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Wilms' tumor: Reduced-dose radiotherapy in advanced-stage Wilms' tumor with favorable histology
Im J Radolion On
Copyright
0360.3016190 $3.00 + .X3 ‘cl 1990 Pergamon Press plc
??Original Contribution
WILMS’ TUMOR: REDUCED-DOSE RADIOTHERAPY IN ADVANCED-STAGE WILMS’ TUMOR WITH FAVORABLE HISTOLOGY ROBERT L. TOBIN, M.D., ‘A JAMES DIANE
L. FAIRCLOUGH, EDWIN A.
DR.P.H.,~
C. DOUGLASS,
P. MAHESH
KUMAR,
H.
FONTANESI,
M.D.,’
LARRY
OMAR
HUSTU,
M.D.,’
M.D.,3
JUDITH
WILIMAS,
M.D.4
AND
JESSE
E.
WILLIAM
KUN, M.D.,’ J. PAO,
M.D.,’
M.D.,3
J. JENKINS,
M.D.’
Departments of ‘Radiation Oncology, ‘Biostatistics, 3Hematology-Oncology. ‘Surgery. and ‘Pathology. St. Jude Children’s Research Hospital. Memphis, TN: and the ‘Department of Radiation Oncology, Thomas Jefferson University Hospital, Philadelphia. PA Fifty-two children with favorable histology Wilms’ tumor who had residual abdominal disease (Surgical Stages III and IV) were treated from 1979 to 1988 on a protocol designed to assess the effectiveness of reduced radiation doses. All patients received three-agent chemotherapy, beginning within 1 week after surgery. To permit assessment of disease response to initial chemotherapy, radiation therapy was delayed for a median of 28 days after surgery (range, 14-71 days). Total doses of abdominal radiation were limited to 12 Gy, given as 150 cGy daily fractions; 18 patients with Stage IV disease received 12 Gy bilateral pulmonary irradiation. Two year disease-free survival was 85% and 71% for Stage III and IV, respectively (p = .24). Abdominal relapses occurred in 3 cases (5.7%). The interval between surgery and initiation of irradiation was not related to disease-free survival. Of several patient and disease-related factors analyzed, only patient age was related to outcome. Disease-free survival was 100% at 3 years for children under the age of 3 versus 78% for children greater than age 3 (p = .05). Reduced-dose abdominal radiotherapy in conjunction with multi-agent chemotherapy and surgery provided excellent disease control with minimal toxicity in advanced-stage, favorable histology Wilms’ tumor. Wilms’ tumor, Abdominal irradiation, Combination therapy.
spread, tumor rupture, lymph node metastases or anaplastic tumor histology. Total doses of 18-40 Gy were associated with significant late effects in early studies (7, 17, 19). In an effort to reduce morbidity while achieving optimal disease control. St. Jude Children’s Research Hospital (SJCRH) instituted a protocol in I979 using reduced-dose radiotherapy following surgery and threeagent chemotherapy. These patients have now been followed for a median of 5 years. Here we focus on treatment outcome and possibly related features in those children with advanced-stage, favorable histology Wilms‘ tumor.
INTRODUCTION Wilms’ tumor
accounts for approximately 8% of pediatric malignancies and is the most common primary renal tumor in children (13). The annual incidence of this malignancy is 7.8 per one million children under the age of 15, with about 500 new cases each year in the United States (25). The prognosis for these children has improved markedly with the development of effective multi-modality therapy and and more precise disease staging. The addition of routine postoperative radiation therapy in the 1950s increased ‘-year survival to 50%) ( 12) compared to 15-200/o survival rates associated with nephrectomy alone (7, 18). With the advent of effective multi-agent chemotherapy, 2-year relapse-free survival now approaches 8595% for limited disease (Stage I and II) and ranges from 60% to 85% for advanced disease (3, 8. 23. 24). Currently, radiation therapy in the treatment of Wilms’ tumor is reserved for patients with unfavorable prognostic factors, such as incomplete resection, intra-abdominal
METHODS
AND
MATERIALS
Putimts
A total of 140 consecutive patients were enrolled on the Wilms’ Tumor Protocol 3 at SJCRH between July 1979 and May 1988. The majority of these patients were referred with a presumptive diagnosis of Wilms’ tumor
Accepted for publication
Reprint requests to: James Fontanesi. M.D. .4cknoMl/rd~ernenf_The authors thank Christy Wright for editorial advice and Patsy Burnside for manuscript preparation. 867
