Results of the United Kingdom Children's Cancer Study Group First Wilms' Tumor Study

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1 Results of the United Kingdom Children's Cancer Study Group First Wilms' Tumor Study By Jon Pritchard, John Imeson, Janet Barnes, Simon Cotterill, David Gough, H.B. Marsden, Pat Morris-Jones, and Dorothy Pearson Purpose: The first United Kingdom Children's Cancer Stucy Group (UKCCSG) Wilms' Tumor Trial (UKW) applied treatment regimens stratified by stage and histology in accordance with National Wilms' Tumor Study (NWTS) criteria, seeking to reduce treatment of lowstage, favorable-histology (FH) tumors without impairing survival and to improve prognosis of stage III and IV (FH) and unfavorable-histology (UH) tumors with more intensive chemotherapy. Patients and Methods: Three hundred eighty-four consecutively diagnosed patients with Wilms' tumor were recruited from the 2 UKCCSG centers and Oslo, Norway, between January 98 and June 986. The regimen for stage I patients was vincristine (Vcr) only, while stage II patients received Vcr and dactinomycin (Act-D). Stage III patients received three-drug therapy and stage IV and UH patients four-drug regimens. Act-D T HE PROGNOSIS for children with Wilms' tumor has improved steadily over the past 3 years' and, since there is no evidence that the proportion of early versus late cases (ie, stages I and II v stages III and IV) has altered, this improvement is almost certainly attributable to advances in treatment. Awareness that radiotherapy (RT) and doxorubicin, in particular, cause unwanted late effects (irreversible hypoplasia of soft and bony tissues within treatment fields, and second tumors and cardiomyopathy, respectively) has led the large, collaborative Wilms' tumor study groups in Europe and the United States to test the hypothesis that the results of refined therapy may be just as good as those of standard treatment.,3 Before 97, treatment results in the United Kingdom (UK) had been similar to those reported from the United States. Data collected from the UK death certificates and cancer registries by Ledlie et a 4 from the Oxford Child- From the United Kingdom Children's Cancer Study Group, Department of Epidemiology and Public Health, University of Leicester, Clinical Sciences Building, Leicester Royal Infirmary, Leicester, United Kingdom. Submitted May 3, 994; accepted September 9, 994. The United Kingdom Children's Cancer Study Group is funded by the Cancer Research Campaign, United Kingdom. Address reprint requests to Jon Pritchard, FRCP, Department of Haematology/Oncology, Hospital for Sick Children, Great Ormond Street, London WCN 3JH, United Kingdom. C 995 by American Society of Clinical Oncology X/95/3-8$3./ was given as pulsed doses of.5 mg/m2 every 3 or every 6 weeks. No lung irradiation was used in stage IV patients. No randomized comparisons were attempted. End points were survival and event-free survival (EFS). Results: Survival at 6 years in FH patients was 96% for stage, 93% for stage II, 83% for stage III, 65% for stage IV, and 5% for UH patients of all stages. Conclusion: Vcr alone is as effective for stage I FH tumors as the two-drug regimen used in the NWTS and International Society of Pediatric Oncology (SIOP) studies. Fractionation of Act-D is unnecessary. The poorer results for stage IV FH and UH patients compared with the NWTS may be due to treatment differences, such as the use of lung irradiation for stage IV FH patients in NWTS3, and/or to case selection bias. J Clin Oncol 995 by American Society of Clinical Oncology. hood Cancer Research Group showed that the overall 3- year survival rate of 335 UK patients diagnosed between 962 through 966 was only 32%. Most of these patients had nephrectomy and RT (9% and 8%, respectively) with curative intent, but only 2 (35%) received chemotherapy, most commonly single-agent dactinomycin (Act- D) at low dose-intensity. There was a trend toward better survival for early-stage patients who received Act-D compared with those who did not, but the difference was not statistically significant. National treatment trials for Wilms' tumor patients started in the UK in 97. The first two studies (MRC, 97 to 974; and MRC2, 974 to 978) were coordinated by the Medical Research Council. The results of MRC, in which all 8 patients received postnephrectomy RT and chemotherapy with either Act-D or vincristine (Vcr) or both, were encouraging, with more than 7% of patients alive at 3 years. 5 However, entry onto that study and onto MRC2 was restricted to patients with nonmetastatic disease who were aged more than year at diagnosis. Staging methods have changed with time, and direct comparison with historical data may be misleading, but the conclusion of MRC was that chemotherapy had made a major contribution to the greatly improved prognosis. In another study from the Oxford Childrens Cancer Research Group, Lennox et al 6 showed that patients eligible for MRC, but not included in it, fared worse (58% 3-year survival rate) than study patients (77% 3-year survival rate). This difference was partly attributable to the fact that more patients in MRC received a full course of chemotherapy. In the MRC2 study, the results of which have been 24 Journal of Clinical Oncology, Vol 3, No (January), 995: pp 24-33

