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Management of Wilms Tumors


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Multimodality management of Wilms Tumor

Published in: Health & Medicine, Technology

Management of Wilms Tumors

  1. 1. Management of Wilms' Tumor Moderator: Dr Sushmita Ghoshal
  2. 2. History <ul><li>The first description from Thomas F. Rance (1814) </li></ul><ul><li>Max Wilms thoroughly reviewed the literature and added 7 new patients in his 1899 monograph Die Mischgeschwuelste </li></ul><ul><li>Wilms also described the histologically “mixed tumors” of other urogenital organs </li></ul>
  3. 3. Epidemiology <ul><li>Annual incidence of Wilms' tumor in the United States was 7.6 cases per million children younger than 15 years. </li></ul><ul><li>6% of pediatric tumors – commonest abdominal pediatric tumor </li></ul><ul><li>5 th most common childhood cancer. </li></ul><ul><li>Frequency higher in blacks, lower in Asians </li></ul><ul><li>Male to female ratio is: </li></ul><ul><ul><li>0.92:1.00 for unilateral disease </li></ul></ul><ul><ul><li>0.60:1.00 for bilateral disease </li></ul></ul>
  4. 4. Epidemiology <ul><li>Mean age of diagnosis: </li></ul><ul><ul><li>46.9 months for females (29.5 mo for B/L tumors) </li></ul></ul><ul><ul><li>41.5 months for males (32.6 mo for B/L tumors) </li></ul></ul><ul><li>Separate Indian population based data non existent </li></ul><ul><li>However HBCR have reported varying rates. </li></ul><ul><li>Largest study by Thiruanathapuram reports that Wilms' Tumors account for 5.4% of all pediatric malignancies </li></ul><ul><li>Several reports find it to be the 2 nd most common solid pediatric tumor in India (after HD) </li></ul>
  5. 5. Pathogenesis
  6. 6. Renal Development Metanephric blastema
  7. 7. Nephrogenic Rests <ul><li>Perinephric rests are persistent mesoblastic tissues beyond the 36 th week of gestation </li></ul><ul><li>Two types: </li></ul><ul><ul><li>Intralobular (assoc. with WAGR, DDS etc) </li></ul></ul><ul><ul><li>Perilobular (assoc. with BWS) </li></ul></ul>
  8. 8. Wilms Tumorigenesis
  9. 9. Genetics of Wilms Tumor <ul><li>Three candidate gene loci identified: </li></ul><ul><ul><li>Chromosome 11p13 (WT-1 gene): </li></ul></ul><ul><ul><ul><li>WAGR syndrome (gene deletions) </li></ul></ul></ul><ul><ul><ul><li>Denys Drash Syndrome (point mutations) </li></ul></ul></ul><ul><ul><ul><li>Paternal gene is “silenced” </li></ul></ul></ul><ul><ul><li>Chromosome 11q15(WT- 2 gene): </li></ul></ul><ul><ul><ul><li>Beckwith -Wiedemann Syndrome (gene deletions) </li></ul></ul></ul><ul><ul><ul><li>Paternal gene is not “silenced” - double dose </li></ul></ul></ul><ul><ul><li>Chromosome 16 – gene not identified </li></ul></ul>
  10. 10. Pathology
  11. 11. Histology <ul><li>Usually a large tumor compressing the normal renal parenchyma </li></ul><ul><li>Tumor usually has a intact fibrous capsule with prominent veins </li></ul><ul><li>Lymphatic / vascular invasion common. </li></ul><ul><li>Yellowish color with heterogeneous appearance – hemorrhagic/cystic areas. </li></ul>
  12. 12. Tumor Components
  13. 13. Special Points <ul><li>Triphasic nature of tumor allows diversity in histology </li></ul><ul><li>Pathological features associated with poor prognosis: </li></ul><ul><ul><li>Diffuse anaplasia </li></ul></ul><ul><ul><li>Anaplasia in extra-renal tumor </li></ul></ul><ul><ul><li>Predominant blastemal pattern </li></ul></ul>
  14. 14. Histology: Anaplastic <ul><li>Anaplasia: </li></ul><ul><ul><li>Giant Tumor cell nucleus (> 3 times diameter of surrounding cell) with chromatin condensation </li></ul></ul><ul><ul><li>Mulitpolar mitotic figures </li></ul></ul><ul><ul><li>Marked Hyperchromatism </li></ul></ul>
  15. 15. Diffuse Anaplasia <ul><li>Present in any extrarenal site , including vessels of the renal sinus. </li></ul><ul><li>Present in a random biopsy specimen. </li></ul><ul><li>Unequivocally expressed in one region of the tumor, but with extreme nuclear pleomorphism elsewhere in the lesion. </li></ul><ul><li>Present in more than one tumor slide , unless </li></ul><ul><ul><li>It is known that every slide showing anaplasia came from the same region of the tumor or </li></ul></ul><ul><ul><li>Anaplastic foci on the various slides are minute and surrounded on all sides by nonanaplastic tumor. </li></ul></ul>
  16. 16. Anaplastic Wilms Tumor <ul><li>Seen in 5-10% patients overall – 80 - 90% have DA. </li></ul><ul><li>Female preponderance: F:M ratio 2:1 for DA </li></ul><ul><li>More common in older children (rare below 2yrs) </li></ul><ul><li>Anaplastic features are commonly seen in the blastemal component </li></ul><ul><li>These areas are preserved after chemotherapy (SIOP results) </li></ul><ul><li>Most present in later /advanced stages with extra-renal extensions </li></ul><ul><li>Metastasis is commoner – 86% develop metastatsis (MC Lung) </li></ul><ul><li>Time to development of of mets early – within 1 yr of diagnosis </li></ul><ul><li>Survival (both DFS and OS) poorer than classical variant – Poorer for DA than FA (41% vs 75% respectively) </li></ul>
  17. 17. Classification <ul><li>NWTS </li></ul><ul><li>Low Risk </li></ul><ul><ul><li>Mesoblatic </li></ul></ul><ul><li>Intermediate risk </li></ul><ul><ul><li>FH Wilms tumor </li></ul></ul><ul><li>High risk </li></ul><ul><ul><li>Anaplastic </li></ul></ul><ul><ul><ul><li>Focal </li></ul></ul></ul><ul><ul><ul><li>Diffuse </li></ul></ul></ul><ul><ul><li>CSSk </li></ul></ul><ul><ul><li>Rhabdoid tumor </li></ul></ul><ul><li>SIOP </li></ul><ul><li>Low risk </li></ul><ul><ul><li>Cystic partially diff. WT </li></ul></ul><ul><ul><li>Mesoblastic Nephroma </li></ul></ul><ul><ul><li>WT with fibroadenomatous structures </li></ul></ul><ul><ul><li>Highly diff. epithelial WT </li></ul></ul><ul><li>Intermediate risk </li></ul><ul><ul><li>Non anaplastic WT </li></ul></ul><ul><li>High risk </li></ul><ul><ul><li>Anaplastic WT </li></ul></ul><ul><ul><li>CSSK </li></ul></ul><ul><ul><li>Rhabdoid tumor </li></ul></ul>
  18. 18. Clinical Features
  19. 19. Symptoms <ul><li>Classically appears as a silent abdominal mass during childhood (60-70%) </li></ul><ul><li>Other symptoms: </li></ul><ul><ul><li>Pain Abdomen (30-40%) </li></ul></ul><ul><ul><li>Flank pain and rapid enlargement of the mass (2 ° to bleeding in the tumor) </li></ul></ul><ul><ul><li>Hematuria (25%) </li></ul></ul><ul><ul><li>Fever (20%) </li></ul></ul>