22 February 1990.
868
I. J. Radiation
Oncology
0 Biology 0 Physics
based on radiographic studies. Initial evaluation included history and physical examination; EKG and echocardiogram; baseline hematologic, liver and renal profiles: and radiographic studies (chest X ray, excretory urograms. abdominal ultrasonography, and computerized tomographic scans of the chest and abdomen). Definitive diagnosis and staging were based on exploratory laparotomy (unilateral nephrectomy, biopsy of enlarged hilar and para-aortic lymph nodes, and palpation of the liver and contralateral kidney, with biopsy of any suspicious areas). Patients with limited stage disease (n = 74) unfavorable histology (n = 11). or with malignant rhabdoid tumor or clear cell sarcoma (n = 3) were excluded from the present analysis. Fifty-two of the 140 children enrolled had Stage III disease or Stage IV with Stage III abdominal disease as defined by the National Wilms’ Tumor Study (Tables 1 and 2). and favorable histology as described by Beckwith and Palmer (1). Treatment descriptions and outcome data are based on these 52 patients.
Chemotherapy, Chemotherapy with a minimum of three agents (dactinomycin. vincristine, and doxorubicin) was started within 1 week after surgical resection and continued for 12 months. Three patients received preoperative chemotherapy (one to three cycles) for bulky abdominal disease and two patients were given etoposide (VP- 16) during the perioperative period. The details of this regimen are available elsewhere (24).
Radiotherapy In previous protocols at SJCRH and other institutions. radiation therapy was started as soon as feasible after surgery (usually within 5-10 days). The protocol described here provided for an interval of 2-5 weeks after surgery to initiate external beam irradiation and permit analysis of chemotherapy response. Patients were treated on a 4 MeV linear accelerator to a total dose of 12 Gy abdominal radiation in 125- 150 cGy daily fractions. Children with Stage IV disease underwent bilateral pulmonary radiation (12 Gy in 8 fractions) 2-4 weeks after completion of abdominal radiotherapy. Abdominal radiation was delivered using AP-PA fields to include the whole abdomen (Fig. 1) until 1985, when treatment policy was modified to include only a local field for Stage III favorable histology patients who did not have diffuse peritoneal contamination from tumor rupture or spillage (Fig. 2). This modification affected 4 of the 52 patients studied here.
Statistical analysis The primary outcome variable, disease-free survival (DFS), was defined as the number of days between diagnosis and the date disease progression was first observed. A DFS of 0 days was assigned if disease control was not achieved. The log rank statistic test was used to assess the
October
1990. Volume 19. Number 4
Table 1. Wilms’ tumor
surgical staging*
Stage I Tumor limited to kidney, completely excised. Capsular surface intact: no tumor rupture: no residual tumor apparent beyond margins of excision Stage II Tumor extends beyond kidney but is completely excised. Regional extension of tumor and vessel infiltration. Tumor biopsied or local spillage of tumor confined to the flank. No residual tumor apparent at or beyond margins of excision Stage III Residual nonhematogenous tumor confined to the abdomen, plus one or more of the following findings: lymph node involvement of hilus, periaortic chains or beyond; diffuse peritoneal contamination by tumor spillage: peritoneal implants of tumor: tumor extends beyond surgical margins either microscopically or macroscopically: tumor not completely resectable because of local infiltration into vital structures Stage IV Deposits beyond Stage III (e.g.. lung. liver. bone, brain) Stage V Bilateral renal involvement at diagnosis * Criteria
of the National
relationship between ment characteristics.
Wilms’ Tumor
DFS and patient,
Study (8).
disease. and treat-
RESULTS At a median follow-up of 60 months (range 8-l 10 months), 2-year disease-free survival for patients with Stage III and Stage IV favorable histology Wilms’ tumor is 85% (SE = 6) and 7 1% (SE = 1 1). respectively (I_’= .24). Overall. control of abdominal disease was achieved in 49 of 52 patients.
Table 2. Patient
characteristics
Sex Male Female Age O-36 mo >36 mo Race White Non white Preoperative tumor Rupture Operative tumor spill Diffuse Local Intra-abdominal tumor Spread Positive lymph nodes
and operative
findings
Stage III (N = 34)
Stage IV (N = 18)
15
11
I9
7
IO 24
2 I6
25 9
12 6
I1
2
4 4
3 I
8
8
I6
8
Wilms’ tumor
869
0 R. L. TOBIN ef ul.
operative rupture, lymph node status, renal vein thrombosis. operative margin status, intrarenal microvascular invasion, and intra-abdominal spread. The only significant relationship was that of patient age and 2-year DFS, which was 100% in patients I 36 months at time of diagnosis compared to 76% in those I 36 months (p = .05). All relapses over the study period occurred in children older than 36 months at diagnosis (see Table 3). Delay > 14 days from completion of surgery to initiation of irradiation was not related to disease-free survival @ > .05).