2 RESULTS OF UKCCSG WILMS' STUDY published only in abstract form,' all patients (N = 44) had nephrectomy at diagnosis and postoperative RT. Lymph node involvement and unfavorable histology (UH) were shown to be predictive of disease recurrence, confirming data from the United States National Wilms' Tumor Studies (NWTS).8Y- In MRC2, there were two randomized treatment trials. Each of 62 stage I patients (all histologies) was randomized to receive either a short, intensive course (6 months) or 2 years of single-agent Vcr. The outcome for the two groups was identical, with an overall 86% 3-year survival rate. This result appeared to conflict with that of an earlier study in the United States, in which only Act-D was used as adjuvant therapy and which showed an advantage for a longer course of chemotherapy." However, in that study, the dose-intensity of chemotherapy in the first 6 postoperative months was far lower than in MRC2. Stage II and III cases (aggregate n = 82) in MRC2 were randomized to either twodrug (Vcr plus Act-D) or three-drug (Vcr plus Act-D plus doxorubicin [Doxo]) chemotherapy after surgery plus RT; the 3-year survival rate in the two arms was similar, although with only 82 patients randomized, small differences might not have been detected. In NWTS2, in which a similar chemotherapy randomization was performed for stage II and III patients, those in the two-drug arm had a significantly lower 2-year event-free survival (EFS) rate (63%) than those in the three-drug arm (77%). However, overall 3-year survival rates were similar. 9 In 979, the UK Childrens' Cancer Study Group (UKCCSG) took over responsibility for organizing national Wilms' trials. The design of the UKCCSG Wilms' Tumor Trial (UKW) was based on results from the MRC and NWTS studies and had two broad aims, as follows: () to determine whether the treatment for stage I and II favorable-histology (FH) patients could be successfully refined by the omission of RT (stage I) or reduction in duration of chemotherapy and of abdominal RT dosage (stage II); and (2) to establish whether the prognosis for patients with stage III and IV disease and those with UH tumors could be improved by using more intensive threedrug (stage III FH) or four-drug chemotherapy. Other important features of UKW are as follows: () all patients with Wilms' tumor who presented to centers taking part in the study, including infants, stage IV, bilateral cases (we have argued against the use of the term stage V),2 and inoperable cases, were registered and included in analyses; (2) histopathology was reviewed centrally; (3) lung RT was not used in most stage IV cases that presented with pulmonary metastases; and (4) patients with stage III or stage IV UH tumors underwent secondlook laparotomy 2 to 2 weeks after nephrectomy, to determine whether local tumor control had been achieved by the intensive four-drug chemotherapy they had received postnephrectomy. If residual disease was detected, local RT (3 Gy) was administered, followed by further four-drug chemotherapy; if second-look laparotomy was negative, the four-drug regimen was continued, but no RT was given. Because the numbers of patients in the various subgroups was relatively small, the study contained no randomizations. In this report, we present the results of UKW, with a median follow-up duration from diagnosis of 4 months and a minimum of 57 months since completion of all first-line therapy. PATIENTS AND METHODS Patient Eligibility, Staging, Histopathology, and Treatment Plans 25 All 2 constituent centers of the UKCCSG (Appendix A) participated in the study, from its inception (January 98) to its closure (June 986). One other center (Oslo, Norway) entered 2 consecutive cases from February 983 to June 986, and three small centers in the British Isles contributed three cases each. The diagnosis of Wilms' tumor was confirmed histopathologically in all cases, either from the nephrectomy specimen or, in children who received chemotherapy before nephrectomy, an open or closed (Trucut, Baxter Healthcare Corp, Valencia, CA) tumor biopsy." 