  20. 20. Physical Examination <ul><li>Primary tumor </li></ul><ul><ul><li>Smooth, rounded lobulated mass in the loin </li></ul></ul><ul><ul><li>Attached kidney may be felt </li></ul></ul><ul><ul><li>Doesn't move with respiration </li></ul></ul><ul><li>Other features: </li></ul><ul><ul><li>Hypertension (25%) </li></ul></ul><ul><ul><li>Varicocele (tumor thrombus in IVC) </li></ul></ul><ul><ul><li>Associated genitourinary abnormalities </li></ul></ul><ul><ul><li>Associated stigma of congenital anomalies </li></ul></ul>
  21. 21. Congenital Anomalies <ul><li>Around 9 - 10% of individuals with Wilms tumour have a congenital anomaly </li></ul><ul><li>Long term F/U of individuals reveals a syndrome in 17% patients </li></ul>
  22. 22. Congenital Anomalies <ul><li>High risk (>20%) </li></ul><ul><ul><li>WT1 deletions (including WAGR syndrome ) </li></ul></ul><ul><ul><li>Truncating and pathogenic missense WT1 mutations (including Denys-Drash syndrome ) </li></ul></ul><ul><ul><li>Familial Wilms tumour </li></ul></ul><ul><ul><li>Perlman syndrome </li></ul></ul><ul><ul><li>Mosaic variegated aneuploidy </li></ul></ul><ul><ul><li>Fanconi anaemia D1/Biallelic BRCA2 mutations </li></ul></ul><ul><li>Moderate risk (5–20%) </li></ul><ul><ul><li>WT1 intron 9 splice mutations (Frasier syndrome) </li></ul></ul><ul><ul><li>Beckwith-Wiedemann syndrome </li></ul></ul><ul><ul><li>Simpson-Golabi-Behmel syndrome caused by GPC3 mutations/deletions </li></ul></ul><ul><li>Low risk (<5%) </li></ul><ul><ul><li>Isolated hemihypertrophy </li></ul></ul><ul><ul><li>Bloom syndrome </li></ul></ul><ul><ul><li>Li-Fraumeni syndrome </li></ul></ul>
  23. 23. WAGR Syndrome Wilms Tumor Aniridia Genitourinary abnormalities Mental Retardation
  24. 24. Denys Drash Syndrome Diffuse Mesangial Sclerosis Male Pseudohermaphorditism Wilms Tumor
  25. 25. Beckwith-Wiedemann Syndrome Microcephaly Umbilical Hernia Ear lobe crease Macroglossia Hemihypertrophy
  26. 26. Workup
  27. 27. Investigations ◄ To establish the diagnosis ◄ Delineate tumor extent ◄ Confirm contralateral renal functional status ◄ Discover any metastasis ◄ Assess fitness for surgery / anaesthesia AIMS
  28. 28. Routine Investigations <ul><li>Hemogram: </li></ul><ul><ul><li>Anemia: 2 ° to tumor bleed </li></ul></ul><ul><ul><li>Thrmobocytosis: 2 ° to tumor bleed </li></ul></ul><ul><li>Coagulogram: </li></ul><ul><ul><li>Association with Von Willebrand Disease (5 -8%) </li></ul></ul><ul><li>Urinanalysis: </li></ul><ul><ul><li>Protein </li></ul></ul><ul><ul><li>Catecholamines: Exclude neuroblastoma & for anesthesia </li></ul></ul><ul><li>Renal Function </li></ul>
  29. 29. Imaging <ul><li>USG abdomen: </li></ul><ul><ul><li>Imaging investigation of choice for local disease </li></ul></ul><ul><ul><li>Organ of origin, </li></ul></ul><ul><ul><li>Extent of any spread </li></ul></ul><ul><ul><li>Patency of the IVC </li></ul></ul><ul><ul><li>Detecting any involved lymph nodes </li></ul></ul><ul><li>To assess renal function: </li></ul><ul><ul><li>IVP </li></ul></ul><ul><ul><li>DMSA renal scan </li></ul></ul><ul><ul><li>CT - IVP </li></ul></ul><ul><li>CT scans: </li></ul><ul><ul><li>Accurate delineation of intra-abdominal tumor. </li></ul></ul><ul><ul><li>Extension into surrounding organs </li></ul></ul><ul><ul><li>Detection of lung mets (?) </li></ul></ul><ul><li>Plain X-rays: </li></ul><ul><ul><li>PA views are adequate for detection of lung mets. </li></ul></ul>
  30. 30. Special investigations <ul><li>CT brain: </li></ul><ul><ul><li>Rhabdoid tumor of kidney </li></ul></ul><ul><li>Bone scan: </li></ul><ul><ul><li>Clear cell sarcoma </li></ul></ul>
  31. 31. Pediatric Renal Mass <ul><li>Renal cell carcinoma </li></ul><ul><li>Multilocular cystic renal tumor </li></ul><ul><li>Clear cell sarcoma </li></ul><ul><li>Rhabdoid tumor </li></ul><ul><li>Renal medullary carcinoma </li></ul><ul><li>Ossifying renal tumor of infancy </li></ul><ul><li>Lymphoma. </li></ul><ul><li>Nephroblastomatosis </li></ul><ul><li>Mesoblastic nephroma </li></ul><ul><li>Angiomyolipoma, </li></ul><ul><li>Metanephric adenoma, </li></ul>
  32. 32. Pediatric Renal masses
  33. 33. Staging
  34. 34. Staging: Historical Aspects ►
  35. 35. Stage I <ul><li>SIOP System: </li></ul><ul><li>Tumor confined to the kidney </li></ul><ul><li>Completely excised </li></ul><ul><li>Capsule intact </li></ul><ul><li>NWTS System: </li></ul><ul><li>Tumor confined to the kidney </li></ul><ul><li>Completely excised </li></ul><ul><li>Capsule intact </li></ul>
  36. 36. Stage II <ul><li>SIOP System </li></ul><ul><li>Tumor extending beyond the kidney </li></ul><ul><li>Extra-renal vessel /ureteric invasion </li></ul><ul><li>Adjacent organ or vena caval invasion </li></ul><ul><li>Regional lymph node involvement (IIN)** </li></ul><ul><li>Resected completely </li></ul><ul><li>NWTS System </li></ul><ul><li>Local extension beyond the renal capsule </li></ul><ul><li>No invasion of adjacent viscera / mets </li></ul><ul><li>Only microscopic residual tumor </li></ul><ul><li>Tumor in renal vessels not beyond the renal sinus </li></ul><ul><li>Bx before resection (except FNAC)** </li></ul><ul><li>Completely resected </li></ul>
  37. 37. Stage III <ul><li>SIOP System : </li></ul><ul><li>Invasion beyond capsule with incomplete excision </li></ul><ul><li>Pre/peri-op Bx </li></ul><ul><li>Peritoneal mets </li></ul><ul><li>Pre/per-op rupture </li></ul><ul><li>PAN below renal artery origin </li></ul><ul><li>NWTS System : </li></ul><ul><li>Macroscopic residual disease in nodes &/or abdomen </li></ul><ul><li>Preop rupture </li></ul><ul><li>Diffuse spillage </li></ul><ul><li>Peritoneal implants </li></ul>
  38. 38. Stage IV <ul><li>SIOP System : </li></ul><ul><li>Hematogenous metastasis </li></ul><ul><li>LAD beyond the abdomen/pelvis </li></ul><ul><li>NWTS System : </li></ul><ul><li>Hematogenous metastasis </li></ul><ul><li>LAD beyond the abdomen/pelvis </li></ul>
  39. 39. Stage V <ul><li>SIOP System : </li></ul><ul><li>Bilateral tumor </li></ul><ul><li>NWTS System : </li></ul><ul><li>Bilateral Tumor </li></ul>N.B.: Both systems specify that the tumors should be individually staged.
