de-escalation of therapy in wilms tumor

1. de-escalation of therapy in wilms tumor robert r johnson march 11, 2010

2. plan of attack • dr. wilms • epidemiology • biology • pathology • presentation • work-up • management • bilateral wilms tumor • toxicity • conclusions

3. dr. wilms • carl max wilhelm wilms • german pathologist • born in 1867 • published die mishgeschwulste der niere in 1899 • the mixed tumor of the kidney • tumor of blastemal, epithelial, and stromal elements in a 3-year-old-girl

4. dr. wilms • also a skilled surgeon • perineal prostatectomy • rib resection for tuberculosis • died of diphtheria in may, 1918 • contracted while performing emergency laryngotomy on french p.o.w.

5. epidemiology • embryonic kidney tumor • nephroblastoma • most common abdominal malignancy in children • 6% childhood cancers • ~ 500 new cases per year in u.s. • bilateral in 4-8% cases

6. epidemiology • median age varies… • 3.5 years for boys with unilateral disease • 4 years for girls with unilateral disease • ~ 1 year earlier for bilateral tumors • 75% present before age 5 • 90% before age 7 • 1.1 : 1 female predominance for unilateral disease • 1.8 : 1 for bilateral disease • african american > european american > asian american

7. biology • ~ 90% cases of wilms tumor sporadic • ~ 10% cases syndromic • specific congenital malformations associated with distinct chromosomal loci • wagr syndrome • denys-drash syndrome • beckwith-wiedemann syndrome

8. biology • wagr syndrome • germline deletion of 11p13 • wilms tumor associated gene (wt1) • tumor suppressor • aniridia, genitourinary anomalies, mental retardation • ~ 33% develop wilms tumor

9. biology • denys-drash syndrome • germline point mutation of wt1 • exon 8/9 • gonadal dysgenesis, early-onset nephropathy • ~ 90% develop wilms tumor • also risk of gonadoblastoma

10. biology • beckwith-wiedemann syndrome • mutation of 11p15.5 • wt2 locus • contains multiple genes • tumorigenesis most closely associated with over-expression of insulin-like growth factor (igf2) • hemihypertrophy, macroglossia, omphalocele, organomegaly • ~ 5-10% develop wilms tumor

11. biology • other chromosomal abnormalities confer aggressive behavior • loss of heterozygosity on 1p and 16q • more on this later

12. pathology • spectrum of tumors included under wilms heading • mesoblastic nephroma • clear cell sarcoma of kidney • rhabdoid tumor of kidney

13. pathology • mesoblastic nephroma • most common tumor in first month of life • median age 3 months • typically benign • lack of malignant epithelial components seen in wilms tumor • nephrectomy curative • local recurrence rare

14. pathology • clear cell sarcoma of kidney • 4% childhood renal tumors • high propensity for bone metastases • high risk in nwts • rfs ~ 71%

15. pathology • rhabdoid tumor of kidney • unrelated to rhabomyosarcoma or wilms tumor • typically diagnosed by 2 years • association with primary cns neoplasms • atypical teratoid rhabdoid tumor • high-risk in nwts • rfs ~ 25%

16. pathology • wilms tumor • typically present as large, solitary, well-circumscribed tumor • calcifications not generally seen • in contrast to neuroblastoma

17. pathology • triphasic embryonal neoplasm • blastemal • epithelial • tubules and glomeruli • stromal

18. pathology • pattern of components varies • mixed type (41%) • blastemal predominant (39%) • epithelial predominant (18%) • stromal predominant (1%)

19. pathology • anaplasia • enlargement of nuclei to three times normal size • hyperchromatism • multiple mitotic figures • focal vs diffuse • uncommon before age 2 • 10% after age 5

20. presentation • most patients have a complaint • abdominal mass (~ 80%) • abdominal pain (~ 40%) • fever (~ 20%) • hematuria (~ 20%) • congenital anomalies • ~ 10% cases syndromic

21. work-up • history • timing and character of symptoms • family history • physical exam • abdominal mass, pain • congenital anomalies • labs • creatinine clearance • proteinuria • denys-drash syndrome

22. work-up • ultrasound has replaced ivp as initial imaging modality • tumor • presence of contralateral kidney • venous extension

23. work-up • ct scan of the abdomen • surgical resectability • retroperitoneal lymph nodes • assess liver for metastases or invasion • assess for involvement of contralateral kidney • mri may be better for this

24. work-up • chest imaging to assess for metastases • plain film • ct scan • plain film negative, ct positive traditionally considered non-metastatic • current cog protocol recommends excisional biopsy

25. work-up • biopsy not recommended in u.s. protocols • automatically upstages to stage iii • flank irradiation • primary surgery serves as biopsy • bilateral disease is exception • biopsy both sides

26. management • national wilms tumor study (nwts) and international society of pediatric oncology (siop) have different strategies • nwts favors surgery first followed by adjuvant therapy • allows comprehensive pathologic assessment • tailor adjuvant therapy • disadvantageous with marginally resectable tumors • benefit of neoadjuvant treatment • siop favors neoadjuvant chemotherapy and/or radiotherapy followed by surgery • easier surgery • less tumor spillage

27. management • surgery • chemotherapy • radiotherapy • staging • nwts trials

28. surgery • wide transverse abdominal approach • en bloc removal of kidney and involved renal vein • ~ 10% • inspection and palpation of contralateral kidney and liver • lymph node sampling • 56% clinically + nodes are pathologically + • 11% clinically – nodes are pathologically +

29. surgery • biopsy • discouraged in u.s. protocols • bilateral tumors • unresectable tumor • direct invasion of liver and/or retroperitoneum • posterior approach preferred • spillage confined to flank instead of peritoneal cavity • ultrasound or ct-guidance

