Renal Tumors, Renal Cell Carcinoma- Dr. Vandana

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Renal Tumors, Renal Cell Carcinoma, RCC, Radiation Oncology,

Dr. Vandana, CSMMU, Lucknow (King George Medical College)

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Renal Tumors, Renal Cell Carcinoma- Dr. Vandana

  1. 1. Presented By:Dr. VandanaDept. of RadiotherapyCSMMU, Lucknow 1
  2. 2. Anatomy of Kidney  pair of organs located in the abdominal cavity on either side of the spine in a retroperitoneal position.  Adrenal glands rest on top of each kidney  Approx. at vertebral level T12 to L3, right kidney being slightly lower than the left.  Long axis of kidney is directed downward and laterally  Approx. 11–14 cm in length, 6 cm wide and 4 cm thick  weighs around 150 gm in males & 135 gm in females.  Mobile Organ, move vertically within retroperitoneum 0.9 cm to 1.3 cm., as much as 4 cm during normal respiration 2
  3. 3.  The kidney is surrounded by tough fibrous tissue, the renal capsule, which is itself surrounded by perinephric fat, renal fascia (of Gerota) and paranephric fat. parenchyma, of the kidney is divided into two major structures: renal cortex and renal medulla Fig: Anterior relations of kidneys Fig: Posterior relations of kidneys 3
  4. 4.  Blood Supply  Approx. 20% of the cardiac output .  From renal arteries, left and right, which branch directly from the abdominal aorta.  renal vein emerges from hilum and drains into the inferior vena cava. Lymph Drainage : to the lateral aortic lymph nodes around the origin of the renal artery. Nerve Supply:  Through renal sympathetic plexus (T10 – L1) fibres, mainly vasomotor.  Afferent nerves T10 to T12 thoracic nerves. Functions  Excretion of wastes,  Acid-base homeostasis,  Osmolality regulation, Blood pressure regulation and Hormone secretion 4
  5. 5. Renal Tumors 51,000 cases diagnosed and more than 12,900 deaths annually in the US Account for approx. 3% of adult malignancy 5
  6. 6. Renal tumors… Benign  Oncocytoma  Papillary adenoma  Angiomyolipoma Malignant  Renal Cell Carcinoma (Adenocarcinoma of Kidney) 6
  7. 7. Renal Cell Carcinoma First described by Konig in 1826. In 1883 Grawitz, noted the fatty content of cancer cells similar to that of adrenal cells. All these tumors arise from Renal tubular epithelium. accounts for 80–85% of kidney cancer 2% to 4% increase in incidence per year 7
  8. 8. Epidemiology Male predominance (1.6:1.0 M:F) Highest incidence between age 50-70 -Median age of diagnosis is 66 years -Median age of death 70 years Majority of RCC occurs sporadically Highest incidence in Scandinavia and North America, lowest in Africa 8
  9. 9. Risk Factors Tobacco smoking contributes to 24-30% of RCC cases - Tobacco results in a 2-fold increased risk Environmental: Cadmium, thorium-di-oxide, petroleum and phenacetin analgesics. Occupational: leather tanners, shoe workers, asbestos workers. Hormonal: diethylistillbestrol, Obesity, HTN 35% - 47% pt on long term dialysis develop Acquired polycystic kidney disease, out of which 5.8% develops Renal cancer. 9
  10. 10. RCC is not one disease… It is made up of no. of different types of cancers with different histology, different clinical courses and caused by different gene. Type Clear cell Papillary type 1 Papillary type 2 Chromophobe OncocytomaIncidence (%) 75% 5% 10% 5% 5% Associated VHL c-Met FH BHD BHD mutations A sarcomatoid variant represents1% to 6% of renal cell carcinoma and these tumors are associated with a significantly poorer prognosis. BHD=Birt-Hogg-Dubé; FH=fumarate hydratase; VHL=von Hippel-Lindau. 10
  11. 11. Hereditary Renal Cancer Syndromes Syndrome Chromosome Renal Other Manifestations Location Manifestations (Gene)Von Hippel- 3p25 Clear cell renal Retinal and central nervous systemLindau (VHL) VHL carcinoma: solid hemangioblastomas; pheochromocytomas; and/or cystic, pancreatic cysts and neuroendocrine multiple and tumors; endolymphatic sac tumors; bilateral epididymal and broad ligament 28%-45% cystadenomas 11
  12. 12. Syndrome Chromosome Renal Manifestations Other Manifestations Location (Gene)Hereditary papillary 7q31 Papillary renal carcinoma Nonerenal carcinoma MET type 1: solid, multiple andtype1(HPRC) bilateralHereditary 1q42-43 Papillary renal carcinoma Uterine leiomyomasleiomyomatosis and FH type 2, collecting duct and leiomyosarcomas;renal cell carcinoma carcinoma: solitary, cutaneous leiomyomas(HLRCC) aggressive 12