  40. 40. Overview of the recent system
  41. 41. Treatment History
  42. 42. Radiation Therapy <ul><li>Model of a radiosensitive tumor </li></ul><ul><li>Adjuvant radiation therapy was shown to significantly prolong survival in Wilms Tumor </li></ul><ul><li>In 1940s surgery attained 5 yr survival rates of 15 -20% in all stages </li></ul><ul><li>Addition of postoperative radiation therapy increased the survival to 47% (Gross and Neuhauser, 1940) </li></ul>
  43. 43. Results <ul><li>Results from largest series reported in 1970 showed the following points: </li></ul><ul><ul><li>Patients who did not undergo nephrectomy didn't survive beyond 3 yrs. </li></ul></ul><ul><ul><li>Overall 3 yr survival rate was 35% (64% stage A, 30% stage B and 6% stage C) </li></ul></ul><ul><ul><li>Patients who received postoperative RT had a better outcome ( 2 ° to selection bias) </li></ul></ul><ul><ul><li>Most patients had distant relapses !! </li></ul></ul>
  44. 44. Roles of Radiotherapy <ul><li>Historical </li></ul><ul><ul><li>Definitive radiation therapy </li></ul></ul><ul><li>Contemporary </li></ul><ul><ul><li>Preoperative Radiation </li></ul></ul><ul><ul><ul><li>Flank </li></ul></ul></ul><ul><ul><ul><li>Whole Abdomen </li></ul></ul></ul><ul><ul><li>Postoperative Radiation </li></ul></ul><ul><ul><ul><li>Flank </li></ul></ul></ul><ul><ul><ul><li>Whole Abdomen </li></ul></ul></ul><ul><ul><ul><li>Lung bath </li></ul></ul></ul><ul><li>Treatment of recurrence </li></ul><ul><ul><li>Abdomen (localized abdominal recurrence) </li></ul></ul><ul><li>Treatment of metastasis </li></ul><ul><ul><li>Lung </li></ul></ul><ul><ul><li>Brain </li></ul></ul><ul><ul><li>Bone </li></ul></ul><ul><ul><li>Liver </li></ul></ul><ul><ul><li>Lymph nodes </li></ul></ul>
  45. 45. Chemotherapy <ul><li>Initially single agent Dactinomycin was used by Faber et al in 1966. </li></ul><ul><ul><li>Tan et al showed that it was associated with a CR rate of 37.5% </li></ul></ul><ul><ul><li>Another study from UK in 1965 showed that administration of 120 μ g/Kg over 12 days improved the 2 yr EFS from 11% to 62% </li></ul></ul><ul><li>Single agent Vincristine was also used in 1960s </li></ul><ul><ul><li>It was associated with an ORR of 61.5% in patients with relapsed WT who had received Act-D </li></ul></ul>
  46. 46. Treatment
  47. 47. Study Groups <ul><li>National Wilms Tumor Study Group (NWTSG) – Now in Children Oncology Group (COG) </li></ul><ul><li>International Society of Pediatric Oncology (SIOP) </li></ul><ul><li>German Pediatric Oncology (GPO) group, </li></ul><ul><li>The Brazilian Pediatric Oncology Group </li></ul><ul><li>The French Societe d’Oncologie Pediatrique (SFOP) </li></ul><ul><li>Italian Association of Pediatric Hematology and Oncology (AIEOP) </li></ul>
  48. 48. Multimodality Management: Why? <ul><li>Wilms Tumors are highly chemo and radiosensitive </li></ul><ul><li>However they typically present with a large size and have a propensity for metastasis (hematogenous) </li></ul><ul><li>Surgery to remove the bulk of the disease and Chemotherapy to eliminate metastatic disease forms the basis of therapy </li></ul><ul><li>Radiation therapy is now a days indicated in a selected few to eliminate the risk of local recurrence </li></ul><ul><li>Multimodality, stage and risk adapted approach is the standard of care. </li></ul>
  49. 49. Management Protocol <ul><li>Management protocol varies according to: </li></ul><ul><ul><li>Age of patient </li></ul></ul><ul><ul><li>Preoperative extent on imaging </li></ul></ul><ul><ul><li>Operative stage </li></ul></ul><ul><ul><li>Post operative histology </li></ul></ul>
  50. 50. Treatment Outline <ul><li>Patients are classically treated with immediate nephrectomy followed by adjuvant Chemotherapy as per the stage and histological features </li></ul><ul><li>Radiation therapy is delivered according to the abdominal stage. </li></ul><ul><li>Radiation therapy and Chemotherapy are classically avoided in very young infants (< 6 months) </li></ul>
  51. 51. Neoadjuvant Chemotherapy <ul><li>Indicated is some select situations like: </li></ul><ul><ul><li>Tumor is deemed inoperable: </li></ul></ul><ul><ul><ul><li>Tumor thrombus in Rt Atrium / IVC </li></ul></ul></ul><ul><ul><ul><li>Extensive tumor with anticipated morbidity </li></ul></ul></ul><ul><ul><ul><li>Invasion of surrounding organs (Liver/ Spleen/ intestines) </li></ul></ul></ul><ul><ul><li>Disseminated disease (Stage IV) </li></ul></ul><ul><ul><li>WT occurring in some special situations: </li></ul></ul><ul><ul><ul><li>Bilateral WT </li></ul></ul></ul><ul><ul><ul><li>WT in unilateral kidney </li></ul></ul></ul><ul><ul><ul><li>WT in presence of genetic syndromes </li></ul></ul></ul><ul><ul><ul><li>WT in horseshoe kidneys </li></ul></ul></ul>
  52. 52. Surgery
  53. 53. Surgery <ul><li>Operability should be determined on the table – imaging overestimates inoperability </li></ul><ul><li>Surgical excision is done through a transverse abdominal incision </li></ul><ul><li>The standard procedure includes: </li></ul><ul><ul><li>Unilateral radical nephrectomy </li></ul></ul><ul><ul><li>Selective sampling of nodes (RPL dissection doesn't alter outcome) </li></ul></ul><ul><ul><li>Renal vein and IVC (6% involvement) should be palpated to exclude intravascular tumor extension </li></ul></ul><ul><ul><li>Exploration of the opposite kidney </li></ul></ul>
  54. 54. Issues in surgery <ul><li>Role of nephron-sparing surgery </li></ul><ul><ul><li>Indicated in bilateral Wilms tumor </li></ul></ul><ul><ul><li>WT in patients with genetic predisposition </li></ul></ul><ul><ul><li>Also in WT in solitary functional kidney / renal failure </li></ul></ul><ul><ul><li>Always preceded by CCT </li></ul></ul><ul><ul><li>Very young infants < 6 months age </li></ul></ul><ul><li>Role of biopsy of opposite kidney </li></ul><ul><ul><li>Condemned for unilateral involved kidney </li></ul></ul><ul><ul><li>May be indicated in the opposite kidney if there is suspicion of nephrogenic rests on preop imaging </li></ul></ul><ul><ul><li>Not to be use routinely, however part of protocol in NTWS 1-4 </li></ul></ul>