Toxicit?> Acute toxicity during abdominal irradiation was limited to mild nausea and vomiting, which was controlled with medication. In no case did toxicity necessitate treatment interruption or dose modification. Postradiotherapy bowel-related complications were seen in 3 of 52 patients. Two of these children required surgical intervention for lysis of adhesions: in the third case, complications resolved with nasogastric suction and bowel rest. There has been no evidence of pulmonary toxicity. with no reported radiation pneumonitis. pleural effusion, or pneumonia, No cardiovascular, hepatic, or renal toxicities have been reported, although further follow-up is required.
Fig. I. Whole-abdomen 1979 to 1985.
radiation
(AP-PA
Fields),
used from
Stuge III disease Abdominal disease control was achieved in all but one of the Stage III patients (97%). Four of the 34 patients experienced pulmonary relapse and one patient relapsed in the abdomen (Table 3). The two patients in whom salvage therapy was successful had experienced pulmonary relapses more than 18 months after diagnosis. Thus, the success of salvage therapy may be related to the length of disease-free survival prior to relapse, although patient numbers are too small to permit statistical analysis.
Stuge IT,’disease Abdominal control was achieved in 16 of 18 patients with Stage IV disease (88%). Pulmonary disease was controlled with 12 Gy total doses of radiation in 14 patients (77%). Five Stage IV patients experienced relapse 7 to 16 months posttreatment (see Table 3). Pulmonary relapse was seen in 4 patients, two of whom also had abdominal relapse; a single patient had an isolated relapse in the brain. Salvage therapy was successful only in the latter patient, who had a 16-month disease-free interval before relapse.
Prognostic variables The following factors were examined to assess their relationship to disease-free survival: age, sex, disease stage,
Fig. 2. Modified radiation field. including and para-aortic lymph nodes.
tumor
bed and hilar
1.J. Radiation
870
Table 3. Characteristics
Age
October 1990. Volume 19. Number
0 Biology 0 Physics
Oncology
of patients
4
with relapsed disease
s
DFI*
F F M M M
8.3 3.4 8.3 32 20
Pulmonary Pulmonary Abdominal
Expired
Pulmonary Pulmonary
NED at 33 mos (in surgical resection plus RT) NED at 44 mos (chemotherapy plus RT)
M
7
F F M M
16 9
Pulmonary Pulmonary Abdominal Brain
+ pulmonary
Expired Expired Expired
+ pulmonary
NED at 72 mo (surgical resection Expired
Relapse
Result
Stage III
1 2 3 4 5 Stage IV 6 I 8 9 10 * Disease-free
interval.
16 I?
Abdominal
Expired Expired
plus RT)
in months.
Height, weight, and body habitus were carefully monitored and plotted at initial evaluation and follow-up examinations. There have been no incidences of scoliosis, soft tissue defects. or significant height changes. However, the follow-up is not yet sufficient to permit a definitive assessment of late effects. Of the five female patients who are now age 12 or older, two have normal menstrual function and three are receiving estrogen therapy (Premarin) for delayed development of secondary sexual characteristics.
DISCUSSION Radiation therapy has played an important role in reducing abdominal recurrences in advanced-stage Wilms’ tumor (6, 9, 10, 15, 16. 21). The current use of radiotherapy is based on the risk of abdominal recurrence. as identified by surgical and pathologic findings in multicenter trials (2-5). The 3-year disease-free survival of 88% for patients with Stage III disease and favorable histology and the low frequency of isolated abdominal recurrence (l/34) found in the present study are encouraging. These findings are similar to those in the recent report of the third National Wilms’ Tumor Study (NWTS-3) (8). In the NWTS-3 trial, there was a 5% incidence of abdominal relapse in Stage III favorable histology patients: 2-year disease-free survival ranged from 7 1% to 86%. Results for favorable histology Stage IV disease (72% to 80% 2-year disease-free survival and 11% abdominal relapse) also accord with those described here. The majority of patients treated in the present study received whole abdominal irradiation; 4 of 52 were treated on a modified protocol with the same total dose ( 12 Gy) using a hemiabdominal field. To date, none of the patients treated with local field irradiation have developed abdominal or distant relapses. As in previous series. the majority of relapses in this study represented metastatic disease to the lungs. Salvage
therapy was successful in three of four patients relapsing in distant sites after a disease-free interval > 12 months. None of the three children who developed isolated pulmonary relapses before 12 months responded to salvage therapy. Thus, a disease-free interval longer than 12 months may be related to an increased likelihood of salvage. The three patients in our series who had abdominal relapses have all succumbed to their disease. Poor survival has been associated with persistent or relapsed abdominal disease in several prior reports (6, 16, 32). Previous data from NWTS suggested that survival was poorer in patients older than 24 months and in cases when irradiation was initiated more than IO days following nedisease-free survival was phrectomy. In our series, _>-vear _ lOOR in patients diagnosed at age 36 months or younger. Unlike early NWTS data. we found no statistically significant effect of delaying radiation for up to 7 1 days following nephrectomy (11, 20). The treatment regimen was well tolerated, with only 3 of 52 patients experiencing gastrointestinal toxicity. With a median follow-up of 5 years, there have been no treatment-related deaths and no evidence of pulmonary, cardiovascular, renal, hepatic, soft tissue. or growth abnormalities. Further follow-up is required to assess late effects, including delayed sexual development and effects on fertility. This non-randomized, single-institution study of the effects of reduced therapy for Wilms’ tumor produced findings similar to those reported in multicenter randomized trials (5,8). Previous NWTS studies and SJCRH protocols have assessed the use of less aggressive chemo-radiotherapy. As the number of survivors of Wilms’ tumor increases, reduction of late effects is assuming greater importance. The present study demonstrates that the radiation dose to the abdominal cavity can be reduced without compromising survival or increasing the risk of abdominal recurrence in patients with favorable histology tumors who
Wilms’ tumor
receive
postoperative
chemotherapy.