  13. 13. Syndrome Chromosome Renal Manifestations Other Manifestations Location (Gene)Birt-Hogg-Dubé 17p11.2 Hybrid oncocytic renal tumors, Benign tumors of hairsyndrome (BHD) BHD chromophobe and clear cell follicle (fibrofolliculomas); renal carcinomas, oncocytomas: lung cysts, spontaneous multiple, bilateral pneumothoracesConstitutional 3p; Not known; Clear cell renal carcinoma: Nonechromosome 3 VHL somatic multiple, bilateraltranslocation mutations 84% - 98% 13
  14. 14. 14
  15. 15. Natural History 7% diagnosed incidentally 45% present with localized disease, 25% with locally advanced disease, 30% with metastatic disease Lymph node metastases- 9% to 27% (renal hilar, para-aortic and paracaval) Renal vein – 21% & IVC 4% Distant metastases- lung (75%), soft tissue (36%), bone (20%), liver (18%), skin (8%) and CNS (8%) 15
  16. 16. Clinical Presentation Clinically occult for most of its course. Classic triad (occur in 5%-10% of patients)  flank pain,  hematuria,  palpable abdominal mass Hematuria present 40% of patients Systemic symptoms  Anaemia, Fatigue, Cachexia, Wt. Loss, Hypercalcemia, Hepatic Dysfunction Paraneoplastic Syndrome  Parathyroid like hormones, erythropoietin, renin, gonadotropins, placental lactogen, prolactin, enteroglucagon, insulin like hormones, adrenocorticotropic hormone and prostaglandins identified in RCC pt. 16
  17. 17. Diagnostic Work-Up General-History, Physical examination Laboratory studies  CBC, LFTs, alkaline phosphotase, BUN, creatinine, urinalysis Radiographic studies- Increased use of imaging has increased the detection of renal lesions most of which are simple cysts.  X-Ray KUB region  Ultrasonography- Excellent in distinguishing cystic from solid masses  Intravenous Urography - Starting point for hematuria evaluations and function of contralateral kidney  Computed tomography- Provides an excellent assessment of the parenchyma and nodal status.  Magnetic Resonance Imaging - excellent demonstration of solid renal masses and is image test of choice to demonstrate extent of vena caval involvement with tumor. Useful in patients with renal insufficiency 17
  18. 18. Metastatic Work-Up Chest X-ray or Chest CT CT/MRI scan of abdomen or pelvis Bone scan with plan films (for elevated alkaline phosphatase or bone pain). 18
  19. 19. Figure : Computed tomography demonstratesa right renal carcinoma (m) with a largecontralateral adrenal metastasis (a). Figure: CT scan shows large left renal mass with calcification (m) invading the left renal vein (arrow). 19
  20. 20. Figure: T1-weighted magneticresonance image demonstratestumor (m) and vascular invasion(arrow). Flowing blood (v) in theleft renal vein is black on this scan. Figure A: Axial T1-weighted image demonstrates a large left renal carcinoma with extension into the left renal vein (m) with protrusion into the IVC (v). B: Sagittal T1-weighted image shows the relation of the tumor thrombus (m) to the IVC (v) in the lateral projection. 20
  21. 21. Robson Modification Of the Flocks & Kadesky Staging of RCCTumor Stage Description I Renal cell carcinoma is confined to the kidneys II Renal cell carcinoma extends through the renal capsule but is confined to Gerota’s fascia III Renal cell carcinoma involves the renal vein or inferior vena cava (IIIA) or the renal hilar lymph nodes (IIIB) IV Renal cell carcinoma has spread to local adjacent organs (other than adrenal gland) or to distant sites 21
  22. 22. TNM stagingT - primary tumourTX Primary tumour cannot be assessedT0 No evidence of primary tumourT1 Tumour confined to kidney, <7cmT1a ≤4cm, confined to kidneyT1b >4cm but <7cm, confined to kidneyT2 Tumour >7cm, confined to kidneyT3 Tumour extends into major veins or adrenal or perinephric tissue but not beyond Gerota’s fasciaT3a Direct invasion of adrenal gland, perirenal and/or sinus fatT3b Gross extension into renal vein or IVCT3c Extends into IVC above diaphragm or wall of IVCT4 Invasion beyond Gerota’s fasciaN - regional lymph nodesNX Nodes cannot be assessedN0 Regional lymph nodes not involvedN1 Metastasis in a single regional lymph nodeN2 Metastases in >1 regional lymph nodeM - distant metastasesMX Metastases cannot be assessedM0 No distant metastasesM1 Distant metastases 22