3 All children with histopathologically proven Wilms' tumor, including those with stage IV and bilateral disease and those with inoperable tumors, were eligible; the only exclusions were patients more than 4 years of age at diagnosis and those who had previously received treatment for Wilms' tumor. Patients with mesoblastic nephroma and renal carcinoma were also registered, but not included in analyses of toxicity or survival. The abdominal stage of each tumor was initially determined by the local pathologist, who was asked to take multiple blocks from around the tumor circumference (a minimum of was recommended), as well as from areas where there was suspicion of tumor spread outside the pseudocapsule. All excised lymph nodes were examined for tumor. Representative and/or equivocal slides from this material were reviewed by the study histopathologist (H.B.M.), who, in consultation with the referring histopathologist, decided on the final diagnosis and histopathologic stage and subtype. Subtypes were as defined for NWTS trials,'" ie, FH and UH, subclassified into Wilms' tumor showing diffuse or focal cytologic pleomorphism (anaplasia),' 4 bone-metastasizing renal tumor of childhood (BMRTC)"; clear-cell sarcoma), and rhabdoid tumor" 4 (it is now appreciated that the latter two types of renal tumor are not subtypes of Wilms', but separate clinicopathologic entities). Staging investigations for all patients included posteroanterior (PA) and lateral chest x-rays, and abdominal ultrasound or abdominal computed tomographic (CT) scan. Lung CT scan was performed in only a few patients and only chest x-rays, not CT scans, were used to up-stage to stage IV. Isotope or radiologic skeletal survey was performed only in patients with BMRTC, and head CT scans were recommended only for patients with BMRTC and rhabdoid tumors. Renal angiography and intravenous urogram (IVU) were optional. Based on these investigations, the surgical/pathologic findings, and the cri-

3 26 teria established for NWTS 2 and 3,.3,9 patients were classified as having either FH or UH tumors stages I, II, III, or IV, or bilateral tumors. Inoperable nonmetastatic tumors (see Surgery, following) were considered to be stage III. Treatment Plan Surgery Initial surgery (ie, surgery at the time of diagnosis) was recommended, but if a surgeon, in conjunction with his oncology and radiology colleagues, felt that an individual tumor was unresectable, preoperative chemotherapy was given. Recommendations for nephrectomy included the following: () a transabdominal, transperitoneal approach; (2) complete laparotomy, including examination of liver surface and biopsy of suspicious areas; (3) examination of all surfaces of the opposite kidney by palpation or direct vision; (4) systematic sampling of renal hilar and ipsilateral paraaortic lymph nodes; (5) early ligation of the renal vein, and (6) avoidance of tumor spill. Nonmetastatic tumors considered unresectable included patients whose imaging strongly suggested to the surgeon that complete surgical resection would be difficult or impossible (the majority), and those whose tumors could not be removed at an initial laparotomy because of close adherence to vital structures. In the case of stage IV disease, centers could opt either to treat with four-drug chemotherapy then nephrectomy, or the reverse. In either case, RT was given when residual abdominal disease was present postoperatively; of 9 patients who had immediate surgery, six (3%) received RT, compared with 2 (58%) of 2 who had preoperative chemotherapy. Factors that influenced the choice between immediate or delayed surgery included nutritional status of the child, presence or absence of hypertension, and degree of anticipated technical difficulty. Most tumors responded to prenephrectomy chemotherapy, sometimes dramatically." Tumor spill occurs less often after chemotherapy, 2 and surgery may be technically easier (D. Gough, personal communication, January 994). However, in UKW, there was no evidence, as the study proceeded, for an increased use of prenephrectomy chemotherapy in operable patients. For instance, (5%) of the first 22 stage IV patients to enter the study had immediate nephrectomy, compared with eight (44%) of the last 8 patients (P =.73). Patients with UH stages III and IV tumors who had surgery at diagnosis were eligible for second-look laparotomy after 9 to 2 weeks of four-drug chemotherapy. The justification for this strategy was as follows: () in MRC studies V and 2,' relapse in UH patients was more common at metastatic sites (alone or in combination with relapse at the primary site) than at the primary site alone; and (2) classical Wilms' treatment involves initial surgery followed by abdominal RT, with full chemotherapy not usually commenced until 5 to 7 weeks after diagnosis, which provides a window through which metastatic tumor growth might progress unhindered. The aim was to determine whether the intensive four-drug chemotherapy, given as soon as possible after surgery, would reduce the incidence of metastatic relapse. Second-look surgery was used to try to establish the true incidence of local tumor control, and thus to establish which patients really needed abdominal RT: if the laparotomy was positive for tumor, RT (3 Gy, see Radiotherapy for details) was given. If the laparotomy was negative, RT was omitted. The technique was as follows: biopsies were performed on the renal fossa and known areas of residual disease (usually marked by clips at initial surgery) even if no tumor was visible to the naked eye. If they could be identified, regional and paraaortic nodes were sampled. PRITCHARD ET AL The opposite kidney, liver, and remainder of the peritoneal contents were inspected and biopsies performed on suspect areas. For individual clinical reasons, only (42%) of 