcome

Patient Age at Side of Tumor no. Date of D x Sex D x tumor weight Outcome

1 February 1982

August 1982 May 1983 September 1983 February 1984 November 1984 November 1985 January 1987

M 8 mo

6 mo 10 mo 6 mo 5 mo 8 mo 4 mo I mo

Right

Left Left Right Right Left Left Left

328 g

215 g 290 g 165 g 157 g 230 g

230 g 90 g

Alive, disease-free after treatment

No recurrence No recurrence No recurrence No recurrence No recurrence No recurrence No recurrence

of contralateral tumor

D x : diagnosis.

266 CANCER July 15 1990 Vol. 66

I (Cassady) Wilms’ tumor. All eight patients were alive and healthy with a mean follow-up of over 5 years. The only disease recurrence was a metachronously occurring bilateral tumor in Patient 1. Bilateral Wilms’ tumor has been associated with external genital abnormalities,” and Patient 1 had hypospadias. Patients with genital anomalies who are diagnosed with Wilms’ tumor should be carefully screened and followed for possible bilateral disease.

The outcome of our patients was comparable with the outcome observed in patients with completely resected, nonmetastatic disease in NWTS 1, 2, and 3 . The 2-year relapse-free survival for Group I patients younger than 2 years in NWTS 1 and NWTS 2 was 89% and 88%, re- spectively.2 The 4-year relapse-free survival for all patients with Stage I disease in NWTS 3 was 90%.3 All of those patients received adjuvant chemotherapy and many also received irradiation. The relapse-free survival in our eight patients treated with nephrectomy alone was 88%.

Patient age at presentation of younger than 24 months and tumor weight less than 250 g were originally dem- onstrated to be good prognostic factors in NWTS 1 .’ The fact that our patients were young (mean age, 7 months) and had small tumors (mean weight, 2 13 g) seems to sup- port these findings. Subsequently, an association between tumor weight and prognosis was not identified in an anal- ysis of prognostic factors for NWTS 2.13 Although the younger patients in NWTS 2 had a better outcome than their older counterparts, this was believed to be dependent on other, more important prognostic factors. The two most important variables in the prediction of good prog- nosis in NWTS 2 were favorable histologic type and lack of lymph node inv~lvement.’~ Favorable histologic type and limited disease continued to be the most predictive prognostic factors in NWTS 3.3 All eight patients had a good prognosis based on these two variables as well. Therefore, using prognostic criteria from NWTS 1, 2, or 3, the patients in the current study all had a predictably good prognosis at the time of diagnosis.

A “microsubstaging” system has been proposed by Weeks and co-workers to identify those patients with Stage I, favorable histologic type Wilms’ tumor who were at risk for relapse. l4 The four histologic features associated with a higher risk of relapse included invasion of the tumor capsule, presence of an “inflammatory pseudocapsule,” renal sinus invasion, and tumor in intrarenal vessels. One or more of these features were observed in 100% of patients in NWTS 3 who relapsed, compared with 46% of patients

who did not relapse. No relapses have been documented in patients who lacked all four of these features. Thus, that system is a very sensitive, yet nonspecific method of predicting relapse. Three of our eight patients had a single adverse “microsubstaging” feature and none relapsed. This observation is consistent with the limitations of the system. It remains to be seen how clinically useful “mi- crosubstaging” will be in patient management.

We report eight patients with Stage I (Cassady) favorable histologic type Wilms’ tumor’ treated with nephrectomy alone. The event-free survival (88%) and overall survival (100%) were comparable with that of similar patients in the NWTS who received adjuvant therapy. In this small prospective pilot study it appeared that such patients could be successfully treated by surgery only, thus avoiding the acute and long-term toxicity of radiation therapy and chemotherapy.

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