  23. 23. Staging I T1 N0 M0 II T2 N0 M0 T3 N0 M0- Stage I-III: Localized disease III T1 N1 M0- Stage IV: Advanced, metastatic T2 N1 M0 disease T4 N0 M0 T4 N1 M0 IV Any T N2 M0 Any T Any N M1 23
  24. 24. Prognostic factors for RCC Pathologic stage 5 yr survival  T1 - 2 organ confined 70-90%  T3 50-70%  N+, M1 5-30% Tumour size  < 4 cm > 90%  4 - 10 cm 50%  > 10 cm 0% Histological type  Clear cell 70%  Papillary, Chromophobe 85%  Multilocular cystic 100%  Medullary, Collecting duct 0% 24
  25. 25. Management Localized disease Metastatic disease 25
  26. 26. Management of Localized disease Localized disease Surgery Radio Therapy 26
  27. 27. Surgery- Radical nephrectomyGold standard treatment for localized RCC withcontralateral normal kidney, adequate surgicalmargin.Principles of Surgery- Early ligation of renal arteryand vein , removal of kidney including Gerota’sfascia, removal of ipsilateral adrenal gland, regionallymphadenectomy from crus of diaphragm to aorticbifurcation. 27
  28. 28. Nephron Sparing SurgeryIndications 1. Bilateral RCC 2. RCC in a solitary functioning kidney 3. Unilateral RCC with contralateral kidney under threat of its future function (Renal artery stenosis, Chronic pyelonephritis , Hydronephrosis, Ureteral reflux, Calculus disease, Systemic disease such as diabetes ) 4. Tumor less than 4cms with normal opposite kidney. 5. Five year survival rate 75% to 85% 6. Local tumor recurrence of 10% is reported.Other Approaches 1. Radio frequency ablations 2. Cryo ablation 28
  29. 29. Radiotherapy Radiosensitivity of RCC is variable Animal experiments suggest a theoretical benefit to preoperative RT (? Reduce intra-operative seeding) Historically several series suggested clinical benefit to adjuvant (post-op) RT  Limited applicability because of long time span, improvements in staging, surgery, changing RT technology 29
  30. 30. Neo-adjuvant radiotherapy Rotterdam study  Radical nephrectomy vs neo-adjuvant RT (30Gy/15# APPA) plus nephrectomy  No overall survival or metastasis-free survival advantage (both 50% 5-year survival)  No improvement in resectability  Further study to 40Gy - still no advantage Swedish study  Poorer 5-year survival with pre-op RT (47% vs 63%)! 30
  31. 31. Adjuvant radiotherapy Some early studies suggested advantage to post-op RT but poorly designed and reported Newcastle (UK) study  Poorer survival with adjuvant RT (55Gy) vs surgery alone  Not stratified by grade or stage Copenhagen study  Stage II/III disease  No difference in RCC relapse  Significantly more GI complications (44%) in RT group  19% of deaths attributed to RT complications 31
  32. 32. Role of RT MSKCC and Kao retrospective series  Potential benefit of RT in selected cases where there is a high risk of local failure, ie:  Pre-op RT in unresectable, locally-advanced tumours (“downstaging”), including T3a/T3c  T3b (vena cava invasion) doesn’t necessarily increase risk of local failure  Incomplete resection with positive margins  Lymph node involvement  RT in these cases may improve local control but probably not overall survival Clear role in palliation 32
  33. 33. RT Techniques High energy photons (10 mv or above) from linear accelerator Conventional External Beam Radiation.  Technique-  AP/ PA field  AP/PA + Oblique field (in large tumor)  Portal  Upper- T10 – T11 Vertebra  Lower- transverse process of L3  Medial- 2 cm from midline or covering the opposite renal pelvis  Lateral- whole flank or tumor  For Rt. Sided tumor field reduction after dose of 3600cGy to 4ooocGy  Safe dose: 5040 cGy in 180 cGy/# over a period of 5-6 weeks  Boost of 540 cGy in 3# to small volume  Total dose: 5580 cGy 33
  34. 34. RT techniques Pre-op RT 40-50Gy to kidney + lymphatics for unresectable lesions may improve resectability 45-50Gy post-op in 1.8 to 2 Gy daily fraction nephrectomy bed and lymph node drainage site  10-15Gy boost (ie. ~60Gy total) to gross residual disease  Include scar to reduce chance of scar recurrence Dose limitations (fully fractionated)  Liver D30 <36-40Gy  Contralateral kidney <20Gy max  Spinal cord <45Gy max 34