26 eligible patients (two of five patients with BMRTC, five of with anaplastic Wilms', and four of with rhabdoid tumors) underwent second-look procedures. Three (27%) of these laparotomies were positive, ie, residual tumor was identified, and eight were negative. The initial tumor stage (ie, stage at first laparotomy) of the three positive second-look procedures was stage III (n = 3), and of those with "negative" procedures, stage II (n = 4) and stage III (n = 4). Radiotherapy Patients with stage I disease received no RT (Table ). Those with stage II and III FH tumors received 2 Gy to the right or left hemiabdomen. The vertical extent of the treatment field was from the dome of the ipsilateral diaphragm to the upper border of the iliac crest, and from the opposite lateral border of the lumbar vertebrae to the lateral abdominal wall. Invariably, these guidelines gave the 2- cm tumor-free margin, in each direction, required by the protocol. The only patients to receive whole-abdominal RT (2 Gy) were rare patients with disseminated preoperative or intraoperative peritoneal rupture/seeding. Planning films were not required, but the exact extent of the RT field had to be drawn on the RT data sheet. Children with UH stage II and III tumors and those with either FH or UH stage IV tumors received abdominal RT (3 Gy) only if there was residual disease after delayed or second-look laparotomy (see Surgery). Criteria for administration of hemiabdominal or whole-abdominal RT and of the extent of treatment fields were the same as for FH patients. All abdominal RT was given using parallel, opposed fields in 5-Gy fractions, daily on weekdays. During RT, Vcr was given weekly. No Act-D or doxo was given during RT, and the doses of Act-D just preceding and just following RT were reduced to 5%, ie,.75 mg/m2. Lung RT was only given as part of first line treatment for stage IV patients if lung secondary tumors had not disappeared on chest x-rays by week 2 from diagnosis. The recommended dose was 2 Gy in 8 to fractions. Four patients received whole-lung RT, and a fifth patient who had only one secondary tumor of the left lung, received RT to the left lung only. By histologic subtype, lung RT was administered to four of 4 patients with stage IV FH tumors and to one of eight with UH tumors. Chemotherapy All children received Vcr (.5 mg/m2) weekly for the first to weeks after diagnosis, then every 3 weeks for a further 5 weeks (total, 25 to 26 weeks) (Table ). This was the only chemotherapy given to children with stage I FH tumors. Those with stage II FH disease received the same Vcr regimen as stage I FH patients, as well as every-3-week.5 mg/m 2 pulses of Act-D for a total of 26 weeks. Patients with stage III FH tumors received triple chemotherapy (Vcr plus Act-D plus Doxo) for year. The pattern of therapy was the same for FH stage II cases, except that Doxo (4 mg/m2 per dose) was alternated every 3 weeks with Act-D and chemotherapy was continued for a total of year. Patients with stage IV disease received four-drug chemotherapy; the regimen was similar to that for stage III FH patients, with the addition of cyclophosphamide (6 mg/m2) every 3 weeks for a total of year. Children with UH tumors, of whatever stage, were given the same four-drug regimen used for stage IV FH patients. Dosages for children under year of age were reduced to 5% of the dosage used for older children, calculated on a per-squaremeter basis.

4 RESULTS OF UKCCSG WILMS' STUDY 27 Table. Treatment Plan for Subgroups of Patients by Stage/Histology Chemotherapy Duration Histology/Stage Surgery Radiotherapy Drugs (months) FH I Initial None Vcr (only) 6 II Initial 2 Gy: hemiabdomen Vcr + Act-D 6 III Initial 2 Gy: hemiabdomen or whole abdomen Vcr + Act-D + Doxo 2 IV Initial or delayed 3 Gy: hemiabdomen or whole abdomen Vcr + Act-D + Doxo + Cyclo 2 UH I Initial None Vcr + Act-D + Doxo + Cyclo 2 II Initial None Vcr + Act-D + Doxo + Cyclo 2 III Initial and second-look None or 3 Gy: hemiabdomen or whole abdomen Vcr + Act-D + Doxo + Cyclo 2 IV Initial and second-look None or 3 Gy: hemiabdomen or whole abdomen Vcr + Act-D + Doxo + Cyclo 2 Inoperable tumors, Delayed None or 3 Gy: hemiabdomen or whole abdomen Vcr + Act-D + Doxo + Cyclo 2 any histology Abbreviations: Vcr, vincristine.5 mg/m2 wk x to then every 3 weeks; Act-D, dactinomycin.5 mg/m 2 every 3 weeks for 6 months (FH stage II) or every 6 weeks, alternating with Doxo every 6 weeks for year (FH stage III and IV and all UH patients); Doxo, doxorubicin 4 mg/m 2 every 6 weeks, alternating with Act-D every 6 weeks for year (FH stage III and IV and all UH patients); Cyclo, cyclophosphamide 6 mg/m 2 every 3 weeks for year. Data Collection and Analysis Data on each patient were submitted to the UKCCSG central office as soon as possible, and in any case within 6 months of diagnosis or of the relevant procedure. Detailed proformas that summarized clinical features, surgical findings, histopathology, and RT were required, as were completed chemotherapy flowcharts for each patient, giving details of both planned and actual drug doses. All of this information was reviewed by the individual chemotherapy, RT, surgical, and histopathologic subgroups, and by a statistician. Overall data for each patient were then reviewed at regular meetings of the study committee, at which time final decisions were made about patients whose stage allocation was controversial (Appendix B). Patients were monitored at 6-month intervals until death (from disease, treatment-induced complication, or other cause) or indefinitely. There were no consistent difficulties in delivering the intended treatment program. The study was analyzed by intention to treat. Survival curves were calculated by the method of Kaplan and Meier.' 