T of Wilms' tumor during the past 10

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1 WILMS' TUMOR-AN INTERDISCIPLINARY TREATMENT PROGRAM WITH AND WITHOUT DACTI N 0 MYCIN LAWRENCE W. MARGOLIS, MD,* W. BYRON SMITH, MD,+ WILLIAM M. WARA, MD,~ JOSEPH H. KUSHNER, MD,~ AND ALFRED A. DELORIMIER, MD" From 1945 through 1970, 61 patients with Wilms' tumor were analyzed for the treatment of primary tumor or metastatic lesions and for the development of metastases. Between 1945 and 1962, 21 patients were treated by nephrectomy and radiation therapy to the tumor beds; 10 of these (48%) remain well. Since 1962, dactinomycin has been added to the treatment program of 40 patients. Twenty-two of these patients were treated entirely at UCSF; 18 (82%) have no evidence of disease after 2 years or more. Eighteen cases were referred after initial treatment elsewhere; seven (39%) remain free of disease for the 2-year at risk period. Maintenance courses of dactinomycin resulted in a marked decrease in the subsequent incidence of pulmonary metastases. It is concluded that an improved cure rate of Wilms' tumor can be achieved with a combination of dactinomycin, radiation therapy, and surgery under the guidance of an experienced oncology team. HE MAJOR CHANGE IN THE TREATMENT T of Wilms' tumor during the past 10 years has been the addition of dactinomycin (Cosmegen, Merck, Sharp and Dohme), and/or vincristine (Oncovin, Lilly) to the therapeutic regimenp.7 While most investigators accept dactinomycin as efficacious, there have been few published controlled studies to demonstrate significant differences between a single course of the drug and multiple intermittent courses.*o Our purpose here is to update results previously reported in patients treated only by surgical removal of the tumor and radiation therapy,'sjs and to compare them with our patients since 1962 who have also received chemotherapy. Al- Presented at the 14th Annual Meeting of the American Society of Therapeutic Radiologists, Phoenix, Ariz., SOV. 1-5, 1972 From the Section of Radiation Oncology, Department of Radiology; Department of Pediatrics and Department of Surgery, ~. University of California, San Francisco, Calif. Supported in part by National Cancer Institute Research Trainiw " Grant in Radiotheraw Number L, CA Assistant Clinical Professor of Radiology. t Fellow in Pediatric Hematology. t Fellow in Radiotherapy. B Associate Clinical Professor of Pediatrics. 11 Associate Professor of Surgery. Address for reprints: L. W. Margolis, MD, Department of Radiology. Section of Radiation Oncology, University of California, San Francisco, Calif Received for publication April 27, though this report is not a randomized trial, it does appear to provide support for the use of maintenance chemotherapy. MATERIALS AND METHODS From 1945 through 1970, 61 patients with the diagnosis of Wilms' tumor were treated and followed for 2 years or more at UCSF Medical Center; 43 of these 61 patients had their entire treatment at UCSF. Eighteen had treatment initiated elsewhere and were transferred to UCSF for additional evaluation and treatment. At our institution, initial diagnostic evaluation is completed as promptly as possible, and now includes excretory urogram, chest x-ray with whole lung tomograms, liver scan, and selective renal arteriograms, encouraging minimal tumor palpation. All 61 cases were staged retrospectively according to the criteria established in the National Wilms' Tumor Study4 staging system by a team consisting of surgeon, radiation therapist, and pediatric oncologist: Stage I: Tumor limited to the kidney and completely resected Stage 11: Tumor extending locally beyond the renal capsule but completely resected Stage 111: Residual tumor confined to the abdomen, incompletely resected tumor, or

2 No. 3 WILMS TUMOR - tumor spilled into the abdomen during resection Stage IV: Hematogenous metastases, i.e. to lung, liver or brain Stage V: Bilateral renal involvement, either initially or at a later date Of the 43 patients treated entirely at UCSF, 9 (21%) were Stage 111-IV, as compared to 18 in whom the treatment was initiated elsewhere in which 10 (56%) were Stage 111-IV (Table 1). Eleven (37y0) of 30 infants under 2 years of age were Stages 111-V, compared with 19 (61y0) of 31 cases in the older age.group. If a tumor was considered to be too large for removal without excessive manipulation, radiation therapy with or without chemotherapy was given preoperatively. The criteria for the diagnosis of Wilms tumor are based on the clinical findings of a renal mass, IVP, and selective renal arteriogram. Radiation is delivered to a field which encompasses the entire tumor mass with the usual midplane dose of 1,500 rads in 2 weeks. Preoperative chemotherapy consisted of initiating dactinomycin 10 pg/kg every other day for 7 days. Since 1970, vincristine has been used rather than dactinomycin for preoperative chemotherapy because of its minimal bone marrow suppression. If there were no indication of regression in tumor size within 10 days (1,000 rads), the tumor was considered to be relatively radioresistant and resection was accomplished without further delay. At operation, a generous transverse abdominal incision was utilized which could be extended into the thorax if necessary. During the operation, if appropriate, metallic clips were placed in the abdomen to outline the tumor area. The renal vein and inferior vena cava were examined to assess the possible extension of tumor into these vessels. The renal vessels were then ligated, followed by a wide Margolis et al. 619 en bloc