Original article
Annals of Oncology 13: 944–948, 2002 DOI: 10.1093/annonc/mdf131
Treatment of childhood Wilms’ tumor without radiotherapy in Nicaragua F. Baez1*, F. Fossati Bellani 2, E. Ocampo1, V. Conter3, A. Flores1, T. Gutierrez1, A. Malta1, G. Mendez 1, C. Pacheco 1, R. Palacios1, A. Sala3, S. Galimberti3, F. Cavalli4 & G. Masera3 1 Manuel de Jaesus Rivera Hospital, La Mascota, Managua, Nicaragua; 2Istituto Nazionale Tumori, Milan, Italy; 3 Pediatric Department, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy; 4Department of Oncology, San Giovanni Hospital, Bellinzona, Switzerland
Received 15 June 2001; revised 7 November 2001; accepted 12 December 2001
Background: Recent trends in therapeutic strategies for Wilms’ tumor are based on an attempt to
Introduction The treatment of Wilms’ tumor (WT) is one of the remarkable success stories in pediatric oncology, and standard therapy with surgery, chemotherapy (CT) and radiotherapy (RT) achieves a long-term event-free survival (EFS) of >80% [1–6]. Recent therapeutic trends have attempted to reduce or omit RT, with the aim of reducing or avoiding severe late effects related to irradiation, including second malignancies. Therefore, it is worth reporting on the experience of treating WT in a country with poor health care resources, where RT was not available and where children were treated by nephrectomy plus CT. Data in the literature on treatment of WT in such countries are scant and scarcely informative [7, 8].
*Correspondence to: Dr F. Baez, Hospital Infantil Manuel de Jaesus Rivera, La Mascota, Managua, Nicaragua. Tel/Fax: +505-2-894984; E-mail:
[email protected] © 2002 European Society for Medical Oncology
Since 1990, thanks to an alliance project involving the La Mascota Children’s Hospital of Managua (Nicaragua), the Pediatric Department of Monza Hospital, Monza, Italy and of Istituto Nazionale Tumori, Milan, Italy and the Oncology Department of Bellinzona Hospital, Switzerland, treatment has been provided free of charge to all children affected by malignant diseases in Nicaragua, as previously reported [9, 10]. The La Mascota Children’s Hospital of Managua is the only pediatric oncology center in Nicaragua, where children are referred from the whole of the Country. Until 1995, RT facilities were not available in Nicaragua and patients with neoplastic diseases, including WT, were treated with CT and/or surgery. Furthermore, due to the lack of adequate resources, histopathological sampling for WT, as routinely done in Western countries, was not performed. This paper describes the clinical and histological features and the therapeutic results obtained in 37 children with WT diagnosed between 1991 and 1996, and treated with CT and surgery at La Mascota Hospital.
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reduce or omit radiotherapy (RT) in a sizable fraction of patients. We report here the clinical and histological features as well as the results obtained in 37 children (23 males, 14 females; median age at diagnosis 3 years, range 0.8–8 years) diagnosed between 1991 and 1996, and treated with chemotherapy (CT) and surgery at La Mascota Hospital, Managua, Nicaragua. Patients and methods: Patients were grouped as follows: those who underwent surgery at diagnosis (group A, n = 4), patients who received preoperative CT because of large tumor size (group B, n = 27), lung metastases (n = 5) or bilateral disease (n = 1) (group C, n = 6). Treatment consisted of vincristine (VCR) and actinomycin-D (ACTD) for 24 weeks in group A, and of VCR, ACTD and adriamycin for 68 weeks in groups B and C. Histology was classified as favorable in 30 patients (81%), unfavorable in six patients (all of group B) and unknown in one. Results: With a median follow-up time of 6.4 years the event-free survival for the whole group was 80.1% ± 6.8 (SE). No event occurred beyond 5 years of diagnosis. Conclusions: These results suggest that RT does not appear necessary for the majority of patients, and that an excellent surgical approach associated with an intensive CT schedule can control the disease, even in the absence of adequate information on the intra-abdominal tumor extent. Key words: childhood, low-income countries, therapy, Wilms’ tumor
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Table 1. Treatment protocol of Wilms’ tumor Group
Pre-surgery chemotherapy
Post-surgery Phase 1
Phase 2 2
Phase 3 2
A
–
VCR 1.5 mg/m + ACTD 20 µg/kg weekly for eight cycles
VCR 1.5 mg/m + ACTD 20 µg/kg every 2 weeks for eight cycles
–
B and C
VCR 1.5 mg/m 2 + ACTD 20 µg/kg weekly for four cycles
VCR 1.5 mg/m2 + ACTD 20 µg/kg weekly for eight cycles
VCR 1.5 mg/m2 + ACTD 20 µg/kg alternated to VCR 1.5 mg/m2 + ACTD 20 µg/kg + ADR 30 mg/m2 every 2 weeks for eight cycles
VCR 1.5 mg/m2 + ACTD 20 µg/kg alternated to VCR 1.5 mg/m2 + ACTD 20 µg/kg + ADR 30 mg/m2 every 4 weeks for 10 cycles
ACTD, actinomycin-D; ADR, adriamycin; VCR, vincristine.