  55. 55. Nephrectomy alone <ul><li>Presently indicated in: </li></ul><ul><ul><li>Age < 2 yrs </li></ul></ul><ul><ul><li>Favourable Histology </li></ul></ul><ul><ul><li>Stage I tumors </li></ul></ul><ul><ul><li>Weight < 550 gms </li></ul></ul><ul><li>Still under protocol study – NWTS 5 found lesser RFS. </li></ul>
  56. 56. Surgical Complications <ul><li>Surgical mortality is < 1% in modern day series </li></ul><ul><li>19.8% incidence of surgical complications (NWTS-4) </li></ul><ul><li>Most common complications of nephrectomy are: </li></ul><ul><ul><li>Small bowel obstruction (7%) </li></ul></ul><ul><ul><li>Hemorrhage (6%) </li></ul></ul><ul><ul><li>Wound infection, hernia (4%) </li></ul></ul><ul><ul><li>Vascular complications (2%) </li></ul></ul><ul><li>Risk factors associated with increased surgical complications: </li></ul><ul><ul><li>Higher local tumor stage </li></ul></ul><ul><ul><li>Incorrect preoperative diagnosis </li></ul></ul><ul><ul><li>Intravascular extension </li></ul></ul><ul><ul><li>En bloc resection of other visceral organs </li></ul></ul>
  57. 57. Post nephrectomy management
  58. 58. Stage I <ul><li>Patients with stage I tumors typically have survival ranging from 92 -95% </li></ul><ul><li>Patients in this stage group can be spared radiation therapy and given adjuvant chemotherapy alone irrespective of histology </li></ul><ul><li>Standard regimen used is the EE4A regimen which utilizes a 18 week course of Vincristine and Actinomycin D </li></ul><ul><li>Only children with rhabdoid tumors are treated with the more intensive RTK regimen </li></ul>A = Actinomycin D (1.35 mg/m 2 ; max 2.3 mg) V = Vincristine (1.5 mg/m 2 ; max 2.0 mg) V*= Vincristine (2.0 mg/m 2 ; max 2.0 mg)
  59. 59. Stage II <ul><li>Survival rates are in the range of 89-92% </li></ul><ul><li>Patient with favorable histology and focal anaplasia receive the same EE4A regimen and radiation can be avoided. </li></ul><ul><li>Patients with unfavourable histology are treated by Regimen I </li></ul><ul><li>Radiation therapy is required in patients with diffuse anaplasia, clear cell tumors and rhabdoid histology (Flank radiation only) </li></ul><ul><li>Patients with Rhabdoid histology are treated with Regimen RTK </li></ul>A = Actinomycin D (1.35 mg/m 2 ; max 2.3 mg) V = Vincristine (1.5 mg/m 2 ; max 2.0 mg) V*= Vincristine (2.0 mg/m 2 ; max 2.0 mg)
  60. 60. Stage III <ul><li>Survival rates are still high in the range of 70 – 88% </li></ul><ul><li>Patients in this stage are treated with the DD4 regimen unless they have diffuse anaplasia or CCSK or RTK </li></ul><ul><li>All patients irrespective of histology should receive flank radiation in this stage (Dose recommended is 10.8 Gy in 1.8 Gy per fraction with optional boost of 10.5 Gy) </li></ul><ul><li>Selective indications for WAR exist </li></ul>A = Actinomycin D (1.35 mg/m 2 ; max 2.3 mg) V = Vincristine (1.5 mg/m 2 ; max 2.0 mg) V*= Vincristine (2.0 mg/m 2 ; max 2.0 mg) D = Doxorubicin (45 mg/m 2 ) D* = Doxorubicin (30 mg/m 2 )
  61. 61. Flank Radiation <ul><li>The technique mostly utilized is a parallel opposing AP arrangement </li></ul><ul><li>Patient is planned and treated in the supine position. </li></ul><ul><li>Pediatric anesthesia is sometimes necessary </li></ul><ul><li>Treatment Portal design : </li></ul><ul><ul><li>Should encompass the tumor bed and the site of the excised kidney </li></ul></ul><ul><ul><li>2-3 cm margins should be given circumferentially </li></ul></ul><ul><ul><li>The medial border must cross the midline to include the entire width of the vertebrae </li></ul></ul><ul><li>Beam energy : Best treated with beam energies of 4-6 MV </li></ul><ul><li>Dose : 10.8 Gy in 1.8 Gy per fraction over 6 fractions. </li></ul>
  62. 62. Surface Marking: Anterior Upper pole: Midway between the plane of the lower end of the body of the sternum and the transpyloric plane 5 cm Lower pole: Situated midway between the transpyloric and intertubercular planes 7 cm Hilum is on the transpyloric plane, 5 cm. from the middle line 5 cm
  63. 63. Surface marking: Posterior Medial border 2.5 cm from the midline Lateral border 9.5 cm from the midline Tip of spinous process of T11 Tip of spinous process of L3 Parallelogram of Morris
  64. 64. Flank Radiation: Manual <ul><li>Superior border : 1 cm above the line between the lower border of body of sternum and transpyloric plane </li></ul><ul><li>Inferior border : Kept along a line passing through the transtubercular plane </li></ul><ul><li>Medial border: Kept 1.5 - 2 cm across the midline to encompass the vertebral bodies and the contralateral paraortic nodes </li></ul><ul><li>Lateral border : To encompass the peritoneal reflection (kept open) </li></ul><ul><li>Field sizes of 10 x 10 – 12 x 12 are adequate </li></ul>
  65. 65. Flank radiation: Simulator <ul><li>IVP is done to assess the site of the opposite renal pelvis </li></ul><ul><li>Superior border: </li></ul><ul><ul><li>1 cm above the superior pole of the kidney (T11) if tumor was at lower pole </li></ul></ul><ul><ul><li>Only extending to dome of diaphragm if the tumor was reaching superiorly </li></ul></ul><ul><li>Inferior border: </li></ul><ul><ul><li>1 cm below the lower most extent of the tumor (usually L5-S1 junction) </li></ul></ul>
  66. 66. Whole Abdomen Radiation <ul><li>Indicated in few patients now a days </li></ul><ul><li>The indications are: </li></ul><ul><ul><li>Diffuse peritoneal implantation </li></ul></ul><ul><ul><li>Diffuse tumor spillage during surgery </li></ul></ul><ul><ul><li>Preoperative tumor rupture </li></ul></ul><ul><li>Dose prescribed is 10.8 Gy in 1.5 Gy / # - this can be followed by a selected boost of 10.5 Gy to the Tumor bed. </li></ul><ul><li>Biweekly hemogram is necessary. </li></ul><ul><li>Typical energy selected is 4-6 MV photons </li></ul>