Combined
therapy
is well tolerated and we are hopeful that the late sequelae previously related to higher radiation doses ( 14, 17. 19)
0 R. L. TOBIN et al.
871
will be substantially reduced or eliminated, an outcome that may be enhanced by the use of hemiabdominal irradiation in selected subgroups of patients.
REFERENCES 1. Beckwith, J. B.; Palmer. N. F. Histopathology and prognosis of Wilms’ tumors: results from the first National Wilms’ Tumor Study. Cancer 4 1:1937- 1948; 1978. 2. Breslow. N.: Churchill, G.: Beckwith. J. B.; Fernbach. D. J.: Othersen. H. B.: Tefft. M.; D’Angio. G. J. Prognosis for Wilms’ tumor patients with non-metastatic disease at diagnosis: result of the second National Wilms’ Tumor Study. J. Clin. Oncol. 3:521-531: 1985. 3. Breslow, N. E.: Churchill, G.; Nesmith. B.: Thomas, P. R. M.: Beckwith. J. B.; Othersen, H. B.; D’Angio, G. J. Clinicopathologic features and prognosis for Wilms’ tumor patients with metastases at diagnosis. Cancer 582501-25 I 1; 1986. 4. Breslow, N. E.: Palmer, N. F.: Hill, L. R.: Buring. J.; D’Angio. G. J. Wilms’ tumor: prognostic factors for patients without metastases at diagnosis: results of the National Wilms’ Tumor Study. Cancer 4 I : 1577- 1589; 1978. 5. Burgers. J. M. V.; Tournade, M. F.: Bey, P.: Burger. D.; Carli, M.: Delemarre. J. F.: Harms, D.; Jereb, B.; de Kraker. J.: Lemerle, J. Abdominal recurrences in Wilms’ tumours: a report from the SIOP Wilms’ tumour trials and studies. Radiother. Oncol. 5: 175-182: 1986. 6. Cassady, J. R.; Jaffe, N.; Filler. R. R. The increasing importance of radiation therapy in the improved prognosis of children with Wilms’ tumor. Cancer 39:825-829: 1977. 7. Cassady, J. R.; Tefft. M.: Filler, R. M.: Jaffe. N.; Paed. D.; Hellman. S. Considerations in the radiation therapy of Wilms’ tumor. Cancer 32:598-608; 1973. 8. D’Angio. G. J.; Breslow. N.: Beckwith. B.: Evans, A.: Baum, E.; delorimier. A.: Fernbach, D.: Hrabovsky. E.: Jones. B.: Kelalis, P.; Othersen, B.; Tefft, M.; Thomas, P. R. M. Treatment of Wilms’ tumor: results of the third National Wilms’ Tumor Study. Cancer 64:349-360: 1989. 9. D’Angio. G. J.: Evans, A. E.; Breslow, N.; Beckwith, B.: Bishop, H.; Feigl. P.: Goodwin, W.: Leape, L. L.; Sinks. L. F.: Sutow, W.: Tefft, M.: Wolff, J. The treatment of Wilms’ tumor: results of the National Wilms’ Tumor Study. Cancer 38:633-646; 1976. 10. D’Angio, G. J.; Evans, A. E.; Breslow. N.; Beckwith. B.: Bishop, H.; Farewell. V.; Goodwin, W.: Leape, L.: Palmer, N.; Sinks, L.; Sutow, W.; Tefft. M.: Wolff, J. Results of the Second National Wilms’ Tumor Study. Cancer 47:2302231 1; 1981. I I. D’Angio, G. J.: Tefft. M.; Breslow. N.: Meyer, J. A. Radiation therapy of Wilms’ tumor: results according to dose, field, post-operative timing and histology. Int. J. Radiat. Oncol. Biol. Phys. 4:769-780: 1978.
