Adult Wilms' tumor: A monoinstitutional experience and a review of the literature

Authors


Abstract

BACKGROUND

The authors reviewed their institutional experience regarding adult patients with Wilms' tumor (WT) to assess their clinical characteristics and compliance with respect to children's treatment guidelines.

METHODS

A total of 17 adult patients (median age at the time of diagnosis of 17.5 years; range, 16–29 years) were referred to the study institute between 1983 and 2001 and were followed for a median of 131 months. The treatment modality was planned according to the two consecutive Italian protocols for WT that were active during the referral years. The patients were staged according to the National Wilms Tumor Study-4 (NWTS) staging system as follows: eight patients had Stage II disease, four patients had Stage III disease, and five patients had Stage IV disease.

RESULTS

All the patients but one underwent nephrectomy, with three incomplete surgeries performed. Two patients with Stage II disease were treated elsewhere with nephrectomy only and they were admitted to the study institution at the time of disease recurrence. Anaplasia was found to be present in only one patient with Stage IV disease. The authors noted 9 cases of disease recurrence or progression occurring during treatment and 6 of these 9 patients died of their disease, with an overall survival rate of 62.4% at 5 years.

CONCLUSIONS

Compared with children, adults with WT are reported to have a worse prognosis. In the current study, the authors found that poor compliance with specific therapeutic guidelines may contribute to this poorer outcome. Because of the rarity of this disease, adults with WT are at a risk of either undertreatment or incorrect treatment. Cancer 2004. © 2004 American Cancer Society.

Wilms' tumor (WT) is the most common primary malignant renal tumor of childhood. At the current time, a significantly high cure rate can be achieved, even in patients with advanced stages of the disease.

The extent and timing of surgery, chemotherapy, and radiotherapy are modulated according to internationally recognized guidelines of multimodal approaches, with extent of disease and histology being the main clinical factors guiding the selection of postsurgical treatment.1

WT is very rare in adolescents and in the adult population. Although its actual incidence is difficult to determine, to our knowledge fewer than 300 cases have been reported in the English literature to date. For this reason, treatment guidelines in adults still are lacking.2 A worse prognosis is reported for adults compared with children, but this can be explained only partially by the diagnosis of more advanced stages of the disease in adults.2–7

In the current study, we reviewed our institutional series of WT in patients age ≥ 16 years to assess the clinical characteristics of adults and compliance with respect to treatment guidelines for children.

MATERIALS AND METHODS

We reviewed our database regarding patients age ≥ 16 years at the time of WT diagnosis who were admitted to the Istituto Nazionale Tumori in Milan at any time in their clinical history. The entire series was staged according to the National Wilms Tumor Study-4 (NWTS) staging system1 and, wherever possible, the histology slides were reviewed by the pathologist in charge for Consiglio Nazionale Ricerche/Associazione Italiana Ematologia Oncologia Pediatrica (CNR/AIEOP) protocols. Rhabdoid tumors and renal clear cell sarcomas were not considered in this analysis.

The treatment plan for this adult population followed the same protocols that, during the referral years, were in use for children: 1980–1987: the first Italian CNR/AIEOP Study8 (Table 1) and 1992–2000: the second Italian CNR/AIEOP-Study9 (Table 2). Primary chemotherapy was administered in selected cases only, mainly to reduce the risk of rupture. Informed consent was required from all patients before they were treated at the study institution.

Table 1. CNR/AIEOP,a 1980–1987: Treatment Plan
  • CNR/AIEOP: Consiglio Nazionale Ricerche/Associazione Italiana Ematologi Oncologi Pediatrici; FH: favorable histology; S: surgery; VCR: vincristine; Act-D: actinomycin-D; RT: radiotherapy; UH: unfavorable histology; ADR: doxorubicin; CT: chemotherapy; PC: primary chemotherapy.

  • a

    Stage was determined according to the National Wilms Tumor Study-4 staging system.