30. chemotherapy • pre-nwts studies showed promise of actinomycin-d (amd) and vincristine (vcr) • recurrent and metastatic disease • amd and vcr still used in most patients • adriamycin (adr) and cyclophosphamide (cpm) used in high-risk patients • etoposide (vp-16) being studied

31. radiotherapy • radiotherapy been used to treat wilms tumor since 1940s • historically, nearly all patients received adjuvant radiotherapy • 3000-4000 cgy • presently, ~ 25% patients treated with radiotherapy • ~ 15% of non-metastatic disease

32. radiotherapy • several important factors • timing • volume • dose • metastases

33. timing • delay in initiation of therapy beyond 10 days related to higher risk of local recurrence • true in nwts-1/2 • mostly unfavorable histology • 1200 patients with favorable histology analyzed in nwts-3/4 • no difference in abdominal or flank relapse with rt started 0-9 days or > 10 days from surgery

34. volume • flank • localized disease • tumor bed and entire width of vertebral bodies • cover para-aortic lymph nodes • prevent scoliosis • minimize liver volume for right-sided tumors • block contralateral kidney • parallel opposed anterior and posterior fields

35. volume • whole abdomen • intraperitoneal rupture, peritoneal implants, massive abdominal disease • cover all peritoneal surfaces • diaphragm to inferior pelvis • block femoral heads • parallel opposed anterior and posterior fields

36. dose • nwts 1/2 used age-dependent range • subsequent trials have successfully de-escalated dose • doses as low as 1080 cgy now used • anaplastic tumors may require higher doses

37. metastases • lung metastases treated with whole lung irradiation (wli) • 1200 cgy • shoulders blocked • anterior and posterior fields • other sites of metastases treated to 3000 cgy • liver, bone, brain

38. staging • first staging system published by cassady in 1973 • tumor > 550 ml shown to be a cutoff for poor prognosis cassady jr et al. cancer 1973;32:598-608. garcia m et al. radiology 1963;80:574-580.

39. staging • nwts-1/2 patients separated into surgically identified groups • more complicated • group ii: beyond kidney but completely excised • para-aortic lymph nodes • group iii: beyond kidney with residual disease • lymph nodes beyond peri-aortic chain • any biopsy

40. nwts • nwts-1 • 606 patients from 1969-1974 • three primary questions: • is adjuvant radiotherapy (rt) necessary in group i? • single agent vincristine (vcr) or actinomycin d (amd) versus combination in groups ii and iii? • neoadjuvant vincristine in group iv? d’angio gj et al. cancer 1976;38:633-646.

41. nwts • nwts-1 cont’d • groups i & ii received flank irradiation • groups iii & iv received whole abdominal irradiation • revised to flank irradiation unless peritoneal seeding • initiate within 2 days of surgery • constraints on normal structures • kidney 1500 cgy • liver 3000 cgy • 1400 cgy wli for lung mets

42. nwts • nwts-1 cont’d • adjuvant rt significantly improved dfs in patients > 2 with group 1 disease • combination chemo significantly better than single-agent vincristine or actinomycin d in groups ii & iii • dfs with trend in os • neoadjuvant vincristine yielded significantly worse os than immediate surgery • small sample size

43. nwts • nwts-1 cont’d • unfavorable histologies (uh) identified • anaplasia • sarcomatous histology • rhadoid histology • no improvement in survival with higher radiation doses • spawned nwts-2…

44. nwts • nwts-2 • 513 patients from 1974-1979 • three more questions: • is amd and vcr equivalent to amd and rt in children > 2 with group i disease? • is 6 months chemo equivalent to 15 months in group i? • all received 15 months in nwts-1 • is the addition of adriamycin (adr) to vcr and amd beneficial in groups ii-iv? d’angio gj et al. ijrobp 1978;4:769-780.

45. nwts • nwts-2 cont’d • radiotherapy given as in nwts-1 • flank only • abdomen for peritoneal seeding • age-dependent dose • initiate within 10 days of surgery • 1400 cgy for lung mets

46. nwts • nwts-2 cont’d • excellent survival in group i with amd and vcr instead of amd and rt • 83% 2-yr rfs with amd and rt in nwts-1 • no difference in survival for 6 months vs 15 months of chemo in group I • significant rfs benefit to adding adr in groups ii and iii with favorable histology (fh) • trend with unfavorable histology (uh) • groups ii-iv taken together: • 2-yr dfs 77% vs 63% (p = 0.0004) in favor of adr * p < 0.05

47. nwts • nwts-2 • validated distinction between fh and uh • group ii and iii: • 3-yr rfs 88% vs 48% • 3-yr os 92% vs 78% • poor prognosis with involved lymph nodes • nodes became stage iii in nwts-3 • 10% pneumonitis with 1400 cgy • 1200 cgy used in nwts-3

48. nwts • nwts-3

49. nwts • nwts-3 • 1489 patients from 1979-1985 • histology considered in treatment algorithm • favorable histology (fh) • unfavorable histology (uh) • five questions: • can duration of chemo be shortened for stage i fh? • can rt be eliminated for stage ii fh? • is adr clearly beneficial for stage ii and iii fh? • what is the minimum effective rt dose for stage iii? • does adding cyclophosphamide (cpm) improve survival in stage iv fh and stage i-iv uh? d’angio gj et al. cancer 1989;64:349-360.

50. nwts • nwts-3 cont’d • radiotherapy doses defined by protocol for fh • 2000 cgy vs none for stage ii • 2000 cgy vs 1000 cgy for stage iii • flank or abdomen • stage iv fh and all uh treated with new age-adjusted scheme!! • lower doses for < 18 months • 1200 cgy for lung mets