Patients and methods
Because of scant technical resources, complete tumor sampling with adequate pathological staging based on National Wilms’ Tumor Study (NWTS) criteria [11] was not performed. Therefore, in the absence of a correct stage assessment, patients were grouped according to the therapeutic approach applied, as follows: group A, four patients with a small tumor, amenable to primary surgery; group B, 27 patients who received preoperative CT to reduce a large tumor; group C, six patients who also received preoperative CT, five because of lung metastases (stage IV according to the NWTS classification) and one because of bilateral disease (NWTS stage V). Five of 37 patients (14%) presented with lung metastases, which is in keeping with data in the literature [2, 4]. All the surgical operations, involving laparotomy, were performed by the same surgeon, and all histological samples obtained at La Mascota Hospital were evaluated by the same two pathologists. The histological diagnosis, performed according to the NWTS criteria [12], showed that six patients in group B and C had an unfavorable histology (two anaplastic WTs, four rhabdoid tumors). As shown in Table 1, patients of group A did not receive pre-surgery CT; treatment after surgery consisted of vincristine (VCR) 1.5 mg/m2 and actinomycin-D (ACTD) 20 µg/kg, weekly for 8 weeks and then every 2 weeks for 8 weeks (24 weeks total duration). Patients of groups B and C were administered with preoperative CT with VCR and ACTD for 4 weeks; after surgery VCR and ACTD were given weekly for 8 weeks; thereafter, alternating cycles of VCR and ACTD or VCR, ACTD and adriamycin (ADR) 30 mg/m2, were given every 2 weeks for eight cycles, then every 4 weeks for 10 cycles (68 weeks total duration). ADR was added to improve local and systemic disease control, since RT was not available and a thorough diagnostic work-up was not performed. All patients were admitted to the hospital for diagnostic work-up and administration of the first cycle of treatment, whereas the remaining cycles were routinely given on an outpatient basis. Tumor response in the patients given preoperative CT was assessed by clinical examination and ultrasound scanning (plus chest X-ray in patients with lung metastases). EFS was estimated according to the Kaplan–Meier method [13]. The starting point was date of diagnosis of WT. Relapse or death in complete
Results The median age at diagnosis of the 37 children (23 males, 14 females) was 3 years (range 0.8–8 years). Clinical features and outcome of each patient are described in Table 2. The most relevant sign at presentation was an abdominal mass in 32 of 37 (86%) patients, followed by hematuria in 12 of 37 (32%) patients, and by hypertension in five (14%) patients. Specimens for histopathological diagnosis were taken only from the tumor and any other specimens to determine the locoregional extent of the disease, as recommended by the major international studies, were not available. Therefore, histological examination was made uniquely to assess the favorable compared with unfavorable classification. Histology was defined as favorable in 30 of 37 patients (81%), and as unfavorable in six (19%), of whom four were in group B and two in group C; for the remaining patient, histology was not defined. No intraoperative tumor rupture was reported. Following preoperative CT, a 50% reduction in tumor size, assessed by clinical examination and ultrasound scanning, was obtained in 11 of 33 patients (33%) of groups B and C. At the time of present analysis, three of four patients of group A were off therapy and disease free, one was lost to follow-up 4 months from diagnosis. In group B, 20 of 27 patients (74%) were off therapy after first-line treatment without evidence of disease; one, relapsed during therapy, remained off therapy and disease free 5 years after second-line treatment; three were lost to follow-up during treatment at 1, 12 and 17 months from diagnosis, respectively; in the remaining three treatment failed (one with local recurrence along with lung metastases while on therapy, two with abdominal node recurrence) and they subsequently died of their disease. Of the six patients of group C, three were off therapy without evidence of disease, and three died during treatment because of progression.
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Patients were routinely evaluated by physical examination and laboratory investigations (including complete blood count, kidney and liver function tests); urography, abdominal ultrasound scan and chest X-ray were also performed to assess the size of the abdominal mass and the presence of other intra-abdominal lesions or lung metastases.
remission were counted as failures. Time was censored at last follow-up date if no failure was observed (26 patients, 70%) or the patient was lost to follow-up (four patients, 11%). Follow-up was updated to October 2000.
946 Table 2. Features and outcome of patients with Wilms’ tumor Patient number
Sex
Age at diagnosis (years)
Groupa
Histology
Reduction (%)b
Status (months plus)
1
F
6
B
Favorable
>50
NED (112)
2
M
3
B
Favorable
50
died (22)
4
F
5
C
Unfavorable
50
NED (74)
6
M
4
B
Favorable