resection of the entire kidney, ureter, hilar and para-aortic nodes, and adjacent hilar structures within Gerota s capsule. If the tumor had spread into the flank muscles, diaphragm, splenic hilum, pancreas or duodenum, these areas were resected with the en bloc specimen. To prevent possible lymphatic and hematogenous dissemination or intraperitoneal spill of the tumor, retraction or manipulation of the tumor was minimized until dissection of the margins had been completed. Whenever possible, the radiotherapist was present at surgery and tentative treatment portal was discussed in consultation with the surgeon. The tumor bed volume usually extended from the diaphragm to a lower border as determined by the IVP, arteriogram, and surgical findings. The fields were designed to include the entire width of the vertebral body, thereby covering both epiphyseal plates and minimizing future scoliotic changes. Postoperative irradiation to the tumor bed was given via cobalt or 4 Mev linear accelerator in all cases, except in patients with Stage I tumors under 1 year of age. In those who received preoperative irradiation, their total course of 3,000-3,500 rads in 4 weeks was completed in the immediate postoperative period. If the tumor ruptured either before or during surgery, the treatment field included the entire peritoneal cavity (obturator foramen to diaphragmatic dome) to a dose of 3,000 rads. The contralateral kidney was shielded at 1,500 rads and the liver at 2,000 rads. When bilateral Wilms tumor was present, the treatment was individualized.6 Every attempt is made in these patients to do at least one heminephrectomy and preserve some normal kidney but, if necessary, a bilateral nephrectomy and transplant are performed. Chemotherapy in the immediate postoperative period was initiated or continued as toler- TABLE 1. UCSF Wilms Tumor Patients Two-year Survival Free of Disease Dactinomycin No chemotherapy Stage Total NED Per cent Total NED Per cent I I I IV V TOTAL = P I.05 Ref: Mathematical Statistics by John E. Freund, Prentice-Hall 1962.

3 ~~ 620 CANCER September 1973 Vol. 32 TABLE 2. Referred Cases* of Wilms Tumor Two-year Survival Free of Disease Stage Total Alive Per cent I I IV V TOTAL * These patients all received surgery, radiation therapy, and chemotherapy except for one Stage 111 patient who remains free of disease. ated. If no preoperative chemotherapy had been given, intravenous dactinomycin was administered daily for 5 days (15.pg/kg/day) for a total of 75 pgikg. If postoperative morbidity occurred. the daily dose was decreased and given over a longer period of time. A second course of dactinomycin was given 6 weeks later, followed by a third course at 3 months postoperatively. Subsequently, dactinomycin was given at 3-month intervals, the last course being given 24 months after the last evidence of detectable disease. At each course, a complete evaluation for metastases was obtained, which included chest x-ray (full lung tomograms if indicated), excretory urogram, liver scan, and chemical evaluation of liver and kidney function. RESULTS Eighteen (82Y0) of the 22 patients whose treatment was initiated at UCSF who received dactinomycin had no evidence of metastatic or recurrent disease for at least 2 years after completion of therapy (Table 1); 10 of 21 (48y0) treated prior to 1962 who did not receive chemotherapy had no evidence of disease. Since 1962, 18 patients were referred to UCSF after prim treatment elsewhere; 7 (39%) survived 2 years or more (Table 2). The survival time in all patients in this study is calculated from the first date of diagnosis. In patients treated prior to 1968, the 5-year survival is identical to the 2-year survival. In our entire group of 61 patients, only one patient (who did not receive prophylactic chemotherapy) developed metastases after an apparent 2-year period free of disease. Of 18 patients presenting free of metastases and treated with prophylactic chemotherapy, 2 (11%) developed lung metastases. Of 20 patients not receiving prophylactic chemotherapy, 9 (45y0) developed lung metastases (Table 3). Lung metastases appeared at approximately the same interval in both groups, i.e., 9.3 vs. 8.9 months, respectively. Twenty-two of 30 patients (73y0), who were less than 2 years of age at the time of diagnosis, remained free of disease for 2 years or more, whereas 15 of 31 (48y0) more than 2 years of age survived (Table 4). There is essentially no difference in the age distribution in the referrecl patients as compared to the UCSF patients with the exception of Stage V where a higher proportion of the referred patients were over 2 years of age. In our patients, acute toxicity to dactinomycin was minimal and consisted of occasional dermatitis (associated with concurrent irradiation), alopecia, leukopenia, nausea and vomiting. It was necessary to discontinue the drug in only one patient; an infant who developed a large esophageal ulcer. One patient received 2,150 rads in 3 weeks to both lungs for metastases, and concurrent dactinomycin, with minimal pneumonitis. During a subsequent course of dactinomycin 3 months later, he developed a fulminant pneumonitis which led to his death. No residual tumor was found at autopsy. DISCUSSION Since Max Wilms classic monograph in 1899,ln there has been a progressive increase in the survival rate in patients with Wilms TABLE 3. Incidence of Late Development of Lung Metastases in UCSF Patients* Dactinomycin No chemotherapy Stage Total Metastases Total Metastases I I V * Stage IV patients excluded as they presented with metastases.,ya = 5.290; P S.05.

