Renal Cell Carcinoma

1
Renal Cell Carcinoma

• Tim Fenske
• April 18, 2003

2
Case presentation

• 57 yo male was Dx with a 5x6 cm RCC in 7/99 by
  CT. Bone scan negative.
• Underwent radical nephrectomy in 9/99. Margins
  were free with no invasion into capsule or renal
  pelvis. Retroperitoneal fat specimen was
  unremarkable.
• 2/01 bone scan negative
• In 12/02 develped ascites and 40 wt loss
• CT scan showed massive RP LAD (22x13 cm in
  aggregate), and celiac LAD new since 6/00, felt
  to be most consistent with lymphoma
• Flow cytometry on ascites fluid showed 96
  non-hematologic cells and 4 reactive T cells
• In 1/03 underwent CT-guided Bx of RP gt
  metastatic RCC

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(No Transcript)
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Epidemiology

• Responsible for 80-85 of primary renal neoplasms
• TCC next most common (8)
• 31,000 cases in U.S. in 2002
• 12,000 deaths per year
• Incidence increased gradually over past 20 yrs,
  probably due to advances in radiology

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Risk factors

• Risk factors
• Smoking (2 fold)
• Possibly asbestos, cadmium or gasoline exposure
  (1.42 fold)
• HTN ?
• Acquired cystic disease of the kidney (30 fold)
• ACKD occurs in 35-50 of chronic dialysis (usu
  after 8-10 yrs of dialysis)

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Other risk factors - genetic

• Von Hippel-Lindau disease (1/3 get RCC)
• Autosomal dominant
• Abnormalities in chromosome 3p
• Hereditary papillary RCC
• Mutated c-met oncogene (chromosome 7p)
• Tuberous sclerosis (lt5)
• Autosomal dominant
• 2 loci have been identified
• chromosome 9 (TSC1)
• chromosome 16p (TSC2), near the gene for the most
  common form of autosomal dominant polycystic
  kidney disease (PKD1)

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Pathology

• Five subtypes
• Clear cell (75-85)
• Proximal tubule origin
• Abnormalities in chromosome 3p
• Chromophilic (15)
• 85 of these are Dx as stage I tumors
• Also prox tubule in origin, but 3p is normal
• Trisomy 12, 16, 20 can be seen
• Chromophobic (5)
• Oncocytic (uncommon) usually not aggressive
• Collecting duct origin
• 11q13 rearrangments in some cases
• Collecting duct (Bellinis duct) tumors very
  rare
• Unclassifiable (lt3) prob has worse prognosis

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Pathology molecular markers

• None are routinely used
• However proliferation markers (Ki-67, PCNA) and
  somatic mutations in VHL gene are being explored

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Pathogenesis

• Role of VHL locus (3p)
• VHL is mutated in 57 of sporadic cases
• In 98 of cases in which VHL is mutated there is
  LOH
• VHL expressed at high levels in kidney and brain
• Codes for elongin B and C
• facilitate rate of transcriptional elongation
• May also serve to suppress TGF-? and TGF-?
• Transfection of normal VHL into RCC cell lines
  leads to decrease tumor in mice but no decrease
  in growth in vitro

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Pathogenesis

• Absence of VHL ? accumulation of hypoxia-induced
  proteins like VEGF ? vascular proliferation ?
  tumorigenesis
• P53 mutations are seen (rarely)

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Clinical features

• Classic triad of flank pain, hematuria, and a
  palpable abdominal renal mass, is uncommon (9)
• If present, strongly suggests metastatic disease
• In a 1971 review, hematuria, abdominal mass,
  pain, and weight loss most common presentation
• In the 1970s, 10 were discovered incidentally,
  61 in 1998
• 25 metastatic at diagnosis

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Presenting signs and symptoms

• Hematuria (40)
• Often with clots (non-glomerular)
• Abdominal or flank mass (more with lower pole
  tumors) if pt thin
• Scrotal varicocele (mostly L sided) 11
• Obstruction of gonadal vein where it enters the
  renal vein
• Vena caval / atrial involvement (5-10)
• can produce ascites, hepatic dysfunction, PE
• Local extension (liver, pancreas, colon)
• S/Sx of metastatic disease
• lung, lymph nodes, bone, and liver
• Brain, ipsilateral adrenal, contralat kidney

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Atriocaval involvement
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Systemic or paraneoplastic symptoms
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Endocrine abnormalities

• Erythrocytosis (1-5)
• Mutate VHL protein impaired 02 sensing
• Excess erythropoietin production
• Excess parathyroid hormone related protein
  (PTHrP)
• Hypercalcemia (15)
• PTHrP, lytic bone lesions, or excess production
  of IL-6 can all contribute