6 The log-rank test" 7 was used to calculate the statistical significance of prognostic factors, including stage, histologic subtype, and age group (< year, to 4 years, and a 5 years). Survival time was defined as the time from diagnosis to death, from any cause, or to date of last follow-up evaluation. EFS was defined as time to relapse, time to death, or date of last follow-up evaluation. As there was no specific treatment plan for patients with bilateral tumors, their management varied considerably. No further details of these patients are included in this report, although overall results are displayed in the life-tables (Figs and 2). RESULTS Patient Entry, Treatment Toxicities, and Treatment Compliance Patients A total of 384 patients with Wilms' tumor were registered onto the study. In addition, there were 8 cases of mesoblastic nephroma and one case of renal carcinoma, which are not considered further in this report. The number of Wilms' tumor patients contributed by each center is listed in Appendix A. During 98 to 985, 39 of 49 children (78%) with Wilms' tumor in Great Britain were included in UKW (C.A. Stiller, unpublished data wap 4- n v Numbers at risk: Stage I Stg I Bilateral Stage III Stage IV Stage II Fig. EFS of all 39 FH patients stratified by stage, including patients with bilateral disease. Numbers at risk, shown at 3-year intervals, are for stage I (top line), II (second line), III (third line), bilateral (fourth line), and IV (bottom line) patients.

5 I 28 PRITCHARD ET AL ^^ I - < year years S, 8n 5+ years 6-4- ' 36 I II Numbers at risk: Fig 2. Survival of all FH patients by stage. Numbers at risk, from top to bottom, are for stage I, II, III, bilateral, and IV patients. from UK National Register of Childhood Tumors). Thus, accrual to UKW was much better than to MRC and, presumably, more representative of the disease in the UK as a whole. UK children with Wilms' tumor diagnosed between 98 and 982 but managed outside pediatric oncology centers tended to be overtreated, especially with RT, 8 which highlights the importance of central referral for optimal management. The male-to-female ratio was.6:, and the age range at diagnosis was to 72 months (median, 37). There was no difference between UH and FH patients with regard to age at presentation, but more boys than girls (29 v 2) had UH tumors, chiefly because 3 of 4 BMRTCs were in boys. We have noted previously the male predominance of this tumor." The numbers in different histopathologic/stage subgroups are shown in Figs through 6. A majority of FH patients had stage I or II tumors, while the reverse was true for UH patients. Twenty-three patients (6% of total) were considered to have tumors that were initially localized but unresectable. Diagnosis in these cases (FH, n = 7; UH, n = 6) was confirmed by open or closed biopsy or at subsequent laparotomy/nephrectomy. The distribution of metastases in stage IV patients was as follows: for 4 FH patients--lung only, 3 (75%); lung plus liver, seven (7.5%); extrapulmonary sites only, three (7.5%); and for eight UH patients-lung only, four; lung plus other sites, four (liver, three; bone marrow, one). No patient had bone metastases at diagnosis. Treatment Toxicities 4 8 Surgical toxicity. Four patients died of surgical complications directly attributable to the initial laparotomy Numbers at risk: Fig 3. Survival of all FH patients according to age group at diagnosis. Numbers at risk, from top to bottom, are < year, to 4 years, and 2 5 years. for nephrectomy. Two had uncontrollable bleeding, one had a fatal pulmonary tumor embolus, and one died of peritonitis after developing multiple intestinal perforations. A fifth child died of multiorgan failure following delayed laparotomy, 4 weeks after diagnosis. There were 5 other recorded episodes, in 3 patients, of later complications attributed primarily to surgery. Fourteen were episodes of intestinal obstruction that occurred 3 days to 95 months (median, 5 months) postnephrectomy, and one was an instance of peritonitis due to intestinal perforation 3 months after surgery. In each case, the blood count was normal, with more than. x -o 4t l- 8- U Numbers at risk: In < year-h I5+ years 5, years -4 years I I t I I I I I Fig 4. Survival of all stage I FH patients according to age group at diagnosis. Numbers at risk, from top to bottom, are < year, to 4 years, and ý 5 years.