  35. 35. Three-dimensional (3D) conformal radiation therapy CT planned, to image and reconstruct the tumor & surrounding kidney tissue in 3D Multiple field techniques, radiation beams can be shaped exactly to the contour of the treatment area, nearby normal tissue is usually spared. 35
  36. 36. Figure: A CT-based treatment plan using a combination of four fields (anterior, posterior, rightlateral, and right posterior oblique) to cover the tumor bed (dark oval) with 54 Gy (isodose linedisplayed). This combination of fields and beam’s-eye-view shaping allows sparing of the liver,bowel, and spinal cord 36
  37. 37. Intensity Modulated Radiation Therapy (IMRT) State-of-the-art radiation system. Treat difficult-to-reach tumors. Effectively treat tumor that surrounds spinal cord with very little radiation reaching cord. Reasonable consideration in kidney cancer due to sensitivity of adjacent surrounding structures. Useful if previously had conventional radiation therapy for kidney cancer, and are experiencing recurrent tumors in the treated area. 37
  38. 38. Management of Metastatic Disease Metastatic Disease Radio Chemo Targeted Immuno Surgery Therapy Therapy Therapy Therapy 38
  39. 39. Surgery Palliative Nephrectomy – Indicated in patients with  Severe hemorrhage,  Severe pain,  Paraneoplastic syndrome  or compression of adjacent viscera  Solitary metastasis can be resected and may show some survival advantage Therapeutic:  Not curative but produce some long-term survivors.  The possibility of disease-free survival increases after resection of primary tumor and isolated metastasis excision.  to decrease tumor burden in preparation for subsequent therapy 39
  40. 40. Surgery… Resection of met’s  in pt. not relieved from palliative RT  In solitary mets. Spontaneous regression of met’s  < 1 % of cases  only 4 (0.8%) of 474 patients in 9 series who underwent nephrectomy experienced regression of metastatic foci 40
  41. 41. Radio Therapy Palliation  Used for local or symptomatic metastatic disease, such as painful osseous lesions or brain metastasis.  Treatment field encompasses metastatic deposit (or local recurrence) with 2-3cm margins  Higher doses (up to 35-40Gy) may be required to overcome radioresistance  Symptomatic relief in 64-84% of patients 41
  42. 42. Chemotherapy RCC is a chemo resistant tumor. Phenomenon due to presence of multi drug resistant glycoprotein (MDR) in tumor cell - causes extrusion of the drug Conventional therapy has little to offer 5-FU alone has a response rate of 10%, On-going clinical trials of combination chemotherapy including Gemcitabine and 5-FU Limited data reveals some response in non-clear cell RCC to Carboplatin, Cisplatin plus Gemcitabine 42
  43. 43. Targeted Molecular Therapy New treatment approach that targets only the cancer. In renal cell carcinoma patients, this type of therapy uses drugs that stop the new blood vessels from growing, and targets certain factors that cause the cells to grow. Tyrosine kinase (TK) inhibitors block the intracellular domain of the VGEF receptor- Sunitinib (Sutent)- Sorafenib (Nexavar) 43
  44. 44. Targeted Molecular Therapy… Monoclonal antibody that binds circulating VEGF preventing the activation of the VEGF receptor- Bevacizumab (Avastin) Mammalian target of rapamycin (mTor) inhibitors  Temsirolimus (TMSR) 44
  45. 45. Immunotherapy Systemic type of treatment used to improve the body’s natural defenses. Boosts the immune system and slows down the cancer growth Clinical response to immunotherapy seen in patients with 1. Good performance status 2. Had a prior nephrectomy 3. Non bulky pulmonary or soft tissue metastasis 4. Asymptomatic patient Interferon (IFN) Interleukin (IL -2) 45
  46. 46. Summary RCC is relatively rare but increasing incidence Associated with tobacco and inherited disorders Surgery is the only curative modality for Stage I, II, and III RCC is radio resistant, RT’s role in paliation Stage IV disease holds poor prognosis despite advancements in molecular understanding IL-2, Sorafenib, Sunitinib, and Temsirolimus are FDA approved treatments for advanced RCC 46
  47. 47. Thank you ! 47

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