1Manuel de Jaesus Rivera Hospital, La Mascota, Managua, Nicaragua; 2Istituto Nazionale Tumori, Milan, Italy; 3Pediatric 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.
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Abstract |
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Recent trends in therapeutic strategies for Wilms tumor are based on an attempt to 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 0.88 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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Introduction |
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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].
Since 1990, thanks to an alliance project involving the La Mascota Childrens 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 Childrens 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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Patients and methods |
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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.
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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 KaplanMeier method [13]. The starting point was date of diagnosis of WT. Relapse or death in complete 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.
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Results |
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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.
With a median follow-up time of 6.4 years the EFS for the whole group is 80.1% ± 6.8 (SE) (Figure 1). No event occurred beyond 5 years from diagnosis.
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Discussion |
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The experience reported here is peculiar for two reasons: (i) treatment choice was not supported by adequate surgical and pathological staging, and (ii) no patient received RT. This suggests that cure rates superimposable onto those of Western countries can also be achieved in countries where health care resources are scanty and the diagnostic work-up is non-optimal by necessity.
It must be underlined that surgical operations on all patients were carried out by the same surgical team, and this stresses the importance of the uniform technical approach in this series of children. The experience with preoperative CT of European studies on WT [16] was also utilized to avoid the risk of tumor ruptures; in fact, 33% of these children achieved a 50% tumor shrinkage, and no tumor rupture occurred.
Patients whose tumor size was judged to be safely operable at diagnosis received only postoperative CT for 6 months. Children with larger tumors, lung metastases or bilateral disease received pre- and postoperative CT for a total treatment duration of 68 weeks. In the post-surgery phase, ADR was added and administered up to a cumulative dose of 270 mg/m2. The aim of this therapeutic schedule was to reduce the risk of local relapse or metastatic spread in the absence of specific risk criteria. Thus, it is possible that some of these patients, in particular those who achieved a response to preoperative CT >50%, might be overtreated. This approach, in our opinion, was justified by the difficulty in assessing the local extent of the disease and yielded no tumor intraoperative ruptures. It is also plausible that the chemotherapeutic program adopted was the key element to the overall favorable outcome in this series.
During phase 2 (see Table 1) CT was given every 2 weeks, because a 2-week schedule, with lower single-drug doses, was regarded as potentially less toxic than the 3-week conventional-dose schedule and, therefore, more easily manageable with respect to myelosuppression and the need for supportive care. Although echocardiographic abnormalities (reduced contractility) have been reported in 23% of children receiving a cumulative dose of anthracyclines up to 270 mg/m2 [17, 18], this dosage is not usually associated with a clinical heart impairment and, thus, can also be considered relatively safe for clinical settings where adequate cardiac follow-up may not be available.
As already mentioned, radiation was not available as a means for a combined treatment approach in this series of children with WT. Only four of the 27 patients of group B relapsed (local plus lung metastases in two, abdominal lymph nodes in two) suggesting that locally advanced disease was adequately controlled by an excellent surgical approach in association with an intensive CT schedule. The outcome was less favorable for patients with metastatic or bilateral disease (treatment failed in three of six) suggesting that this group could benefit from RT.
Six patients were diagnosed as having unfavorable histology, and four of six had a rhabdoid tumor; this finding is slightly higher than the incidence in the literature [2]. Four of these patients were alive and disease free, one relapsed and died, and one was lost to follow-up. No conclusions can be drawn from these data.
All failures occurred within 4.3 years from diagnosis, similar to data from the major series reported in the literature [26], and all deaths were related to disease progression and never to treatment toxicity.
Although the overall favorable outcome obtained in the patients with localized WT of this series does not call for new treatment strategies, an effort should be made to identify subsets of patients amenable to less intensive treatment and, to this purpose, a correct staging of the disease should be pursued. RT, which has become recently available in Nicaragua, could find employment in selected cases, since it does not appear to be needed for most patients as shown by this experience.
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Acknowledgements |
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Footnotes |
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References |
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