Renal Tumors, Renal Cell Carcinoma, RCC, Radiation Oncology, Dr. Vandana, CSMMU, Lucknow (King George Medical College)

1. Presented By:
Dr. Vandana
Dept. of Radiotherapy
CSMMU, Lucknow 1

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.  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.  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. 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. Renal tumors…
 Benign
 Oncocytoma
 Papillary adenoma
 Angiomyolipoma
 Malignant
 Renal Cell Carcinoma (Adenocarcinoma of Kidney)
6

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. 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. 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. 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 Oncocytoma
Incidence (%) 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. Hereditary Renal Cancer Syndromes
Syndrome Chromosome Renal Other Manifestations
Location Manifestations
(Gene)
Von Hippel- 3p25 Clear cell renal Retinal and central nervous system
Lindau (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. Syndrome Chromosome Renal Manifestations Other Manifestations
Location (Gene)
Hereditary papillary 7q31 Papillary renal carcinoma None
renal carcinoma MET type 1: solid, multiple and
type1(HPRC) bilateral
Hereditary 1q42-43 Papillary renal carcinoma Uterine leiomyomas
leiomyomatosis and FH type 2, collecting duct and leiomyosarcomas;
renal cell carcinoma carcinoma: solitary, cutaneous leiomyomas
(HLRCC) aggressive
12

13. Syndrome Chromosome Renal Manifestations Other Manifestations
Location
(Gene)
Birt-Hogg-Dubé 17p11.2 Hybrid oncocytic renal tumors, Benign tumors of hair
syndrome (BHD) BHD chromophobe and clear cell follicle (fibrofolliculomas);
renal carcinomas, oncocytomas: lung cysts, spontaneous
multiple, bilateral pneumothoraces
Constitutional 3p; Not known; Clear cell renal carcinoma: None
chromosome 3 VHL somatic multiple, bilateral
translocation mutations 84%
- 98%
13

14. 14

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. 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. Diagnostic Work-Up
 General-History, Physical examination
 Laboratory studies
 CBC, LFT's, 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. 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. Figure : Computed tomography demonstrates
a right renal carcinoma (m) with a large
contralateral adrenal metastasis (a).
Figure: CT scan shows large left renal mass
with calcification (m) invading the left renal
vein (arrow).
19

20. Figure: T1-weighted magnetic
resonance image demonstrates
tumor (m) and vascular invasion
(arrow). Flowing blood (v) in the
left 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. Robson Modification Of the Flocks &
Kadesky Staging of RCC
Tumor 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. TNM staging
T - primary tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Tumour confined to kidney, <7cm
T1a ≤4cm, confined to kidney
T1b >4cm but <7cm, confined to kidney
T2 Tumour >7cm, confined to kidney
T3 Tumour extends into major veins or adrenal or perinephric tissue but not beyond Gerota’s fascia
T3a Direct invasion of adrenal gland, perirenal and/or sinus fat
T3b Gross extension into renal vein or IVC
T3c Extends into IVC above diaphragm or wall of IVC
T4 Invasion beyond Gerota’s fascia
N - regional lymph nodes
NX Nodes cannot be assessed
N0 Regional lymph nodes not involved
N1 Metastasis in a single regional lymph node
N2 Metastases in >1 regional lymph node
M - distant metastases
MX Metastases cannot be assessed
M0 No distant metastases
M1 Distant metastases
22

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. 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. Management
 Localized disease
 Metastatic disease
25

26. Management of Localized disease
Localized disease
Surgery Radio Therapy
26

27. Surgery- Radical nephrectomy
Gold standard treatment for localized RCC with
contralateral normal kidney, adequate surgical
margin.
Principles of Surgery- Early ligation of renal artery
and vein , removal of kidney including Gerota’s
fascia, removal of ipsilateral adrenal gland, regional
lymphadenectomy from crus of diaphragm to aortic
bifurcation.
27

28. Nephron Sparing Surgery
Indications
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. 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. 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. 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. 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. 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. 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. 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. Figure: A CT-based treatment plan using a combination of four fields (anterior, posterior, right
lateral, and right posterior oblique) to cover the tumor bed (dark oval) with 54 Gy (isodose line
displayed). This combination of fields and beam’s-eye-view shaping allows sparing of the liver,
bowel, and spinal cord
36

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. Management of Metastatic Disease
Metastatic
Disease
Radio Chemo Targeted Immuno
Surgery
Therapy Therapy Therapy Therapy
38

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. 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. 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. 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. 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. 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. 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. 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. Thank you !
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