Renal Cell Carcinoma Tim Fenske April 18, 2003 Case - PowerPoint PPT Presentation

Loading...

PPT – Renal Cell Carcinoma Tim Fenske April 18, 2003 Case PowerPoint presentation | free to download - id: 3ba7d2-NTdjY



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

Renal Cell Carcinoma Tim Fenske April 18, 2003 Case

Description:

Renal Cell Carcinoma Tim Fenske April 18, 2003 Case presentation 57 yo male was Dx with a 5x6 cm RCC in 7/99 by CT. Bone scan negative. Underwent radical nephrectomy ... – PowerPoint PPT presentation

Number of Views:135
Avg rating:3.0/5.0
Slides: 54
Provided by: hematolog9
Category:
Tags: april | carcinoma | case | cell | fenske | renal | tim

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Renal Cell Carcinoma Tim Fenske April 18, 2003 Case


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

3
(No Transcript)
4
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

5
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)

6
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)

7
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

8
Pathology molecular markers
  • None are routinely used
  • However proliferation markers (Ki-67, PCNA) and
    somatic mutations in VHL gene are being explored

9
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

10
Pathogenesis
  • Absence of VHL ? accumulation of hypoxia-induced
    proteins like VEGF ? vascular proliferation ?
    tumorigenesis
  • P53 mutations are seen (rarely)

11
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

12
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

13
Atriocaval involvement
14
Systemic or paraneoplastic symptoms
15
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

16
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

17
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

18
Staging
19
Prognosis
20
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

21
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

22
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

23
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)

24
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

25
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

26
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.

27
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

28
Medical management
  • 50 of pts have locally advanced or metastatic
    disease at presentation
  • Surgery alone is not considered curative

29
Medical management
  • Hormonal Rx
  • Progestins 0-20 resp rate
  • Androgens, antiestrogens
  • 1-2 resp rates, brief
  • Medroxyprogesterone
  • Prob no benefit except stimulation of appetite

30
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

31
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.

32
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

33
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

34
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

35
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)

36
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

37
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

38
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)

39
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

40
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)

41
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

42
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

43
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)

44
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)

45
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

46
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).

47
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

48
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

49
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

50
Management of paraneoplastic problems
  • Hypercalcemia
  • Pamidronate or zolendronate
  • These may also alter the bone microenvironment in
    a way that interrupts tumor growth

51
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

52
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

53
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
About PowerShow.com