The management of nephroblastoma is significantly different in the USA versus Europe.
The information on this page is sourced from Pediatric Radiation Oncology by Halperin et al as well as several journal articles.
Management in the USA (NWTSG/COG)
Management is guided by the Children's Oncology Group (COG), which has incorporated experience from the National Wilms Tumour Study Group (NWTSG). The principles of initial management depend on the extent of disease.
National Wilms Tumour Study Group
The NWTSG was the American group dedicated to the study of nephroblastoma or Wilms Tumour. It conducted a series of studies until it transformed into the COG.
- NWTS-1 randomised several groups of patients.
- Group I patients were randomised to receive initial surgery followed by chemotherapy alone or chemotherapy and radiotherapy. In young children under 2, radiotherapy added no survival benefit. The same was not true for older children where adjuvant radiotherapy improved survival from 80 to 98%.
- Group II/III patients were randomised to surgery, radiotherapy and one of actinomycin, vincristine or both; the study demonstrated that the combined regimen was superior to single agents
- Group IV patients were randomised to receiving neoadjuvant vincristine prior to surgery or initial surgical therapy. There was a major difference in 4 year survival (83% vs 29%) in favour of up-front surgery, possibly dictating the future direction of the NWTSG studies.
- An important finding of NWTS-1 was determining 'favourable' and 'unfavourable' histologies; those with favourable histologies had close to 90% 4 year survival compared to 23% in patients with unfavourable histology.
- The other important finding of NWTS-1 was that, for radiotherapy, there seemed to be no dose-response relationship for doses between 10 and 40 Gy
- NWTS-2 built upon these experiences:
- Group I patients were treated with 3 cycles of vincristine/actinomycin chemotherapy at 6 weeks, 3 months and 6 months; the group was then randomised to receive no further chemotherapy or further chemotherapy at 3 monthly intervals (up to 15 months). Children in the shorter course performed better than long course treatments
- Group II/III/IV patients were randomised to actinomycin/vincristine versus actinomycin/vincristine/adriamycin following surgery, radiotherapy and 6 weeks of common actinomycin/vincristine chemotherapy. The addition of adriamycin improved disease free and overall survival in both favourable and unfavourable histology groups.
- NWTS-3 changed from groups to stages and built further upon NWTS-1 and -2; it also split treatment according to histological type (favourable/unfavourable)
- Stage I patients, with favourable histology, received no radiotherapy and were randomised to 10 week versus 6 month chemotherapy courses; the 10 week course was non-inferior
- Stage II patients were randomised twice; comparing radiotherapy versus no radiotherapy and comparing actinomycin/vincristine/adriamycin to an intensive actinomycin/vincristine course. Radiotherapy could be safely omitted; adriamycin had minimal effect in this group.
- Stage III patients were randomised twice (similar to Stage II); however, radiotherapy was either 10 or 20 Gy. The dose made minimal impact on outcomes, however the adriamycin had an important role in local control.
- Stage IV patients with favourable histology benefited from the addition of cyclophosphamide to their actinomycin/vincristine/adriamycin schedule. All these pateints received radiotherapy (20 Gy).
- Patients with unfavourable histology did worse than any stage with favourable histology and the addition of cyclophosphamide only made a significant difference in those with diffuse anaplasia
- NWTS-4 evaluated the length and intensity of chemotherapy regimens:
- Stage I patients were treated with either pulsed or standard chemotherapy (20 vs 26 weeks); the outcomes were similar between groups
- Stage II patients were treated with short course or long course actinomycin and vincristine (22 vs 66 weeks); outcomes were also similar
- Stage III/IV and those with unfavourable histologies were treated with short or long course actniomycin, vincristine and adriamycin; outcomes were again similar. Radiotherapy was only used in these groups, to the abdomen (10 Gy) and/or lungs (12 Gy) as indicated.
- Summary: NWTS-4 demonstrated that shorter courses of chemotherapy are just as effective as longer courses.
- NWTS-5 was not a randomised study, but looked at the effect of loss of heterozygosity of chromosomes 1 and 16. Importantly, young children under 2 with favourable histology and stage I tumours, adjuvant chemotherapy was omitted completely.