  67. 67. WAR Manual Marking <ul><li>Superior border : </li></ul><ul><ul><li>At the upper border of the nipples </li></ul></ul><ul><li>Inferior border : </li></ul><ul><ul><li>Superior border of the symphysis pubis </li></ul></ul><ul><li>Shielding of the following structures done: </li></ul><ul><ul><li>Opposite kidney : Posterior 5 HVL shield </li></ul></ul><ul><ul><li>Acetabulum and femoral heads – both AP-PA shields </li></ul></ul>
  68. 68. WAR: Simulator markings <ul><li>Indicated in stage III / diffuse abdominal spills </li></ul><ul><li>Superior border : </li></ul><ul><ul><li>Extend to the level of dome of diaphragm </li></ul></ul><ul><li>Inferior border : </li></ul><ul><ul><li>To the level of inferior border of the obturator foramen. </li></ul></ul><ul><li>Lateral border : </li></ul><ul><ul><li>Extends to the lateral peritoneal reflection </li></ul></ul><ul><li>Acetabular head and the femoral head shielded to prevent slipped femoral epiphyses </li></ul>
  69. 69. Stage IV <ul><li>The NWTS advocates primary surgery even in the setting of metastatic disease if the disease is operable with the provision that chemotherapy is started at week 0. </li></ul><ul><li>Alternative approach is to go for neoadjuvant chemotherapy (detailed later) </li></ul><ul><li>In patients with FH/ FA the DD4A regimen is used while the regimen I is used in presence of CSSK / DA. </li></ul><ul><li>In patients with RTK – RTK regimen is used. </li></ul><ul><li>Radiation therapy is to be delivered as per the local stage but a minimum dose of 10.8 Gy to the flank is given. </li></ul><ul><li>RT is also indicated in other metastatic sites but primarily in pulmonary mets as whole lung radiation . </li></ul>
  70. 70. Lung Irradiation <ul><li>Recommended in the NWTS protocol in patients with CXR defined* lung mets </li></ul><ul><li>Kraker et al reported on the results of a pilot study by SIOP where they omitted pulmonary irradiation in stage IV patients </li></ul><ul><ul><li>No reduction in the DFS (83% at 5 yrs) </li></ul></ul><ul><ul><li>Further only 7 of 38 patient received RT after adjuvant CCT </li></ul></ul><ul><li>UKW1 trial reported significantly inferior results upon the omission of the chest RT in stage IV patients - ? More intensive CCT in SIOP overcame need for RT </li></ul><ul><li>Pulmonary RT complications : </li></ul><ul><ul><li>Radiation pneumonitis : CCT dose reduction by 50% recommended </li></ul></ul><ul><ul><li>Pneumocystis carinii pneumonia </li></ul></ul>
  71. 71. Lung Bath: Manual <ul><li>Superior border : </li></ul><ul><ul><li>3cm above the middle 1/3 rd of clavicle </li></ul></ul><ul><li>Inferior border : </li></ul><ul><ul><li>Below the xiphisternum </li></ul></ul><ul><li>Lateral borders : </li></ul><ul><ul><li>Lateral border of areola of nipple </li></ul></ul>
  72. 72. Lung bath: Simulator marking <ul><li>Superior border : </li></ul><ul><ul><li>Extends above the superior border of the lateral edge of clavicle </li></ul></ul><ul><li>Inferior border : </li></ul><ul><ul><li>Below extends to level of L1 (transpyloric plane) </li></ul></ul><ul><ul><li>Field border is kept below the costophrenic angles </li></ul></ul><ul><li>Shielding for humeral head necessary. </li></ul><ul><li>Some add a midline shield for larynx. </li></ul>
  73. 73. Other recommended doses <ul><li>Lung Mets 10.5 – 12 Gy in 1- 1.5 Gy per fraction (8 – 10 fractions ) </li></ul><ul><li>Brain Mets 30.6 Gy whole brain in 17 fractions (Alternative 20 Gy to whole brain followed by 10 -15 Gy boost) </li></ul><ul><li>Bone Mets 25–30 Gy to the lesion plus 3-cm margin </li></ul><ul><li>Nodal Mets 19.8 Gy to lymph nodes in 17 fractions </li></ul>
  74. 74. Unfavourable Histology <ul><li>Survival of these patients is poor with average rates of </li></ul><ul><li>In presence of diffuse anaplasia or CCSK the chemotherapy regimen used is Regimen I: Consisting of Doxorubicin / Cyclophosphamide/ Etoposide and Vincristine (except Stage I DA) </li></ul><ul><li>“ Stage Adapted” Radiation therapy is needed for all patients (except stage I DA) </li></ul>
  75. 75. Age adjusted doses <ul><li>Fears regarding the toxicity of Radiotherapy have led to recommendations of age adjusted doses </li></ul><ul><li>These are used for unfavorable histology patients </li></ul><ul><li>These are as follows: </li></ul><ul><ul><li>0 – 12 months : 12 - 18 Gy </li></ul></ul><ul><ul><li>13 – 19 months: 18 - 24 Gy </li></ul></ul><ul><ul><li>19 – 30 months: 24 - 30 Gy </li></ul></ul><ul><ul><li>31 – 40 months: 30 - 35 Gy </li></ul></ul><ul><ul><li>41 months - more: 35 - 40 Gy </li></ul></ul>
  76. 76. Rhabdoid Tumors <ul><li>The most unfavorable histological subtype. </li></ul><ul><li>Requires a separate type of chemotherapy regimen as specified in the latest NWTS protocol. </li></ul><ul><li>Radiation therapy is indicated in all stages as in unfavorable histology </li></ul>
  77. 77. Neoadjuvant Chemotherapy <ul><li>The current protocol followed in the West includes Actinomycin D and Vincristine </li></ul><ul><li>4 weeks of chemotherapy has recently been shown to be adequate </li></ul><ul><li>In PGI we use a neoadjuvant protocol with Vincristine (1.5 mg/m 2 x 3 cycles) along with etoposide (100mg/m 2 x 2 cycles) for over a 4 – 6 week period followed by surgery. </li></ul>
  78. 78. Preoperative Chemotherapy: Merits <ul><li>Achieves down-staging of the tumor: </li></ul><ul><li>Allows better surgical resection </li></ul><ul><li>Reduces surgical morbidity </li></ul><ul><li>Reduces risk of local relapse </li></ul><ul><li>Reduction in need for radiation therapy in event of tumor spillage </li></ul><ul><li>Assessment of tumor response to CCT important predictive factor in selecting future therapy </li></ul><ul><li>Allows reduction in CCT/RT intensity in the postoperative period </li></ul>