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Pre-surgical evaluation

• Diagnosis most often occurs now due to abdominal
  CT or ultrasound performed for another reason
• Ultrasound can differentiate simple cysts from
  other lesions with gt95 accuracy. If not clearly
  a cyst ? CT. D/Dx mainly RCC, hamartoma,
  xanthogran pyelo
• CT scan 91 accurate for staging (as compared to
  stage after surgery)
• 98 sens, 96 spec for renal vein invasion
• 83 sens, 88 spec for metastatic LAD
• 46 sens, 98 spec for perinephric invasion
• 100 spec for adjacent organ invasion

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Pre-surgical evaluation (cont.)

• CXR if no LAD on abdom CT, otherwise, get chest
  CT
• MRI useful if IVC/atrial involvement suspected
  and to identify extent of IVC involvement
• Bone scan esp if gtT3a or if nodes
• PET scan may be more sens for bony mets
• Renal arteriography if nephron sparing approach
  planned

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Staging
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Prognosis
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Prognostic factors

• Invasion into caval wall
• Tumor thrombus extending above diaphragm
• For pts with advanced disease, overall survival
  is poor, but certain features are relatively
  favorable
• Long interval from surgery and mets
• PS 0-1
• Single site of met disease (esp if lung)
• No RP LAD
• High LDH, Ca gt10, anemia, prior chemo - adverse

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Obtaining tissue

• If synchronous lesions Bx of met lesion is
  preferred
• Isolated solid renal mass ? resect
• Partial or complete nephrectomy
• Pre-op needle Bx not usually done due to concerns
  of seeding peritoneum and due to low specificity

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Surgical management

• Stage I (lt7cm) or Stage II (gt7cm but limited to
  kidney, no nodes or mets)
• ? partial or rad nephrectomy
• Partial if
• Bilat tumors
• Pt with solitary kidney
• CRI
• Small (4cm) or tumor at pole
• Lap nephrectomy possible if mass lt10cm
• Less operative morbidity and shorter hosp stays

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Surgical management

• Stage III
• invasion into adrenal or perinephric region
• Not beyond Gerotas fascia
• Enlarged nodes in abdomen (often inflammatory and
  not malignant)
• Renal vein or IVC invasion
• ? Rad nephrectomy
• If IVC involvement above hepatic veins,
  technically difficult surgery (often requires C-P
  bypass)

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Surgical management

• Stage IV disease
• Extension beyond Gerotas fascia
• More than one regional node group
• Frank mets
• ? Nephrectomy done only for palliative purposes
  or as part of an immunoRx treatment program
  (Debulking nephrectomy)
• Dissection of regional nodes can provide
  important prognositc info
• If microscopic node involvement, 50 5yr OS

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Surgical management

• Debulking nephrectomy
• Flanigan et al (NEJM 2001)
• 246 pts, met RCC at presentation
• IFN alpha, 5MU/m2 3x per week alone, vs
  nehprectomy, then IFN alpha
• 11mo vs 8 mo med survival in favor of latter
• Michisch et al (Lancet 2001)
• Similar design, 83 pts
• Median survival 17 mo vs 7 mo in favor of DN
• However Benefit to DN only in those who go one
  to get immunoRx. So need to choose pts carefully

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Debulking nephrectomy

• Criteria
• gt75 debulking possible
• No CNS, extensive liver or bone mets
• Adequate pulm and cardiac function
• Clear cell histology (if histo known)
• Otherwise, many pts wont end up getting immunoRx
  and benefit of DN will be lost.

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Non-medical management of metastatic disease

• Metastatic disease
• If single or a few met lesions (esp if lung, bone
  or ipsi adrenal) ? resection can be curative
• Resection of residual disease after response to
  IL-2 appears effective with a 37 2 yr PFS
• Path often shows lymphocytic infiltrate around
  residual tumor, or no residual tumor cells
• Stereotactic radiosurgery for small (lt3cm) brain
  mets
• One study looked at pts with avg of 6 lesions
• Local control rate of 99
• If gt1 lesion, addition of WBI may help
• RF or cryo-ablation
• Possible alternative to surgery
• Under investigation for small tumors

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Medical management

• 50 of pts have locally advanced or metastatic
  disease at presentation
• Surgery alone is not considered curative

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Medical management

• Hormonal Rx
• Progestins 0-20 resp rate
• Androgens, antiestrogens
• 1-2 resp rates, brief
• Medroxyprogesterone
• Prob no benefit except stimulation of appetite

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Systemic chemotherapy

• Single agent
• Vinblastine 2.5 25 resp rate
• Floxuridine 10-20 resp rates in small studies
• Review of 72 diff regimens (mainly single agent),
  found resp rate of 5.6
• Mostly limited responses, rare to see increased
  survival

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Chemotherapy

• Combination chemoRx
• Gemcitabine / 5FU (Rini et al, JCO 2000)
• 17 resp rate
• PFS 29 weeks
• Unclear if superior to single agent Rx
• Overall, RCC is considered chemoRx resistant, and
  no regimen can be considered standard of care at
  this time.