12. Gross, R. E.: Neuhauser, E. B. D. Treatment of mixed tumors of the kidney in children. Pediatrics 6:843-852: 1950. 13. Hanson, M. R.; Halvihill, J. J. Epidemiology of cancer in the young. In: Levine, A. S., ed. Cancer in the young, 1st edition. New York: Masson Publishing: 1982:3. 14. Heaston. D. K.: Libshitz. H. I.; Chan, R. C. Skeletal effects of megavoltage irradiation in survivors of Wilms’ tumor. Am. J. Roentgenol. 133:389-395; 1979. 15. Hussey, D. H.; Castrol, J. R.; Sullivan, M. P.: Sutow, W. W. Radiation therapy in management of Wilms’ tumor. Radiology 10 I :663-668: I97 1. 16. Jeal, P. N.; Jenkin. R. D. Abdominal irradiation in the treatment of Wilms’ tumor. Int. J. Radiat. Oncol. Biol. Phys. 6:655-66 1; 1980. 17. Oliver, J. H.; Gluck, G.: Gledhill, R. B.; Chevalier, L. Musculoskeletal deformities following treatment of Wilms’ tumour. Can. Med. Assoc. J. I 19:459-464: 1978. 18. Priestley, J. F.: Schultz. T. L. The treatment of Wilms’ tumor. J. Urol. 47:7-12; 1942. 19. Tefft. M. Radiation related toxicities in National Wilms’ Tumor Study Number I. Int. J. Radiat. Oncol. Biol. Phys. 2:455-463; 1977. 20. Teth, M.; D’Angio. G. J.; Beckwith, B.; Farewell. V.: Meyer, J. A. Patterns of intra-abdominal relapse (IAR) in patients with Wilms’ tumor who received radiation: analysis by histopathology. A report of the National Wilms’ Tumor Studies I and 2 (NWTS-I & 2). Int. J. Radiat. Oncol. Biol. Phys. 6:663-667; 1980. 21. Tefft, M.; D’Angio, G. J.; Grant, W., III. Postoperative radiation therapy for residual Wilms’ tumor: review of Group III patients in the national Wilms’ Tumor Study. Cancer 37:2768-2772: 1976. 22. Thomas. P. R. M.; Tefft, M.: Farewell, V. T.: Norkool, P.: Storer, B.; D’Angio. G. J. Abdominal relapses in irradiated Second National Wilms’ Tumor Study patients. J. Clin. Oncol. 2:1098-l 101: 1984. 23. Thomas, P. R. M.: Tefft. M.: Farewell. E. T.: Norkool. P. Validation of the radiation dose reduction in the Third National Wilms’ Tumor Study (Abstr.). Proc. Am. Assoc. Cancer Res. 29:227; 1988. 24. Wilimas, J. A.: Douglass, E. C.: Lewis, S.: Fairclough. D.: Fullen. G.: Parham, D.; Kumar. A. P. M.; Hustu, H. 0.: Fleming, I. Reduced therapy for Wilms’ Tumor: analysis oftreatment results from a single institution. J. Clin. Oncol. 6:1630-1635: 1988. 25. Young, J. L., Jr.: Miller, R. W. Incidence of malignant tumors in U.S. children. J. Pediatr. 86:254-258; 1975.
Copyright
0360.3016190 $3.00 + .X3 ‘cl 1990 Pergamon Press plc
??Original Contribution
WILMS’ TUMOR: REDUCED-DOSE RADIOTHERAPY IN ADVANCED-STAGE WILMS’ TUMOR WITH FAVORABLE HISTOLOGY ROBERT L. TOBIN, M.D., ‘A JAMES DIANE
L. FAIRCLOUGH, EDWIN A.
DR.P.H.,~
C. DOUGLASS,
P. MAHESH
KUMAR,
H.
FONTANESI,
M.D.,’
LARRY
OMAR
HUSTU,
M.D.,’
M.D.,3
JUDITH
WILIMAS,
M.D.4
AND
JESSE
E.
WILLIAM
KUN, M.D.,’ J. PAO,
M.D.,’
M.D.,3
J. JENKINS,
M.D.’