4 No. 3 WILMS' TUMOR Margolis et d TABLE 4. Age and Stage of Disease Related to Survival < 2 years of age > 2 years of age Stage Total Alive Per cent Total Alive Per cent I I IV V TOTAL x2 = 5.003; P I;.05. tumor. In 1950, Gross and Neuhausers demonstrated that postoperative irradiation with nephrectomy resulted in the best survival rates. The survival in various seriesljlj2 prior to 1959 ranged from 15.2 to 47.3y0, and significant improvement was reported by Farbefl and Fernbach7 both in 1966 by utilizing dactinomycin in conjunction with radiation therapy and surgery. Since the introduction of dactinomycin in 1962, the 2-year survival rate at UCSF has been SZ% compared with 48% in a comparable group of patients (UCSF only) treated prior to 1962 who did not receive chemotherapy. This is the only appreciable difference in the two groups as the surgical approach has not changed since 1947, except for minor modification in patients with advanced disease including en bloc resection, lymph node dissection, and more aggressive approach to metastatic disease in the lung and liver. The only significant changes in the radiation therapy approach have been the use of irradiation in patients with metastatic disease to the lung and/or liver. These improved results have been obtained by the aggressive use of all three treatment modalities, careful evaluation of each patient, and a close communication between the surgeon, radiation therapist, and pediatric oncologist. Repeated reevaluation of each patient by a team during the course of initial therapy also minimized potential complications. This is possible when the entire management of the child is conducted by our group. The results of the patients treated entirely at UCSF show an 82y0 survival as compared to 39% survival in those with treatment initiated elsewhere and referred for completion of therapy. We realize that the patients referred are a selected sample of difficult patients, but they did have an unusually high incidence of abdominal spill at initial surgery and metastatic disease so advanced that survival seemed less likely. The staging system is thought to be a function of disease progression within the abdomen and of the surgeon's technique in total tumor removal. However, because we use a relatively aggressive approach at surgery, it reflects a greater percentage of Stage I1 patients at UCSF. Three patients operated on elsewhere had tumor spillage at surgery and were, therefore, classified as Stage 111; two of these would have otherwise been Stage I. Our operative approach for control of the primary tumor is based on several factors: 1. the frequent extension of the tumor beyond the renal capsule into the perinephric fat, 2. the finding of regional lymph node metastases in of cases," 3. the possibility of direct extension of tumor into the pelvis-ureter and/or into the renal vein-inferior vena cava, and 4. the possibility that the tumor can be bilateral in 5 to 10% of cases.2joj6 Preoperative irradiation is used when the surgeon believes the tumor to be too large for resection without undue manipulation. Although preoperative vincristine may be helpful in obtaining tumor reduction,17 our surgeons prefer to add radiation therapy; 1,500 rads will usually significantly reduce the size of the tumor, facilitate removal, and minimize the possibility of tumor rupture. Approximately one third of our patients receive preoperative irradiation with the diagnosis based on the clinical findings, IVP, and selective renal arteriogram. Although there are reports of up to 70/, error rate in the preoperative diagnosis,4 to date we have had no cases of wrong diagnosis. Prior to the use of dactinomycin, none of our nine patients who developed lung metastases survived despite whole lung irradiation. Of six patients who presented with Stage IV disease (or later developed metastases) and were treated with lung irradiation and dactinomycin, three have been alive for 2 years or