Stage I, FHS-> VCR weekly for 8 weeks then every 2 weeks for 8 doses; Act-D daily for 5 days, Weeks 1 and 6
Stage II, FHS-> VCR weekly for 8 weeks then every 2 weeks for 8 doses; Act-D daily for 5 days, Weeks 1 and 6; RT
Stage I and Stage II, UH; Stage III FH and UHS-> VCR weekly for 8 weeks then every 2 weeks for 10 months; Act-D daily for 3 days every 8 weeks alternating with ADR every 8 weeks for 10 months; RT
Stage IVVCR weekly for 3 weeks; Act-D daily for 5 days week 1->S-> CT according to Stage III, RT
PC in selected cases onlyVCR weekly for 3 weeks; Act-D daily for 5 days Week 1
Table 2. CNR/AIEOP,a 1992–2000: Treatment Plan
  • CNR/AIEOP: Consiglio Nazionale Ricerche/Associazione Italiana Ematologi Oncologi Pediatrici; FH: favorable histology; UH: unfavorable histology; S: surgery; VCR: vincristine; Act-D: actinomycin-D; ADR: doxorubicin; RT: radiotherapy; IFO: ifosfamide; CBDCA: carboplatin; VP-16: etoposide; PC: primary chemotherapy.

  • a

    Staging was determined according to the National Wilms Tumor Study-4 staging system.

Stage I, FH/UHS-> VCR weekly for 8 weeks, Act-D every 3 weeks for 3 doses
Stage II, FHS-> VCR weekly for 8 weeks then every 3 weeks for 6 doses; Act-D every 3 weeks for 9 doses
Stage III, FHS-> VCR weekly for 8 weeks; Act-D every 2 weeks for 4 doses and ADR every 4 weeks for 2 doses- > RT- > VCR every 3 weeks for 17 doses; Act-D every 3 weeks for 11 doses alternating with ADR every 3 weeks for 9 doses
Stage IV, FHVCR weekly for 8 weeks, Act-D every 2 weeks for 4 doses and ADR every 4 weeks for 2 doses- > S- > RT- > VCR every 3 weeks for 17 doses, Act-D alternating with ADR every 3 weeks for 7 doses
Stage II, Stage III, Stage IV, UHS-> VCR, Act-D alternating with IFO, VCR alternating ADR, VCR alternating with CBDCA, VP-16 every 3 weeks for 50 weeks; RT from week 2
PC in selected cases onlyVCR weekly for 8 weeks; Act-D every 2 weeks for 4 doses; ADR every 8 weeks for 2 doses

Disease-free survival (DFS) was calculated from the date of diagnosis, represented by initial surgery or biopsy, to the date of disease progression or the last follow-up examination. Overall survival (OS) was determined from the date of diagnosis to the date of death or last follow-up examination. Survival curves were generated using the Kaplan–Meier method.10

RESULTS

Seventeen young adults with WT (11 females and 6 males) were treated between 1983 and 2001. The median patient age at the time of diagnosis was 17.5 years (range, 16–29 years). There were eight patients with Stage II disease, four patients with Stage III disease, and five patients with Stage IV disease; none of the patients had Stage I disease. The diagnosis was obtained at the time of nephrectomy in 12 patients and from a needle biopsy in 5 patients; of these latter patients, 4 received primary chemotherapy whereas 1 patient with Stage IV disease died before undergoing nephrectomy.

Overall, 16 nephrectomies were performed and in 3 cases an incomplete surgical procedure was documented: no lymph node sampling was performed in 1 patient with Stage II disease, tumorectomy with minimal intraoperative tumor rupture was performed in a second patient with Stage II disease, and no exploration of the ureter was performed in one patient who presented with macroscopic residual tumor and was classified as having Stage III disease because of massive intraoperative tumor rupture. All the above surgical interventions had been performed elsewhere and the latter two patients underwent a second surgical procedure at the study institution with the goal of obtaining complete removal of the residual tumor.

All tumors were classified as nephroblastomas without diffuse anaplasia, except for one patient who was diagnosed with a Stage IV anaplastic tumor.

Nine patients were treated according to the first Italian protocol and eight patients were treated according to the second.

Table 3 summarizes the treatment and survival experiences of the patients in the current series.

Table 3. Summary of the Current Case Series
 No. of patientsChemotherapyRadiotherapyDFSOS
  • DFS: disease-free survival; OS: overall survival; 3D: three drugs: vincristine, actinomicyn D, and doxorubicin; 2D: two drugs: vincristine and actinomycin D; RT: radiotherapy; cGY: centigrays; WA: whole abdomen.

  • Staging was determined according to the National Wilms' Tumor Study 4 staging system.

  • a

    Second complete remission.