In summary, the NWTSG studies demonstrated that:
- Actinomycin and vincristine are highly effective chemotherapeutic agents in favourable histology stage I and II tumours
- Adriamycin should be added for stage III and IV favourable histology tumours
- Patients with unfavourable histology have significantly poorer prognosis and treatment escalation is warranted (eg. addition of cyclophosphamide)
- Early stage patients with favourable histology can have dose reductions performed safely (stage I and stage II)
- Radiotherapy doses of 10 Gy (to abdomen) and 12 Gy (to lung) provide adequate control of disease
Children's Oncology Group
The NWTSG has been incorporated into COG, which are now undertaking a variety of studies involving nephroblastoma.
Patients with localised disease undergo surgical excision of the tumour mass (including ipsilateral nephrectomy). This is possible in over 90% of cases, even if there is extension into the renal vein, inferior vena cava or atrium. The surgeon also performs lymph node sampling and explores the liver and contralateral kidney for evidence of metastases or concurrent tumours. The complications of surgery are:
- Tumour spillage (15-30%)
- Other surgical complication/morbidity (10%)
For the small number of patients with unresectable disease ( < 10%), pre-operative chemotherapy is usually recommended. This includes patients with bilateral nephroblastoma, who require partial nephrectomies to preserve renal function (see below).
If not included on a study, the following guidelines apply:
- VERY LOW RISK: Children under 2 with stage I, favourable histology, and tumour mass < 550 g need no further treatment. Loss of heterozygosity is not included.
- LOW RISK: A complex group of favourable histology patients with no loss of heterozygosity, either stage I (except very low risk group) or II. Treated with 18 weeks of dactinomycin and vincristine.
- STANDARD RISK: Even more complex. Includes stage I/II with loss of heterozygosity, stage III with no loss of heterozygosity and stage IV disease with no loss of heterozygosity where lung metastases respond completely to chemotherapy within 6 weeks.
- Chemotherapy involves vincristine/dactinomycin/doxorubicin
- Flank radiotherapy (10.8 Gy) is recommended for patients with stage III disease where peritoneal contamination has not occured (eg. lymph node positive, incomplete resection)
- Whole abdominal radiotherapy is recommended for patients with peritoneal contamination (biopsy, surgical spillage, positive peritoneal cytology)
- HIGHER RISK: Children with stage III/IV disease and loss of heterozygosity or slow response to chemotherapy (> 6 weeks) should receive chemotherapy with dactinomycin, vincristine, doxorubicin, cyclophosphamide and etoposide
- Flank or whole abdominal radiotherapy is offered as per standard risk group
- Whole lung radiotherapy (12 Gy) is offered for patients with lung metastases
- Brain radiotherapy (21.6 Gy if < 16; 30.6 Gy if > 16) if metastases present
- Liver radiotherapy (19.8 Gy) if metastases present
- Bone radiotherapy (25.2 if < 16; 30.6 if > 16) if metastases present
- HIGH RISK: This includes patients of any stage with focal anaplasia and those with stage I disease and diffuse anaplasia. This group also includes stage I-III clear cell sarcoma. These patients receive radiotherapy and dactinomycin/vincristine/doxorubicin chemotherapy; the clear cell sarcoma group receive alternating vincristine/cyclophosphamide doxorubicin/etoposide/cyclophosphamide.
- HIGHEST RISK: This includes patients with stage II-IV diffuse anaplastic nephroblastoma, stage IV clear cell sarcoma and any stage of rhabdoid tumour. These patients receive radiotherapy to metastases as well as alternating vincristine/doxorubicin/cyclophosphamide and etoposide/carboplatin/cyclophosphamide.
Management in Continental Europe (SIOP)
SIOP encourages pre-operative treatment with chemotherapy and/or radiotherapy prior to surgical excision. The initial study by Schweisguth in 1963 demonstrated cure rates of 33% using pre-operative radiotherapy followed by nephrectomy and future SIOP studies built upon this.