Departments of ‘Radiation Oncology, ‘Biostatistics, 3Hematology-Oncology. ‘Surgery. and ‘Pathology. St. Jude Children’s Research Hospital. Memphis, TN: and the ‘Department of Radiation Oncology, Thomas Jefferson University Hospital, Philadelphia. PA Fifty-two children with favorable histology Wilms’ tumor who had residual abdominal disease (Surgical Stages III and IV) were treated from 1979 to 1988 on a protocol designed to assess the effectiveness of reduced radiation doses. All patients received three-agent chemotherapy, beginning within 1 week after surgery. To permit assessment of disease response to initial chemotherapy, radiation therapy was delayed for a median of 28 days after surgery (range, 14-71 days). Total doses of abdominal radiation were limited to 12 Gy, given as 150 cGy daily fractions; 18 patients with Stage IV disease received 12 Gy bilateral pulmonary irradiation. Two year disease-free survival was 85% and 71% for Stage III and IV, respectively (p = .24). Abdominal relapses occurred in 3 cases (5.7%). The interval between surgery and initiation of irradiation was not related to disease-free survival. Of several patient and disease-related factors analyzed, only patient age was related to outcome. Disease-free survival was 100% at 3 years for children under the age of 3 versus 78% for children greater than age 3 (p = .05). Reduced-dose abdominal radiotherapy in conjunction with multi-agent chemotherapy and surgery provided excellent disease control with minimal toxicity in advanced-stage, favorable histology Wilms’ tumor. Wilms’ tumor, Abdominal irradiation, Combination therapy.
spread, tumor rupture, lymph node metastases or anaplastic tumor histology. Total doses of 18-40 Gy were associated with significant late effects in early studies (7, 17, 19). In an effort to reduce morbidity while achieving optimal disease control. St. Jude Children’s Research Hospital (SJCRH) instituted a protocol in I979 using reduced-dose radiotherapy following surgery and threeagent chemotherapy. These patients have now been followed for a median of 5 years. Here we focus on treatment outcome and possibly related features in those children with advanced-stage, favorable histology Wilms‘ tumor.
INTRODUCTION Wilms’ tumor
accounts for approximately 8% of pediatric malignancies and is the most common primary renal tumor in children (13). The annual incidence of this malignancy is 7.8 per one million children under the age of 15, with about 500 new cases each year in the United States (25). The prognosis for these children has improved markedly with the development of effective multi-modality therapy and and more precise disease staging. The addition of routine postoperative radiation therapy in the 1950s increased ‘-year survival to 50%) ( 12) compared to 15-200/o survival rates associated with nephrectomy alone (7, 18). With the advent of effective multi-agent chemotherapy, 2-year relapse-free survival now approaches 8595% for limited disease (Stage I and II) and ranges from 60% to 85% for advanced disease (3, 8. 23. 24). Currently, radiation therapy in the treatment of Wilms’ tumor is reserved for patients with unfavorable prognostic factors, such as incomplete resection, intra-abdominal
METHODS
AND
MATERIALS
Putimts
A total of 140 consecutive patients were enrolled on the Wilms’ Tumor Protocol 3 at SJCRH between July 1979 and May 1988. The majority of these patients were referred with a presumptive diagnosis of Wilms’ tumor
Accepted for publication
Reprint requests to: James Fontanesi. M.D. .4cknoMl/rd~ernenf_The authors thank Christy Wright for editorial advice and Patsy Burnside for manuscript preparation. 867
22 February 1990.
868
I. J. Radiation
Oncology
0 Biology 0 Physics
based on radiographic studies. Initial evaluation included history and physical examination; EKG and echocardiogram; baseline hematologic, liver and renal profiles: and radiographic studies (chest X ray, excretory urograms. abdominal ultrasonography, and computerized tomographic scans of the chest and abdomen). Definitive diagnosis and staging were based on exploratory laparotomy (unilateral nephrectomy, biopsy of enlarged hilar and para-aortic lymph nodes, and palpation of the liver and contralateral kidney, with biopsy of any suspicious areas). Patients with limited stage disease (n = 74) unfavorable histology (n = 11). or with malignant rhabdoid tumor or clear cell sarcoma (n = 3) were excluded from the present analysis. Fifty-two of the 140 children enrolled had Stage III disease or Stage IV with Stage III abdominal disease as defined by the National Wilms’ Tumor Study (Tables 1 and 2). and favorable histology as described by Beckwith and Palmer (1). Treatment descriptions and outcome data are based on these 52 patients.
Chemotherapy, Chemotherapy with a minimum of three agents (dactinomycin. vincristine, and doxorubicin) was started within 1 week after surgical resection and continued for 12 months. Three patients received preoperative chemotherapy (one to three cycles) for bulky abdominal disease and two patients were given etoposide (VP- 16) during the perioperative period. The details of this regimen are available elsewhere (24).