  • b

    Disease recurrence occurred while the patients still were receiving treatment.

  • c

    Anaplastic tumor.

Stage II82 patients, noneNo RT4 mos and 7 mosAlive at 56 mos;a dead at 54 mos
  1 patients, 3D3960 cGY to flank213 mosAlive at 213 mos
  5 patients, 2DNo RT47 mos, 72 mos, 131 mos, 42 mos, and 12 mosAlive at 47 mos, 72 mos, 131 mos, and 66 mos; dead at 25 mos
Stage III44 patients, 3D2 patients, 3150 and 3300 cGy to flank;10b and 151 mosAlive at 162 mos and 151 mos
   1 patient, 1960 cGy to WA;153 mosAlive at 153 mos
   1 patient, 3660 cGy to flank and 1200 cGY to lungs202 mosAlive at 202 mos
Stage IV55 patients, 3D1 patient, 4800 cGY to C36 mosDead at 9 mos
   1 patient, 3000 cGy to flank and L5-S118 mosAlive at 18 mos
   3 patients, no RT2, 12, and 19 mosDead at 3 mos,c 40 mos and 21 mos

Two of the eight patients classified as having Stage II disease received primary chemotherapy; initial biopsy was suggestive of extraosseous Ewing sarcoma in one patient whereas the second patient was found to have extrarenal tumor. In the first patient, primary chemotherapy was comprised of vincristine, actinomycin D, and cyclophosphamide, according to our protocol for Ewing sarcoma, whereas the second patient received vincristine and actinomycin D, as described in Table 1.

The patient in whom no lymph node sampling was performed at the time of surgery (which was performed elsewhere) did not receive any adjuvant treatment and was admitted to the study institution 7 months after surgery, at the time of disease recurrence. One other patient with Stage II disease received no adjuvant therapy and was admitted to the study institution after disease recurrence, 4 months after surgery. Six of eight patients with Stage II disease received adjuvant chemotherapy: five patients received a two-drug regimen and no radiotherapy and one patient received a three-drug chemotherapy regimen and radiotherapy to the hemiabdomen because of the extent of extrarenal disease at the time of presentation, as recommended for patients with Stage III disease. Overall, 4 cases of disease recurrence were documented in 8 patients with Stage II disease, 2 of whom died of progressive disease 25 months and 54 months after diagnosis, respectively; another patient remained in complete disease remission 24 months after disease recurrence and the 4th patient was in complete disease remission 30 months after salvage treatment after a second disease recurrence.

Of the four patients with Stage III disease, one received primary chemotherapy because the biopsy was suggestive of extraosseous Ewing sarcoma. All the patients were treated with postoperative chemotherapy with three drugs and adjuvant radiotherapy. One of the patients also received total lung irradiation because she was considered to be at risk of microemboli during removal of a thrombus from the superior vena cava. Ten years and 8 months later, this female patient developed breast carcinoma and subsequently a small cell lung carcinoma for which she was receiving chemotherapy at the time of last follow-up. At the time of last follow-up, all four patients were alive, one of them after disease recurrence and salvage therapy.

Among the five patients with Stage IV disease, four patients underwent primary nephrectomy. One patient had a residual tumor mass in a horseshoe kidney and was treated according to the Stage IV regimen of the second Italian Nephroblastoma protocol. At the time of last follow-up 18 months later, the patient was free of disease. The remaining four patients had died of disease progression.

A total of nine tumor recurrences/disease progressions occurred, six of which had a fatal outcome. At the time of last follow-up, 2 patients were alive in complete disease remission 24 months and 152 months, respectively, after disease recurrence, and 1 patient was in complete disease remission 30 months after a second disease recurrence. With a median follow-up of 131 months for surviving patients (range, 18–213 months), the 5-year and 10-year OS rates were 62.4% (95% confidence interval [95% CI], 38.4–86.4%) and the 5-year and 10-year DFS rates were 45.8% (95% CI, 21.5–70.0%). Excluding the patient with diffuse anaplasia, the 5-year and 10-year DFS and OS rates were 50% and 68.7%, respectively.

DISCUSSION

Adult with WT have been reported to have a worse outcome compared with pediatric WT patients. In reviewing our data and the published reports, the objective of the current study was to attempt to determine whether this worse outcome could be improved by adopting for adults the same diagnostic and treatment guidelines internationally agreed on for childhood WT.