- SIOP 1 randomised children to neoadjuvant radiotherapy followed by surgery +/- further RT compared to surgery followed by RT. The main difference was a 4% rupture rate in the neoadjuvant group compared to 30% in the surgery first group. This cemented the use of neoadjuvant therapy in Europe
- SIOP 2 was non-randomised and explored the use of neoadjuvant radiotherapy and actinomycin, also demonstrating lowered rates of tumour spillage with a combination of these therapies
- SIOP 5 compared neoadjuvant radiotherapy/actinomycin with neoadjuvant chemotherapy alone (vincristine/actinomycin). Those in the neoadjuvant chemotherapy-only arm with stage 1 disease received further actinomycin/vincristine only, whereas all other patient groups received adjuvant chemotherapy and radiotherapy. The rates of tumour rupture were equivalent, as were the 3 year disease-free survival rates.
- SIOP 6 compared several adjuvant schedules for different stages of diseasem using the neoadjuvant chemotherapy arm from SIOP 5:
- Stage I disease was randomised to 2 or 5 cycles of vincristine/actinomycin therapy; the results were not signficant but favoured the shorter arm
- Stage II patients with no nodal disease were randomised to adjuvant chemoradiotherapy versus radiotherapy alone; the results were also not significantly different
- Stage II patients with nodal disease, and stage III patients, were randomised to receive adjuvant radiotherapy and chemotherapy (actinomycin/vincristine) with either intensive vincristine or doxorubicin. The patients receiving doxorubicin did significantly better than the intensive vincristine arm and triple therapy is now the standard chemotherapy regiment used for this stage.
- SIOP 9 explored the duration of neoadjuvant chemotherapy (4 or 8 weeks). Outcomes were equivalent and 4 weeks is now the standard duration of therapy.
- SIOP 93-01 explored treatment reduction in the adjuvant setting, depending on the stage of disease and the histological subtype (see the pathology section; either low, medium or high risk
- Low risk, Stage I patients received no adjuvant therapy
- Intermediate risk, Stage I patients were randomised to 4 weeks of actinomycin/vincristine with or without maintenance for a further 18 weeks. There was no evidence of improved outcomes with maintenance therapy
- Stage II-III, intermediate risk pateints received actinomycin/vincristine/epirubicin for 27 weeks
- High risk patients with stages I-III received actinomycin/vincristine/epirubicin/ifosfamide and radiotherapy (omitted in Stage I patients) for a total of 34 weeks
- Stage IV patients received neoadjuvant chemotherapy with actinomycin, vincristine and epirubicin followed by nephrectomy and metastatectomy if possible. If patients had no remaining metastases, they received an additional 27 weeks of similar chemotherapy, as well as radiotherapy to the whole abdomen if the local stage was II or III
- Stage IV patients who had persistent metastatic disease after initial chemotherapy, nephrectomy and metastatectomy received 34 weeks of the high risk patient schedule (above) as well as radiotherapy to the lungs (if involved) and abdomen (if local stage II or higher).
SIOP 2001 is the latest trial from SIOP and these recommendations are taken from there.
- All patients should receive four weeks of neoadjuvant chemotherapy with actinomycin and vincristine before proceeding to nephrectomy +/- metastatectomy (stage IV only)
- For Stage I
- Low Risk: No further treatment
- Intermediate Risk: 4 weeks of actinomycin/vincristine
- High Risk: 27 weeks of actinomycin/vincristine/adriamycin
- For Stage II
- Low Risk: 27 weeks of actinomycin/vincristine
- Intermediate Risk: Randomised to 27 weeks of doxorubicine and the low risk schedule or doxorubicin and actinomycin/vincristine/adriamycin
- High Risk: 27 weeks of actinomycin/vincristine/adriamycin + abdominal radiotherapy
- For Stage III
- Low Risk: As for stage II
- Intermediate Risk: Randomised as for stage II, but with addition of radiotherapy
- High Risk: As for stage II
- For Stage IV
- Where metastases are completely resected, 27 weeks of actinomycin/vincristine/doxorubicin with addition of radiotherapy for local stage III patients
- Where metastases are present, 34 weeks of etoposide, doxorubicin, cyclophosphamide and carboplatin; radiation reserved for local stage III patients
Use of Radiotherapy (SIOP)
Radiotherapy is only employed in specific circumstances:
- When there is intermediate or high risk stage III disease
- When there is high risk stage II disease
- When there is metastatic disease
Halperin indicates that radiotherapy rates in the SIOP trials are falling over time, replaced by chemotherapy.
Halperin, EC (2011) Pediatric Radiation Oncology, 5th Edition, Chapter 13