5 622 CANCER September 1973 Vol. 32 more without evidence of disease. Since the addition of maintenance courses of dactinomycin to the treatment regimen, only 2 of 18 (11%) presenting with Stages I, 11, 111, or V disease developed later pulmonary metastases as compared to 45y0 prior to the use of dactinomycin. This decrease in the frequency is comparable with the series of 122 cases from eight institutions reviewed by Burgert and Glidewell.3 Although we have adopted the policy of 2 years of maintenance chemotherapy, the current literature suggests that 15 months may be sufficient.4*20 The use of chemotherapeutic drugs is not entirely innocuous. One of the three deaths in our series was due to radiation-chemotherapy-induced pneumonitis exacerbated by a course of dactinomycin. Radiation tolerance of lung, liver, and other viscera is appreciably diminished when dactinomycin is given concurrently.13 Therefore, lung metastases are treated by irradiating both lungs to 1,500 rads in 12 fractions, followed by an additional 1,500 rads to small fields over residual isolated lesions when dactinomycin is given. Our results indicate a more favorable prognosis for children who present with disease under 2 years of age. This is in contrast to other series,s in which there is no significant difference in survival with age at diagnosis. The difference may be due to detection of tumor at an earlier stage in the younger patient (Table 4). SUMMARY The treatment and prognosis of 61 cases of Wilms tumor is evaluated utilizing the National Wilms Tumor Study Staging System. Since the introduction of maintenance courses of chemotherapeutic agents, in addition to radiation therapy and surgery, the cure rate is currently 82%. The value of repeated courses of dactinomycin in decreasing the subsequent development of lung metastases is demonstrated. Further, having the entire course of treatment done within one large center gains the benefit of close collaboration among the surgeon, radiation therapist, and pediatric oncologist. REFERENCES 1. Abeshouse, B. S.: The management of Wilms tumor as determined by national survey and review of literature. J. Uro1.77: , Bishop, H. C.. and Hope, J. W.: Bilateral Wilms tumors. J. Pediatr. Surg. 1: , Burgert, E. O., Jr., and Glidewell, 0.: Dactinomycin in Wilms tumor. JAMA 199: D Angio, J. J.: Management of children with Wilms tumor. Cancer 30: , delorimier, A. A., Belzer, F. O., Kountz, S. L., and Kushner, J. H.: Treatment of bilateral Wilms tumor. Am. J Surg , Farber, S.: Chemotherapy in the treatment of leukemia and Wilms tumor. JAMA 198: , Fernbach, D. J., and Martyn, D. T.: The role of Dactinomycin in the improved survival of children with Wilms tumor. JAMA 195: , Fleming, I. D., and Johnson, W. W.: Clinical and pathologic staging as a guide in the management of Wilms tumor. Cancer 26:-5, Gross, R. E., and Neuhauser, E. B. D.: Treatment of mixed tumors of the kidney in childhood. Pediatrics 6~ , Jagasia, K. H., Thurman, W. G., Pickett, E., and Grabstaldt, H.: Bilateral Wilms tumors in children. J. Pediatr , Klapproth, H. J.: Wilms tumor: A report of 45 cases and an analysis of 1,351 cases reported in the world literature from J. Urol. 81: , Ladd. W.E., and Gross, R. E.: Abdominal surgery of infancy and childhood. Philadelphia, W. B. Saunders Co., 1941; pp Margolis, L. W., and Phillips, T. L.: Whole-lung irradiation for metastatic tumor. Radiology 93: , Martin, L. W., and Reyes, P. M., Jr.: An evaluation of 10 years experiehce with retroperitoneal lymph node dissection for Wilms tumor. J. Pediatr. Surg. 4: , Ng, E., and Low-Beer, B. V. A.: The treatment of Wilms tumor. J. Pediatr. 48: , Rickham, P. P.: Bilateral Wilni s tumor, Br. J. Surg. 44: , Sullivan. M. P., Sutow, W. W., Caner, A., and Taylor, G.: Vincristine sulfate in management of Wilms tumor. JAMA 202:38, Vaeth, J. M., and Levitt, S.H.: Five-year results in the treatment of Wilms tumor of children. J. Urol. 90: , Wilms, M.: Die Mischgeschwultste, Leipsic, A. Georgi, Wolff, J. A., Krivit, W., Newton, W. A., and D Angio, G. J.: Single versus multiple dose dactinomycin therapy of Wilms tumor. A controlled co-operative study conducted by the Children s Cancer Study Group A (formerly Acute Luekemia Co-operative Choemtherapy Group A) prepared by Writing Committee: J. A. Wolff (chairman), W. Krivit, W. A. Newton, Jr.. and G. J. D Angio. N. Engl. J. Med. 279:29&294, 1968.