  79. 79. Preoperative Chemotherapy: Demerits <ul><li>Loss of staging information secondary to down-staging makes comparision of results difficult </li></ul><ul><li>Treatment according to the reduced stage may be detrimental as occult tumor may be missed – higher probablity of abdominal relapse </li></ul><ul><li>Unnecessary Chemotherapy if incorrectly diagnosed. </li></ul><ul><li>Loss of histological information in the post operative specimen </li></ul><ul><li>Chances of customization of therapy are reduced. </li></ul>
  80. 80. Radiation Timing <ul><li>Important information from the NWTS 3 / 4 trial </li></ul><ul><li>Showed that radiation therapy delay by more than 10 days may result in increased risk of recurrence. </li></ul><ul><li>NWTS 1 showed that if RT was initiated after 10 days there was a 10% risk of local relapse especially in patients with UFH </li></ul>
  81. 81. Modern day results
  82. 82. Trials in Wilms Tumor
  83. 83. Management Practice NWTSG SIOP S x CCT S x CCT
  84. 84. Why the difference <ul><li>Dr R.E.Gross the chief pediatric surgeon of BCH: </li></ul><ul><ul><li>Showed that the mortality with the use of surgery had reduced to <1% </li></ul></ul><ul><ul><li>Considered that no Wilms tumor was inoperable </li></ul></ul><ul><ul><li>Found poor results with preop-RT </li></ul></ul><ul><ul><li>Defined the US practice </li></ul></ul><ul><li>In France Bamberger and Schweisguth: </li></ul><ul><ul><li>Advocated preop RT </li></ul></ul><ul><ul><li>They mostly dealt with WT from North Africa </li></ul></ul><ul><ul><li>Tumors were too huge to be removed </li></ul></ul><ul><ul><li>Defined the European practice </li></ul></ul>
  85. 85. SIOP vs NWTS regimens
  86. 86. Time-line of SIOP/NWTS trials SIOP 1 (1971-74) SIOP 2 (1974-76) SIOP 5 (1977-80) SIOP 6 (1980-87) SIOP 9 (1987-93) NWTS 1 (1969-74) NWTS 2 (1974-79) NWTS 3 (1979-85) NWTS 4 (1986-94) NWTS 5 (1995-03) SIOP 93-01 (1993-99)
  87. 87. NWTS 1 (1969-74) <ul><li>Questions: </li></ul><ul><li>Is postoperative RT needed in group I disease? </li></ul><ul><li>Single agent CCT with Vcr/ActD equivalent to their combination in stage II/III </li></ul><ul><li>Is there value in the addition of preop Vincristine in stage IV patients? </li></ul><ul><li>M&M: </li></ul><ul><li>Randomized. </li></ul><ul><li>N = 359 </li></ul>
  88. 88. NWTS 1 Results <ul><li>No in the 4 yr OS in patients who did not receive post op RT in stage I especially among children < 2 yrs age. </li></ul><ul><li>Combination CCT resulted in better survival (84% vs 71%). </li></ul><ul><li>Preoperative VCR was significantly poorer with respect to OS </li></ul><ul><li>Large tumor size, nodal involvement and age > 2yrs were significant prognostic variables </li></ul><ul><li>In children < 2yrs age there was non significant improvement in the 4 yr OS. </li></ul><ul><li>No radiation dose response observed despite age modulated radiation doses. </li></ul>
  89. 89. SIOP 1 (1971-74) <ul><li>Questions: </li></ul><ul><li>Is addition of preoperative radiation to postoperative radiation better? </li></ul><ul><li>Is Single postoperative course of Actinomycin D equivalent to multiple courses(6)? </li></ul><ul><li>M&M: </li></ul><ul><li>Randomized. </li></ul><ul><li>N = 194 (397 eligible) </li></ul><ul><li>10% erroneous diagnosis </li></ul>
  90. 90. SIOP 1 results <ul><li>Preoperative RT reduced the risk of intraoperative tumor rupture from 33% to 4% ( p = 0.001) </li></ul><ul><li>Significant reduction in 5yr recurrence free survival – 51% vs 27% (but no difference in 8 yr survival) </li></ul><ul><li>No survival disadvantage of 6 courses of Act D over 1 course (15 μ g/d x 5 days) </li></ul>
  91. 91. NWTS 2 (1974-79) <ul><li>Questions: </li></ul><ul><li>Can Vincristine and ActD substitute for RT in Older Children with Group I disease? </li></ul><ul><li>Is long course adjuvant ActD + Vcr better in group I disease? </li></ul><ul><li>Is addition of Adjuvant doxorubicin helpful in stage II - IV disease? </li></ul><ul><li>M&M: </li></ul><ul><li>Randomized. </li></ul><ul><li>N = 495 </li></ul>
  92. 92. NWTS 2
  93. 93. NWTS 2 results <ul><li>Survival in patients not receiving radiation was not impaired if post op Vcr + ActD was given </li></ul><ul><li>15 months of ActD + Vcr was not better than a 6 months course. </li></ul><ul><li>Significant improvement in the 3 yrs RFS (88% vs 70%) with the use of patients with stage II/III (FH) </li></ul><ul><li>Significant improvement on addition of Adriamycin to Stage IV patients too.(3 yr RFS 60% vs 43%) </li></ul><ul><li>Signifant impact of lymphnode involvement with 2yr RFS reduced to 54% from 82% for node positive patients </li></ul>
  94. 94. SIOP 2 (1974-76) <ul><li>Questions: </li></ul><ul><li>Is addition of preoperative radiation (20 Gy) and Actinomycin D to postoperative radiation better? </li></ul><ul><li>M&M: </li></ul><ul><li>Non randomized. </li></ul><ul><li>N = 86 (397 eligible) </li></ul>
  95. 95. SIOP 5 (1977-80) <ul><li>Questions: </li></ul><ul><li>Is Preoperative ActD (15 μ g/kg/d x 3 days x 2 courses) + Vincristine (1.5mg/m2 x weekly x 4 courses) equal to 1 course of Act D + Preop RT (20 Gy) </li></ul><ul><li>M&M: </li></ul><ul><li>Randomized. </li></ul><ul><li>N = 172 </li></ul>
  96. 96. SIOP 5 results <ul><li>Use of preoperative CCT did not impact the survival parameters or reduced the risk of tumor rupture as compared to pre-op RT + CCT. </li></ul><ul><li>Downstaging was equal in both groups (43% vs 52% stage I) </li></ul><ul><li>Overall 3 yr survival same (89% vs 83%) </li></ul><ul><li>Major change in the pathological pattern e.g. massive necrosis more common with preop CCT + RT arm (53% vs 17%, p < 0.001) </li></ul>