6 RESULTS OF UKCCSG WILMS' STUDY 29 9 neutrophils and more than x 9 platelets at the time of the surgical complication. The causes of the episodes of intestinal obstruction were as follows: adhesions, episodes (with two children each suffering two separate episodes); intussusception, intraabdominal obstructed hernia, and volvulus, one episode each. Two of the complications proved fatal. The boy with the volvulus, who developed complicating pneumonia, and the girl with the intestinal perforation died despite laparotomy and antibiotic therapy. The children who recovered had delays of 2 weeks or less in RT and/or chemotherapy after the surgical complication. Radiotherapy toxicity. There were no fatal complications. The acute and late RT-related toxicity have been summarized previously." 9 Chemotherapy toxicity. There were 42 recorded complications requiring hospitalization, in 36 children, directly attributable to myelosuppression (29 episodes of febrile neutropenia and 3 episodes of bleeding due to thrombocytopenia). The majority (24; 57%) of these patients were receiving the stage IV/UH four-drug regimen. All children recovered with appropriate supportive therapy, although one child, who developed pneumococcal U2 ^^ Numbers at risk: Fig 6. Survival of all UH patients stratified by stage. Numbers at risk, from top to bottom, are for patients with stage I, II, III, and IV tumors..5 :2 Numbers at risk Fig 5. Survival of all 4 UH patients stratified by histologic subtype and compared with all FH patients. Numbers at risk, from top to bottom, are for FH patients, BMRTC, anaplastic, and rhabdoid groups meningitis while neutropenic, had residual partial deafness and seizures controlled by anticonvulsant therapy. Twenty-seven (7%) of 384 children developed clinically significant neuropathy due to Vcr. In eight instances, the principle feature was intestinal ileus: all of these patients recovered within days with nonsurgical therapy. The other 9 children developed various forms of peripheral neuropathy that varied from mild ptosis to disabling foot-drop. In all 27 cases, subsequent Vcr doses were delayed, decreased, or both, but Vcr was discontinued in only four children. There were no fatalities. All of the children who survived their Wilms' tumor regained lost neurologic function. In the absence of comparable published data, it is impossible to determine whether the incidence of Ver-related toxicity is different in this study from other series. Ten patients developed a hepatopathy/thrombocytopenia syndrome (HTS), characterized by thrombocytopenia with or without liver enlargement, jaundice, and ascites, due to Act-D-precipitated venoocclusive disease. 2,2 Five of these children had also received abdominal RT. Detailed analyses of these cases, and HTS cases from the UKW2 study, are provided elsewhere.2 The

7 3 most severely affected children required RBC and platelet transfusions, diuretics, and other supportive measures, but all made a complete recovery within 2 days. Act-D was reintroduced in all cases without precipitating a further episode of HTS. The mean total cumulative dose of Doxo for stage III FH patients was 32 mg/m 2 and for stage IV and UH patients 28 to 36 mg/m 2. One child died of congestive cardiomyopathy 8.5 years after diagnosis. Although mesna (6-mercapto-ethane sulfonate) was not given, there was only one documented episode of cystitis following cyclophosphamide administration among 8 children who received this agent. As for CNS toxicity, three children developed seizures during the study, one in association with inappropriate secretion of antidiuretic hormone (SIADH). None had long-term neurologic sequelae. Outcome PRITCHARD ET AL Patient sex, tumor weight, presence or absence of hematuria, and tumor laterality had no impact on outcome. Size of the treatment center (- v > patients entered, P =.7) and degree of compliance with treatment, according to preset criteria for protocol violation (P =.97), also had no prognostic significance. However, patient age at diagnosis, histologic subtype, and stage were all of prognostic importance. Figures and 2 show EFS and overall survival for FH patients, stratified by stage. The differences in prognosis were highly significant (P <. in each case). The survival rates for FH patients are as follows: stage I- 9% EFS and 96% overall survival at 3 years, and 89% EFS and 96% overall survival at 6 years; stage -85% EFS and 94% and 93% overall survival at 3 and 6 years, respectively; stage -82% EFS and 83% overall survival at 3 years and at 6 years; and stage IV-58% EFS and 65% overall survival at 3 years, and 5% EFS and 65% overall survival at 6 years. Confidence intervals for survival at 6 years are as follows: stage I, 92% to %; stage II, 86% to %; stage III, 76% to 9%; and stage IV, 5% to 8%. It should be