Radiotherapy In previous protocols at SJCRH and other institutions. radiation therapy was started as soon as feasible after surgery (usually within 5-10 days). The protocol described here provided for an interval of 2-5 weeks after surgery to initiate external beam irradiation and permit analysis of chemotherapy response. Patients were treated on a 4 MeV linear accelerator to a total dose of 12 Gy abdominal radiation in 125- 150 cGy daily fractions. Children with Stage IV disease underwent bilateral pulmonary radiation (12 Gy in 8 fractions) 2-4 weeks after completion of abdominal radiotherapy. Abdominal radiation was delivered using AP-PA fields to include the whole abdomen (Fig. 1) until 1985, when treatment policy was modified to include only a local field for Stage III favorable histology patients who did not have diffuse peritoneal contamination from tumor rupture or spillage (Fig. 2). This modification affected 4 of the 52 patients studied here.
Statistical analysis The primary outcome variable, disease-free survival (DFS), was defined as the number of days between diagnosis and the date disease progression was first observed. A DFS of 0 days was assigned if disease control was not achieved. The log rank statistic test was used to assess the
October
1990. Volume 19. Number 4
Table 1. Wilms’ tumor
surgical staging*
Stage I Tumor limited to kidney, completely excised. Capsular surface intact: no tumor rupture: no residual tumor apparent beyond margins of excision Stage II Tumor extends beyond kidney but is completely excised. Regional extension of tumor and vessel infiltration. Tumor biopsied or local spillage of tumor confined to the flank. No residual tumor apparent at or beyond margins of excision Stage III Residual nonhematogenous tumor confined to the abdomen, plus one or more of the following findings: lymph node involvement of hilus, periaortic chains or beyond; diffuse peritoneal contamination by tumor spillage: peritoneal implants of tumor: tumor extends beyond surgical margins either microscopically or macroscopically: tumor not completely resectable because of local infiltration into vital structures Stage IV Deposits beyond Stage III (e.g.. lung. liver. bone, brain) Stage V Bilateral renal involvement at diagnosis * Criteria
of the National
relationship between ment characteristics.
Wilms’ Tumor
DFS and patient,
Study (8).
disease. and treat-
RESULTS At a median follow-up of 60 months (range 8-l 10 months), 2-year disease-free survival for patients with Stage III and Stage IV favorable histology Wilms’ tumor is 85% (SE = 6) and 7 1% (SE = 1 1). respectively (I_’= .24). Overall. control of abdominal disease was achieved in 49 of 52 patients.
Table 2. Patient
characteristics
Sex Male Female Age O-36 mo >36 mo Race White Non white Preoperative tumor Rupture Operative tumor spill Diffuse Local Intra-abdominal tumor Spread Positive lymph nodes
and operative
findings
Stage III (N = 34)
Stage IV (N = 18)
15
11
I9
7
IO 24
2 I6
25 9
12 6
I1
2
4 4
3 I
8
8
I6
8
Wilms’ tumor
869
0 R. L. TOBIN ef ul.
operative rupture, lymph node status, renal vein thrombosis. operative margin status, intrarenal microvascular invasion, and intra-abdominal spread. The only significant relationship was that of patient age and 2-year DFS, which was 100% in patients I 36 months at time of diagnosis compared to 76% in those I 36 months (p = .05). All relapses over the study period occurred in children older than 36 months at diagnosis (see Table 3). Delay > 14 days from completion of surgery to initiation of irradiation was not related to disease-free survival @ > .05).
Toxicit?> Acute toxicity during abdominal irradiation was limited to mild nausea and vomiting, which was controlled with medication. In no case did toxicity necessitate treatment interruption or dose modification. Postradiotherapy bowel-related complications were seen in 3 of 52 patients. Two of these children required surgical intervention for lysis of adhesions: in the third case, complications resolved with nasogastric suction and bowel rest. There has been no evidence of pulmonary toxicity. with no reported radiation pneumonitis. pleural effusion, or pneumonia, No cardiovascular, hepatic, or renal toxicities have been reported, although further follow-up is required.
Fig. I. Whole-abdomen 1979 to 1985.
radiation
(AP-PA
Fields),
used from
Stuge III disease Abdominal disease control was achieved in all but one of the Stage III patients (97%). Four of the 34 patients experienced pulmonary relapse and one patient relapsed in the abdomen (Table 3). The two patients in whom salvage therapy was successful had experienced pulmonary relapses more than 18 months after diagnosis. Thus, the success of salvage therapy may be related to the length of disease-free survival prior to relapse, although patient numbers are too small to permit statistical analysis.
Stuge IT,’disease Abdominal control was achieved in 16 of 18 patients with Stage IV disease (88%). Pulmonary disease was controlled with 12 Gy total doses of radiation in 14 patients (77%). Five Stage IV patients experienced relapse 7 to 16 months posttreatment (see Table 3). Pulmonary relapse was seen in 4 patients, two of whom also had abdominal relapse; a single patient had an isolated relapse in the brain. Salvage therapy was successful only in the latter patient, who had a 16-month disease-free interval before relapse.