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Reasons for chemo resistance of RCC

• Proximal tubule cells (source of most RCC), have
  high expression of P-glycoprotein (MDR) mRNA
• In one study 6/8 RCCs and 4/4 RCC cell lines
  overexpressed MDR
• Another study if 1 or gt cells () for MDR, PFS
  4mo vs 27 mo
• Attempts to use MDR modifiers like CsA or PSC 833
  have so far been unrewarding

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Immunotherapy

• Interferon alpha
• Approx 15 resp rate
• Median time to response 4 mo
• Often short-lived and/or partial responses
• CR rate only 2
• Largest study to eval long-term outcome (Motzer
  et al, JCO 2002)
• Retrospective review of 463 pts on 6 trials
• Median OS 13 mo
• 14 2yr PFS

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Immunotherapy

• No clear benefit to IFN-alpha vinblastine or
  5-FU
• IFN-alpha cis-retinoic acid (Motzer et al, JCO
  2000)
• IFN-alpha at 3-9 MU/d SC /- cis retinoic acid
• 19 vs 10 2 yr PFS in favor of combination
  (p0.05)
• IFN-gamma
• 11 resp rates in some studies
• Other studies no signif activity as monoRx

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Immunotherapy

• IFN alpha IFN gamma
• Promising results in mice
• 8-30 resp rates in phase I studies
• 11 resp rate with 28 rate of grade IV tox
• IFN alpha vinblastine
• 16mo vs 9 mo medial survival in one study
• 10 resp rate for both in another study
• Overall prob no better than IFN alone
• IFN alpha floxuridine (Falcone et al, Cancer
  1993)
• 33 rate in one small study (16 pts)

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Immunotherapy IL-2

• High dose bolus IL-2 LAK cells
• In mid-1980s
• Dramatic and durable responses in some pts
• Later, IL-2 alone shown to be equivalent
• High-dose IL-2
• 1992 FDA approval based on 7 phase II trials
  (255 pts)
• 600,000 720,000 IU/kg q8h up to 14 doses.
  Repeat q 12 weeks, up to 3 cycles
• Pts with excellent organ function.
• May need ICU monitoring

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Immunotherapy IL-2

• High-dose bolus IL-2
• 14 resp rate
• 7 CR, 7 PR
• 23 mo median duration of response
• 4 toxic death
• If CR or PR? surgery ? CR, rare to relapse after
  20 mo. Some of these are prob cured

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Immunotherapy IL-2

• Cont infusion IL-2
• Slight decrease in resp rate
• No improvement in toxicity
• Inhalational Rx
• Results confusing, as it was given with SC doses
  as well
• Outpt SC admin
• 6 PR rate in one study
• 22 PR rate in another (incomplete f/u in this
  study Sleijfer, JCO 1992)

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Immunotherapy IL-2

• Lower dose IL-2 IV therapy
• Only 4 resp rate c/w 16 for std dosing and 11
  for SC dosing.
• Low dose IL-2 and SC dosing had less toxicity
• Repeat IL-2 treatement
• For pts who respond and then relapse, only 2
  will respond to the same IL-2 regimen

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Immunotherapy IL-2

• Minimizing toxicity of IL-2
• IL-2 stimulates IL-1, TNF alpha, IFN gamma, NO
• Co-admin of L-NMMA (NO inhibitor) led to
  improvement in hypotension in all patients with
  IL-2 induced hypotension (Kilbourn et al, Cancer
  J Sci Am 2000)

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Combinations of IL-2 and IFN gamma

• Low dose IL-2 IFN gamma
• Intermed dose IL-2 IFN gamma
• Low dose IL-2 IFN gamma CD8 TILs
• Some studies have shown benefit (often not
  reproducable)
• Data not convincing enough to replace hi-dose
  bolus IL-2 as std of care

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Nonablative stem cell transplantation

• Since RCC is very sensitive to immunomodulation,
  would expect graft versus tumor effect would be
  possible for RCC
• Childs et al (NEJM 2000)
• 19 pts with refractory RCC
• Cytoxan / fludarabine conditioning
• HLA-ident or mismatched sib allo Tx
• Reponse delayed only seen after 100 donor
  cells in marrow
• GVHD grade 2-4 ? 90 chance of response
• Overall 47 resp rate