emphasized that these results include data on all stage III and IV patients considered unresectable at diagnosis. Figure 3 shows that older patients with FH tumors fared worse, as a whole, than younger children (EFS, P =.2, data not shown; overall survival, P =.8). However, there was no difference in EFS (P =.5) and overall survival (Fig 4; P =.9) between children less than year old, to 4 years old, and - 5 years old with stage I FH tumors. In Fig 5, life-tables for UH patients, stratified by subtype, are compared with the survival of FH patients overall. The differences between these groups were highly statistically significant both for EFS (P <., data not shown) and for overall survival (P <.). Comparing UH subtypes versus FH, results were as follows: FH versus pleomorphic, P =.; FH versus rhabdoid, P =.; and FH versus BMRTC, P =.9. Extrapolating from the NWTS studies, ' 3 ' 9 we conclude that Doxo has favorably influenced the prognosis for our BMRTC patients, compared with the MRC studies.' 7 In Fig 6, UH patients are shown stratified by stage. There is a highly significant correlation of stage with prognosis (P <.). Late Effects The median follow-up duration from diagnosis is 4 months (range, 69 to 66). To date, no systematic attempt has been made to document the late effects of UKW treatment. However, annual surveillance for second malignancies is performed, and none have been noted to date. DISCUSSION In this study, we used the NWTS staging system' and an identical histopathologic subclassification. 4 In addition, more than 85% of patients (% of those with stage I and II disease) had tumor removal before chemotherapy and similar protocols for surgery and RT. We are unable to account for a difference between patients in UKW and those randomized in NWTS 3 in the proportions of stage I, II, and III patients, which are as follows: stage I-NWTS3, 52% and UKW, 39%; stage II-NWTS3, 24%, and UKW, 2%; and stage III-NWTS3, 24%, and UKW, 4%. D'Angio et a 3 demonstrated only small differences in stage distribution between randomized and followed patients in NWTS3 (the followed category includes those with unresectable tumors), so Wilms' tumors may be diagnosed earlier in the United States than in the UK. This anomaly notwithstanding, direct comparisons with NWTS data are valid and revealing. First, we consider patients with FH tumors. For stages I, II, and III, 5-year EFS and overall survival rates for NWTS2 and 3 and UKW are virtually identical. In UKW, the same excellent outcome as for NWTS2 and 3 was achieved for stage I FH patients, regardless of age (Fig 4), by the intensive use of Vcr, without exposing children to the discomfort and toxicity, including an approximately 3% risk of hepatopathy (HTS), 2 of the much more emetogenic Act-D. Comparison of EFS and overall survival with NWTS3 suggests that salvage therapy for relapsing UKW FH stage I and II patients 22 ' 23 was as

8 RESULTS OF UKCCSG WILMS' STUDY 3 effective as in NWTS3, which suggests that more intensive Vcr therapy in UKW does not significantly alter the relapse pattern or the incidence of pleiotropic drug resistance in residual or recurrent disease. Treatment of stage II and III patients in UKW was similar to that in NWTS2 and 3, so the similar outcomes are not surprising, although they do suggest that pulsed every-3-week or every-6-week Act-D at a dose of.5 mg/m 2 is as effective, without undue toxicity, as fractionated Act-D. This observation confirms the results of a study performed by the Brazilian Wilms' Tumor Study Group, in which patients were randomized to receive either pulsed or fractionated Act-D. 24 The outcomes (EFS and overall survival) were almost identical, and the pulsed regimen was cheaper and socially less disruptive for the families. Results in UKW for patients with stage IV FH disease appear inferior to results in NWTS2 and 3. For instance, survival at 6 years for these patients in UKW was 65%, compared with 82% at 4 years in NWTS3 (P =.4). There is no evidence of selection bias for inclusion in the randomized trials of NWTS compared with UKW (D.M. Green, unpublished observation, June 994) and the composition of the chemotherapy regimens (in the case of NWTS3, the four-drug arm) are similar. The survival difference may therefore be explained by the following: () the longer duration of chemotherapy (5 months in NWTS3 v 2 months in UKW); (2) the uniform use of whole-lung irradiation in the NWTS trials; or (3) a combination of these, and possibly other, factors. A different perspective is that at least 5% of patients with pulmonary metastases can be cured without lung RT. In the International Society of Pediatric Oncology (SIOP) studies, 25 in which RT is not usually used, results are similar (83% 4-year EFS and overall survival) to those of NWTS3. 