  97. 97. NWTS 3 (1979-85) <ul><li>Questions: </li></ul><ul><li>Can Duration of Chemotherapy be shorted for stage I FH? </li></ul><ul><li>Can radiotherapy be eliminated for stage II FH patients? </li></ul><ul><li>Maximum effective RT dose for stage III FH patients? </li></ul><ul><li>Is Adriamycin necessary in stage II / III FH patients? </li></ul><ul><li>Will cyclophosphamide improve the survival in stage I – III UFH and Stage IV patients? </li></ul><ul><li>M&M: </li></ul><ul><li>Randomized. </li></ul><ul><li>N = 1160 </li></ul>
  98. 98. NWTS 3
  99. 99. NWTS 3 Results <ul><li>Short Course therapy equivalent to long course CCT in stage I FH (10 wk Vcr + ActD) </li></ul><ul><li>4 yrs RFS equivalent in patients with stage II FH with / without RT </li></ul><ul><li>10 Gy equivalent to 20 Gy in stage III FH, however patients with receiving Adriamycin + 10 Gy was 4% vs 10% in patients receiving 10 Gy with Vcr + ActD </li></ul><ul><li>Cyclophosphamide was helpful in patients with focal anaplasia where it improved the 4 yr RFS. </li></ul>
  100. 100. SIOP 6 (1980-87) <ul><li>Questions: </li></ul><ul><li>Is radiation (20 Gy) required in stage II patients in the post-op period? </li></ul><ul><li>Benefit of addition of doxorubicin in stage III patients vs intensified AV regimen? </li></ul><ul><li>Impact of long course of postoperative Act D (38 weeks vs 17 weeks)? </li></ul><ul><li>M&M: </li></ul><ul><li>Randomized. </li></ul><ul><li>N = 396 </li></ul>
  101. 101. SIOP 6 results <ul><li>In Stage II patients there were 8 relapses in non irradiated patients and 7 were “infield” compared to 1 relapse in 58 patients with local recurrence. </li></ul><ul><li>However all patients who died – did so as a result of disseminated Wilms Tumor </li></ul><ul><li>There was no difference in 4 yr OS (85% vs 90%) in the two arms </li></ul><ul><li>In stage I patients there was no significant benefit of the short course chemotherapy </li></ul><ul><li>In stage III patients there was a significant advantage in the addition of post op Doxorubicin </li></ul>
  102. 102. SIOP 9 (1987-93) <ul><li>Questions: </li></ul><ul><li>Appropiate duration of preop CCT 4 weeks vs 8 weeks? </li></ul><ul><li>“ Stage adapted adjuvant therapy” intoduced. </li></ul><ul><li>M&M: </li></ul><ul><li>Randomized. </li></ul><ul><li>N = 382 (852 registered) </li></ul>
  103. 103. SIOP 9 results <ul><li>4 weekly schedule of preoperative chemotherapy did not adversly impact upon the downstaging or the survival </li></ul><ul><li>5 yr OS was 92% vs 87% favouring the short course arm (p = NS) </li></ul><ul><li>Overall incidence of stage I tumors 63% </li></ul><ul><li>However in the stage II patients who did not receive flank RT there was a local relapse rate of 6.6% </li></ul><ul><li>The use of a more intensive AVE protocol in non irradiated patients with stage IIN0 disease was mandated by the findings of the SIOP 6 results. </li></ul>
  104. 104. NWTS 4 <ul><li>Questions: </li></ul><ul><li>Asked if a CCT regimen with reduced economic burden was effective: i.e. pulsed intensive ActD + Vcr in stage I-II FH patients and pulsed intensive ActD+Vcr+Dox in stage III-IV FH and stage I-IV UFH? </li></ul><ul><li>Impact of reduction of treatment duration from 15 months to 6 months in FH stage II – IV tumors. </li></ul><ul><li>“ Age modulated” radiation doses were used as in NWTS-1 for UFH stage I-IV. </li></ul><ul><li>M&M: </li></ul><ul><li>Randomized. </li></ul><ul><li>N = 495 </li></ul>
  105. 105. NWTS 4
  106. 106. NWTS 4
  107. 107. NWTS 5 results <ul><li>No significant difference was demonstrated between the 2-year relapse-free percentages for patients treated with the pulse-intensive regimens (89.4% vs 90.5%) </li></ul><ul><li>Pulse-intensive regimens produced less hematologic toxicity than the standard regimens, </li></ul><ul><li>The administered drug dose-intensity was greater on the pulse-intensive regimens. </li></ul><ul><li>At least $790,000 per year would have been saved if all United States children with stages I to IV favorable-histology Wilms' tumor were treated using the pulse-intensive regimens. </li></ul><ul><li>Use of shorter course of chemotherapy produced no reduction in the control or survival rates (4 yr RFS 88.7% vs 89.8%) </li></ul>
  108. 108. SIOP 93-01/GPOH <ul><li>Questions: </li></ul><ul><li>Treatment of stage I anaplastic / intermediate grade tumors with 4 weeks post operative program vs 8 weeks. </li></ul><ul><li>M&M: </li></ul><ul><li>Randomized. </li></ul><ul><li>N = 440 </li></ul>
  109. 109. NWTS 5 <ul><li>It was a non randomized study to evaluate the prognostic factors involved in WT </li></ul><ul><li>Also evaluated the impact of Surgery alone in children < 2yrs with FH stage I tumors weighing < 550 gms </li></ul><ul><li>Trial closed early due to RFS at 2 yrs < 90% (expected cufoff) – actual value 86% ; OS still remained at 100% </li></ul><ul><li>LOH at Chr 1p and 16q were significant in determining an adverse prognosis. </li></ul>
  110. 110. UKW-3 trial <ul><li>Randomized comparison of preoperative CCT vs Immediate Surgery </li></ul><ul><li>Conducted by the UK Children's Cancer Study Group </li></ul><ul><li>Time period: 1991 – 2001 </li></ul><ul><li>Pre-CCT trucut biopsy mandatory </li></ul>Preoperative Chemotherapy* Immediate Surgery Delayed Surgery after 6 weeks Protocol specific Adjuvant Therapy Vincristine: 1.5 mg/m 2 weekly ActinomycinD: 1.5mg/m 2 * Preoperative Adriamycin in doses of 30mg/m 2 x 3 weekly was given in event of pre-op unfavorable histology V V V V V V A A
  111. 111. Adjuvant Therapy
  112. 112. Results: Pretreatment Biopsy <ul><li>No needle track seeding </li></ul><ul><li>No increase in risk of recurrence </li></ul><ul><li>Resulted in another diagnosis in 12% patients </li></ul><ul><li>In 4% biopsy was not diagnostic </li></ul><ul><li>Complications: </li></ul><ul><ul><li>Fall in hemoglobin – 20% </li></ul></ul><ul><ul><li>Flank pain – 19% </li></ul></ul><ul><ul><li>Massive tumor bleed with emergency nephrectomy in 1 patient </li></ul></ul>