Until the report from Arrigo et al.4, which demonstrated a significant improvement in survival (67% at 3 years), prior experiences led us to believe that adult WT was a fatal disease, with survival rates ranging from 18–27%.2, 4, 10–14 These results could be ascribed in part to the fact that the disease was at an advanced stage at the time of diagnosis, with the histology demonstrating no apparent differences compared with WT occurring in children.13 Patients with Stage III and Stage IV disease are reported to account for > 50% of most adult series and the results of the current series are consistent with this trend, with 53% of patients presenting with advanced stages (Stage III and Stage IV) of disease and no patients reported with Stage I disease. However, even after a stage-to-stage comparison, the prognosis still appears to be worse in adults than in children.12

Some authors have suggested that the classic three-drug regimen used in childhood WT (actinomycin D, doxorubicin, and vincristine) may not be effective in adults, indicating the need for new drug combinations. However, other case series, including the current study, have not confirmed this lack of effectiveness.

In 1982, the NWTS group reported for what to our knowledge was the first time experience with 31 adult WT patients who were treated according to multimodal therapy between1968–1979. All but 3 patients underwent surgery, all but 1 patient received chemotherapy, and 24 patients (77.4%) received postoperative radiotherapy. Advanced disease at the time of diagnosis (Stage III and Stage IV disease) represented 51.7% of the series and details regarding histology were not available. The 3-year survival rate was 24% compared with 74% in childhood patients. The authors concluded that adult WT has a worse prognosis compared with WT occurring in children and should be treated aggressively with 3-drug chemotherapy and radiotherapy to the tumor bed (4500 centigrays [cGy]), regardless of the stage of disease.12

The NWTS report of 1990 again was to our knowledge the first to report a better treatment outcome obtained by adopting the multimodal therapy used in the pediatric setting. Between 1979–1987, data regarding 27 adults with WT were collected. Four patients with Stage IV disease had anaplastic tumors and the incidence of advanced stage disease was in excess of 50%. Two patients did not receive any adjuvant treatment. Overall, 25 of 27 patients were treated with chemotherapy and 20 of 27 patients (74%) were treated with radiotherapy. The 3-year survival rate of the entire series was 67% when anaplastic tumors were included, and 79% when they were excluded. These data represented an important improvement over prior results, and led to the following recommendations: no radiotherapy and 2-drug chemotherapy for patients with Stage I disease and radiotherapy to the tumor bed (2000 cGy) and 3-drug chemotherapy for patients with Stage II, Stage III, and Stage IV disease.4

In 1994, the French group reported its experience in 22 patients age > 16 years with nephroblastoma who were treated over a 19-year period. All the patients underwent nephrectomy; 15 patients received chemotherapy and radiotherapy, 6 patients received chemotherapy, and 1 patient received radiotherapy only. With a median follow-up of 100 months, 55% of the patients were alive and 45% were free of disease. The group concluded that a three-drug chemotherapy regimen plus radiotherapy for patients with Stage II disease and upward are recommended for the treatment of adult patients.15

During the recent meeting of the International Society of Paediatric Oncology (SIOP), the German group focused on 30 adult patients who were treated according to the SIOP 93-01 study. All the patients had a central pathology review and 6 tumors (13%) were classified as having high-risk histology. Ten patients (33%) were found to have distant metastases at the time of diagnosis. All patients underwent primary surgery, all received chemotherapy, and 14 of the 30 patients received irradiation as well. At a median follow-up of 4 years, the event-free survival and the OS rates were 57% and 83%, respectively. The authors concluded that the prognosis is good when patients are treated according to pediatric protocols.16

The current case series reports a survival rate of 62.4% at 5 years and 10 years, a result that was obtained despite a very low compliance with the specific childhood diagnostic and therapeutic protocols. We believe that the rarity of WT in adults carries an inherent risk of the disease being undertreated. In fact, three patients in the current series underwent incomplete resections and two patients received no adjuvant chemotherapy.

The limited size of the sample in the current study precludes any firm conclusions concerning specific treatment programs. However, we are convinced that the proper application of diagnostic and treatment strategies as applied to childhood WT patients and more effective cooperation with pediatric oncologists and pediatric surgeons are important steps toward the achievement of improved outcome in adult patients as well.

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