3 Pulmonary RT has adverse late effects, particularly when Doxo is also used. A randomized trial of pulmonary RT in stage IV FH disease is now needed, but the difficulties of organizing such a study may, in practice, be insurmountable. 26 Although the difference was not statistically significant (P =.7), the overall outcome for UH patients in UKW was superior to that of those treated in MRC2 (63% v 33% for stage I to III patients). However, overall results for UKW UH patients seem inferior to those achieved in NWTS3 3 (5% 6-year survival in UKW compared with 66% 4-year survival in NWTS3), although, again, the difference was not statistically significant (P =.7). As UKW chemotherapy is similar to the NWTS J regimen (used for 5% of their UH patients), possible explanations for the differences include the following: () delay or omission of RT, although it is of interest that 5% of all UKW stage UH II and III patients (all of whom would have received RT in the NWTS3 study) are disease-free without abdominal RT; (2) differing referral patterns between the two studies; or (3) both of these factors. However, our results indicate that abdominal RT is not always essential for the cure of UH disease, as long as chemotherapy is of sufficient intensity. Despite a systematic approach to second-look laparotomy, with multiple sampling biopsies, a number of patients with negative findings later relapsed at the primary tumor site. It seems that laparotomy at 9 to 2 weeks is not a sufficiently sensitive method to detect residual disease in these patients, and the procedure has now been discontinued by the UKCCSG. The overall EFS and overall survival rates for children treated in UKW (EFS, 77% [95% confidence interval, 73% to 82%]; overall survival, 83% [79% to 87%]) versus the most recently completed SIOP study (SIOP 6) are similar. Of 353 patients in SIOP 6 with nonmetastatic unilateral disease, 295 (83.5%) had stage I or II tumors, compared with 58 of 264 (59.8%) in UKW and 885 of,6 (76.3%) in NWTS3. 26 Thus, overall, 6 weeks of preoperative Vcr/Act-D chemotherapy downstages some Wilms' tumor patients. As a consequence, fewer patients in SIOP 6 than in UKW or NWTS3 received abdominal RT. Reduction in RT usage and dosage has also been effectively achieved in a large single-institution study 27 and in the second UKCCSG Wilms' Tumor Study (UKW2), (R. Shannon and J. Imeson for the UKCCSG Wilms' Tumor Study Committee, unpublished observation, January 994). Safe reduction of RT is now universally agreed to be a desirable goal in pediatric oncology. There is also concern about late cardiotoxicity following Doxo therapy.28,29 There was one documented death from cardiotoxicity, 8 years after diagnosis, in UKW, but a study of NWTS, 2, and 3 patients suggests an incidence of congestive cardiac failure, at 5 years, of.7% in children who have received Doxo compared with % in those who have not. In children who have also received pulmonary RT, the incidence is reported as 5%.29 In the third UKCCSG Wilms' Trial (UKW3), there is a headto-head randomized comparison, in children greater than 6 months old with nonmetastatic unilateral Wilms' tumor, of immediate nephrectomy versus 6 weeks of preoperative Vcr and Act-D. The goal of this study is to provide answers to the continuing transatlantic "dispute" concerning the best management strategy for patients with Wilms' tumor. 22 In conclusion, these final results of the UKW study

9 32 suggest that single-agent Vcr, without RT, is as effective in children with stage I FH tumors as the two-drug regimen still used in NWTS and SIOP studies; that pulsed Act-D is effective in stages II and III FH disease, which confirms the observation from the Brazilian trial 24 that fractionation of Act-D as in NWTS, 2, and 3 is unnecessary; and that, possibly because most of them did not PRITCHARD ET AL receive lung irradiation, children with stage IV disease fared worse than in NWTS3. ACKNOWLEDGMENT We thank the pediatric surgeons, radiotherapists, nurses, pharmacists, and other staff who helped in the management of these patients, together with the many pediatricians who shared care of the children and administered much of the chemotherapy. APPENDIX A Centers That Entered Patients No. of Patients UKCCSG Aberdeen St Bartholomew's Belfast 4 Birmingham 32 Bristol 2 Cambridge 5 Cardiff 2 Dublin, Eire 24 Edinburgh 8 Glasgow 9 Great Ormond Street, London Leeds 2 Leicester 6 Liverpool 7 Manchester 36 Newcastle 4 Nottingham 7 Royal Marsden 4 Sheffield Southampton Non-UKCCSG Cork, Eire 3 Oxford 3 Norfolk/Norwich 3 Oslo, Norway 2 Total 384 APPENDIX B. UKW Study Committee Chemotherapy P. Morris-Jones J. Pritchard Statistics and Data Management J. Barnes S. Cotterill J. Imeson Histopathology H.B. Marsden Radiotherapy D. Pearson Surgery D. Gough

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