Prognostic variables The following factors were examined to assess their relationship to disease-free survival: age, sex, disease stage,
Fig. 2. Modified radiation field. including and para-aortic lymph nodes.
tumor
bed and hilar
1.J. Radiation
870
Table 3. Characteristics
Age
October 1990. Volume 19. Number
0 Biology 0 Physics
Oncology
of patients
4
with relapsed disease
s
DFI*
F F M M M
8.3 3.4 8.3 32 20
Pulmonary Pulmonary Abdominal
Expired
Pulmonary Pulmonary
NED at 33 mos (in surgical resection plus RT) NED at 44 mos (chemotherapy plus RT)
M
7
F F M M
16 9
Pulmonary Pulmonary Abdominal Brain
+ pulmonary
Expired Expired Expired
+ pulmonary
NED at 72 mo (surgical resection Expired
Relapse
Result
Stage III
1 2 3 4 5 Stage IV 6 I 8 9 10 * Disease-free
interval.
16 I?
Abdominal
Expired Expired
plus RT)
in months.
Height, weight, and body habitus were carefully monitored and plotted at initial evaluation and follow-up examinations. There have been no incidences of scoliosis, soft tissue defects. or significant height changes. However, the follow-up is not yet sufficient to permit a definitive assessment of late effects. Of the five female patients who are now age 12 or older, two have normal menstrual function and three are receiving estrogen therapy (Premarin) for delayed development of secondary sexual characteristics.
DISCUSSION Radiation therapy has played an important role in reducing abdominal recurrences in advanced-stage Wilms’ tumor (6, 9, 10, 15, 16. 21). The current use of radiotherapy is based on the risk of abdominal recurrence. as identified by surgical and pathologic findings in multicenter trials (2-5). The 3-year disease-free survival of 88% for patients with Stage III disease and favorable histology and the low frequency of isolated abdominal recurrence (l/34) found in the present study are encouraging. These findings are similar to those in the recent report of the third National Wilms’ Tumor Study (NWTS-3) (8). In the NWTS-3 trial, there was a 5% incidence of abdominal relapse in Stage III favorable histology patients: 2-year disease-free survival ranged from 7 1% to 86%. Results for favorable histology Stage IV disease (72% to 80% 2-year disease-free survival and 11% abdominal relapse) also accord with those described here. The majority of patients treated in the present study received whole abdominal irradiation; 4 of 52 were treated on a modified protocol with the same total dose ( 12 Gy) using a hemiabdominal field. To date, none of the patients treated with local field irradiation have developed abdominal or distant relapses. As in previous series. the majority of relapses in this study represented metastatic disease to the lungs. Salvage
therapy was successful in three of four patients relapsing in distant sites after a disease-free interval > 12 months. None of the three children who developed isolated pulmonary relapses before 12 months responded to salvage therapy. Thus, a disease-free interval longer than 12 months may be related to an increased likelihood of salvage. The three patients in our series who had abdominal relapses have all succumbed to their disease. Poor survival has been associated with persistent or relapsed abdominal disease in several prior reports (6, 16, 32). Previous data from NWTS suggested that survival was poorer in patients older than 24 months and in cases when irradiation was initiated more than IO days following nedisease-free survival was phrectomy. In our series, _>-vear _ lOOR in patients diagnosed at age 36 months or younger. Unlike early NWTS data. we found no statistically significant effect of delaying radiation for up to 7 1 days following nephrectomy (11, 20). The treatment regimen was well tolerated, with only 3 of 52 patients experiencing gastrointestinal toxicity. With a median follow-up of 5 years, there have been no treatment-related deaths and no evidence of pulmonary, cardiovascular, renal, hepatic, soft tissue. or growth abnormalities. Further follow-up is required to assess late effects, including delayed sexual development and effects on fertility. This non-randomized, single-institution study of the effects of reduced therapy for Wilms’ tumor produced findings similar to those reported in multicenter randomized trials (5,8). Previous NWTS studies and SJCRH protocols have assessed the use of less aggressive chemo-radiotherapy. As the number of survivors of Wilms’ tumor increases, reduction of late effects is assuming greater importance. The present study demonstrates that the radiation dose to the abdominal cavity can be reduced without compromising survival or increasing the risk of abdominal recurrence in patients with favorable histology tumors who
Wilms’ tumor
receive
postoperative
chemotherapy.
Combined
therapy
is well tolerated and we are hopeful that the late sequelae previously related to higher radiation doses ( 14, 17. 19)
0 R. L. TOBIN et al.
871
will be substantially reduced or eliminated, an outcome that may be enhanced by the use of hemiabdominal irradiation in selected subgroups of patients.
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