  113. 113. Results: Down-staging <ul><li>11% increase in stage I population (65.2% vs 54.3%, p = 0.13) </li></ul><ul><li>Significant improvement in down staging of stage III tumors (28% vs 9%, p = 0.008) </li></ul><ul><li>15 tumor ruptures in the immediate surgery vs 0 in the preoperative CCT group </li></ul><ul><li>Local relapses increased (11% vs 5% , p = NS) </li></ul><ul><li>No difference in OS / EFS </li></ul>
  114. 114. Results: Surgical Aspects <ul><li>Duration of surgery reduced significantly (96 min vs 104 min, p =0.0004) </li></ul><ul><li>Reduced blood loss </li></ul><ul><li>Reduced adhesions and ease of resection </li></ul><ul><li>Reduced risk of ruptures </li></ul>
  115. 115. Impact of the trial <ul><li>6 week course of preoperative CCT results in a more favourable stage distribution </li></ul><ul><li>Reduced risk of tumor spillage and surgical complications </li></ul><ul><li>Reduced overall treatment burden in the delayed treatment group due to stage adopted therapy: </li></ul><ul><ul><li>19.8% reduction in need for Doxorubicin and RT </li></ul></ul><ul><ul><li>11.4% reduction in need for Actinomycin D </li></ul></ul><ul><li>Question for future? - Is doxorubicin needed in the management of stage II patients after preoperative therapy (SIOP – 2001 trial looking into the issue!!) </li></ul>
  116. 116. Wilms Tumor in special situations
  117. 117. Relapsed / Refractory WT <ul><li>The most frequent site of relapse overall is the lungs </li></ul><ul><li>54% of all relapses were isolated pulmonary events </li></ul><ul><li>Factors that indicate an increased likelihood of salvaging relapsed tumors : </li></ul><ul><ul><li>Tumors with favourable histology </li></ul></ul><ul><ul><li>Recurred only in the lungs </li></ul></ul><ul><ul><li>Relapse in the abdomen where radiotherapy had not been included in the primary treatment; </li></ul></ul><ul><ul><li>Relapse that occurred more than 12 months from diagnosis. </li></ul></ul><ul><li>The overall survival following relapse was only 24 -30 % . </li></ul>
  118. 118. Relapsed / Refractory WT <ul><li>Best results till date have been reported with the use of ICE regimen (Ifosfamide / Carboplatin / Etoposide) – given initially by the SFOP. </li></ul><ul><ul><li>Doses for Ifosfamide were 1.8 g/m 2 /d x 5 days, Carboplatin 400 mg/m 2 /d x 2 days, and etoposide 100 mg/m 2 /d x 5days (Abu-Ghosh et al) </li></ul></ul><ul><ul><li>RR – 73- 80% </li></ul></ul><ul><ul><li>Survival – 50 -60 % at 3yrs </li></ul></ul><ul><ul><li>Recent St Jude study evaluated modified doses of carboplatin (Calvert's Formula) to reduce the toxicity. </li></ul></ul><ul><li>Investigational chemotherapeutic agents: Irinotecan and oxaliplatin </li></ul><ul><li>In children with relapse without remission High dose chemotherapy with stem cell transplantation is an alternative. </li></ul>
  119. 119. RT for Recurrent Tumors <ul><li>For recurrent tumors recommendations are: </li></ul><ul><ul><li>< 12 mo of age: 12.6–18 Gy </li></ul></ul><ul><ul><li>In older children 21.6 Gy if previous radiation dose is ≤ 10.8 Gy. </li></ul></ul><ul><ul><li>A boost dose of up to 9 Gy to gross residual after surgery. </li></ul></ul><ul><ul><li>Total dose including previous irradiation not to exceed: </li></ul></ul><ul><ul><ul><li>30.6 Gy (<1 y of age) </li></ul></ul></ul><ul><ul><ul><li>39.5 Gy in older children. </li></ul></ul></ul>
  120. 120. Bilateral Wilms Tumor <ul><li>Account for 7% of all WT – 6% synchronous </li></ul><ul><li>Associated in 20% with genetic syndromes </li></ul><ul><li>NWTS 3,4 and 5 have refined the treatment </li></ul><ul><li>Both sides staged seperately </li></ul><ul><li>Metachronous tumors fare worse than synchronous </li></ul><ul><li>Long term survival rates 70 -80%. </li></ul>Initial open biopsy / Trucut biopsy and staging Downstaging with Chemotherapy Bench Surgery* Partial nephrectomy
  121. 121. Wilms Tumor in Adults <ul><li>Median age at presentation was 25 years </li></ul><ul><li>Most common presenting symptom was pain </li></ul><ul><li>There were more patients with stage III and IV disease than in childhood </li></ul><ul><li>Actuarial survival was only 24% at 3 years. </li></ul>
  122. 122. Wilms Tumor in Horseshoe Kidneys <ul><li>Abnormal fusion of metanephric blastema of the lower pole of the future kidneys at 6 th -7 th weeks of gestation. </li></ul><ul><li>50 -60 cases recorded in literature </li></ul><ul><li>2 fold increased risk of development of WT </li></ul><ul><li>Partial nephrectomy / bench surgery typically used for reduction of disease burden </li></ul><ul><li>Preoperative chemotherapy may be used to reduce the bulk of tumor </li></ul><ul><li>Post operative adjuvant radiation if given should be confined to the involved flank and a dose of 10.8 Gy is recommended. </li></ul>
  123. 123. Follow up and Toxicity
  124. 124. Treatment toxicity <ul><li>Chemotherapy </li></ul><ul><ul><li>Vincristine: Neurotoxicity (7-8%) </li></ul></ul><ul><ul><li>Actinomycin D: Hepatic Veno-occlusive disease </li></ul></ul><ul><ul><li>Anthracyclines: Long term cardiotoxicity (10 -25% with cumulative doses of 300 mg/m 2 ) </li></ul></ul><ul><li>Surgery </li></ul><ul><ul><li>32% have some renal dysfunction in opposite kidney after 10 yrs </li></ul></ul><ul><ul><li>9% proteinuria </li></ul></ul><ul><ul><li>11% hypertension </li></ul></ul><ul><li>Radiation therapy </li></ul><ul><ul><li>Loss in potential height (loss of potential height 7cm at 1 yr) </li></ul></ul><ul><ul><li>Second malignancies </li></ul></ul>
  125. 125. Follow up Protocol
  126. 126. Conclusion <ul><li>MC renal tumor of childhood </li></ul><ul><li>Usually has a large size on presentation and high chance of distant spread </li></ul><ul><li>However prognosis excellent with modern day therapy </li></ul><ul><li>Surgery with adjuvant chemotherapy is the mainstay of therapy </li></ul><ul><li>Radiation therapy given judiciously can reduce recurrences and improve QOL </li></ul><ul><li>Treatment deintensification has been the theme of successive RCTs. </li></ul>
  127. 127. Thank You