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Nonablative stem cell transplantation

• Rini et al (JCO 2002)
• 15 pts, conditioned with fludara / cytoxan
• Tacrolimus mycophenolate for GVH proph
• GVHD seen only in 8 pts
• 33 resp rate (44 in those with persistent
  engraftment)

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Other agents

• IL-12 rare responses in phase I trials
• Angiogenesis inhibitors
• Anti-VEGF Abs appear to have some acitivity
• Thalidomide low resp rate, but 56 without
  progression after 6 or more months
• 28 PR or stable disease (gt6mo) (Escudier, Ann
  Oncol 2002)
• 55 PR or stable disease (Daliani, Cancer 2002)
• 50 PR or stable dz (gt 6mo)
• IL-4, IL-6 minor responses
• CCI-779 (mTOR inhibitor), anti-EGF Ab (ABX-EGF)

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Immunotherapy other

• Antigen pulsed dendritic cells
• vaccination with hybrid cells consisting of
  autologous tumor and allogeneic dendritic cells
• 17 patients with metastatic disease
• 6/17 pts responded (4 with CR)
• Next step is to test DC vaccines IL-2 or IL-12
  to drive the immune response generated
• Anti-lymphocyte Rx (ex-vivo activated memory T
  cells) (Graham et al, Semin Urol 1993)
• Increase in survival seen - 21 vs 8.5 mo

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Immunotherapy - other

• Autologous tumor vaccines
• (Doehn, Proc Am Soc Clin Onc 2002, abstract)
• 558 patients with resected pT2-3b, pN0-3, M0 RCC
• Randomized to to six monthly applications of an
  autologous tumor cell vaccine vs no adjuvant Rx
• Advantage seen only in patients with resected pT3
  disease (three year progression-free survival 74
  versus 66 percent).

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Adjuvant therapy - IFN

• Pizzocaro et al (JCO 2001)
• 2137 Stage II/III pts
• IFN alpha-2b, 6MU 3x/week x 6 mo
• No significant survival advantage
• Trump et al (Proc Am Soc Clin Onc, 1996 abstract)
• T3b-T4 or N1-N2 pts
• No advantage to adjuvant IFN overall
• A subgroup may (T3c, T4 or N2 pts) may have
  benefited being tested in a separate trial

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Adjuvant Rx - radiation

• 3 different studies of post-op XRT
• No benefit in 2, some benefit in 1
• However unsophistocated techniques and XRT
  protocols used, with high (20) mortality
• Studies of pre-op XRT have also been done
• No benefits seen, but again each had major flaws

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Ongoing trials

• CALGB 69901 A phase II randomized trial of
  carboxyaminoimidazole
• May work as an angiogenesis inhibitor
• A Multi-center, Randomized Phase III Study of
  Adjuvant Oncophage Versus Observation
• a vaccine made from the patients tumor
• Gemcitabine (weekly x 3 weeks) capecitabine (qd
  x 3 weeks), 2 cycles
• UCN-01, a protein kinase C inhibitor
• Stereotactic XRT to 1-3 brain mets
• CCI-779 (mTOR inhibitor) plus IFN
• IL-12 IFN alpha
• IL-12 IL-2
• Thalidomide Taxol
• Nonablative stem cell Tx protocols

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Management of paraneoplastic problems

• Hypercalcemia
• Pamidronate or zolendronate
• These may also alter the bone microenvironment in
  a way that interrupts tumor growth

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Palliative / supportive care

• Pain, bleeding
• Analgesic medications
• XRT to sites of painful mets (esp bone mets)
• XRT for cord compression
• Angioinfarction (renal art embolization)
• No survival benefit but can relieve Sx
• Clot colic
• Ureteral stents
• hydration
• HyperCa, fatigue, fever, decr appetite
• NSAIDs, bisphosphonates, hydration, appetite
  stimulants

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Who to Screen for RCC ?

• For patients at high risk
• VHL
• Tuberous sclerosis
• ESRD on HD for gt 3-5 yrs
• Strong Fam Hx
• Possibly pts with h/o XRT

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Conclusions

• Can present in numerous ways (the internists
  tumor)
• Interesting advances in understanding the
  underlying pathogenesis
• Surgical management is best hope for cures
• Numerous immunotherapies have benefit
• Emerging role for nonablative SCTx in certain
  patients
• No clear role for chemoRx or any adjuvant Rx
• Several interesting trials ongoing