Adrenocortical Carcinoma Current Management and Future Directions

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Adrenocortical Carcinoma- Current Management and
Future Directions

• James C. Mosley, III, M.D.

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J.K.

• HPI 57yo WF with h/o HTN, hypothyroidism,
  presents with 3 week history of painless
  gradually increasing BLE edema.
• Presented to PCP who ordered a CT C/A/P .
  Notable for large L renal mass with possible
  extension into the IVC and L renal vein.
• MRI obtained, notable for 10.2 x 8.3cm L adrenal
  mass with extension into IVC and L renal vein.
• Admitted to GU service for further evaluation.

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J.K.

• PMH
• HTN
• Surgical hypothyroidism 2/2 Hashimotos
• Bipolar II
• OA
• GERD
• Meds
• Hydralazine
• Synthroid
• Nexium
• Trazodone
• Depakote
• Talwin
• ALL cipro, codeine, demerol, azithromycin

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J.K.

• FH
• Father and several uncles with prostate CA
• HNSCC in great uncle
• SH
• RN in STL, married, no tob/EtOH/IVDU

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J.K.

• PE AF, BP 160/92, HR 88
• HEENT mildly coarsened facial features, OP
  clear, healed necklace incision
• CV RR
• Lungs CTAB
• Abdomen soft, NTND, BS, no masses, no HSM
• Ext no C/C/2 BLE to groin
• Neuro NF

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J.K.

• Labs
• WBC 5.3
• Hgb 9.8
• Plt 342K
• BUN 15
• Cr 1.4
• Na 139
• K 4.2
• LFTs wnl
• TSH 0.79
• Aldo 26.7

• Renin activity 2.6
• 24 free urine cortisol 18
• Normeta 0.39
• Meta undetectable
• Dopamine undetectable
• Epinephrine undetectable
• Norepi 314
• DHEA 3.8

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MRI

• 10.2 x 8.3 cm mass in left adrenal gland
• T2 hyperintensity and heterogeneity
• No signal drop-out to suggest adipose tissue
• Clear fat plane between mass and kidney
• Extends into L renal vein and IVC to just below
  the hepatic venous confluence

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PET

• Large L adrenal mass with extension into L renal
  vein and IVC with intense FDG uptake of SUV 49.
• No evidence of metastatic disease

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DDx

• Adrenocortical carcinoma
• Pheochromocytoma
• Lymphoma
• Etc

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Pathology

• FNA and core biopsies consistent with adrenal
  cortical neoplasm
• Unable to determine adenoma versus carcinoma

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Adrenocortical Carcinoma
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Background

• Rare diagnosis with incidence 0.2 to 1 per
  million per year, leading to 0.2 of cancer
  deaths
• Bimodal age distribution, with peaks in early
  childhood and 4th-5th decades
• Slightly more frequent in women
• Tobacco and OCP use may pose increased risk

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Pathogenesis

• Still unclear
• ACC has frequency of 1 in Li-Fraumeni
• Several series also have noted p53 mutations in
  sporadic cases of ACC
• BWS also associated with increased frequency of
  ACC
• Some sporadic cases noted to have rearrangement
  of the 11p15 locus with overexpression of IGF-II,
  either by duplication of paternal allele or loss
  of maternal allele.
• Increased expression of IGF-II demonstrated in
  gt90 of sporadic ACC in one series by microarray
  analysis
• ACC cell lines have demonstrated that IGF-II
  acting via IGF-IR is relevant for proliferation

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Presentation

• Historically, 60 of ACC present with signs of
  hormonal excess
• Cushings syndrome most common
• Sex steroids or precursors with resultant
  virilization/feminization or menstrual
  irregularities
• Hyperaldosteronism is relatively rare
• Remaining 40 occasionally present with local
  symptoms due to mass effect as tumor grows, but
  most present with very few symptoms at all.

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Laboratory Evaluation

• Thorough endocrine evaluation mandatory
• Pattern of endocrinopathy may provide clues to
  malignant potential
• Estradiol secretion in men
• High serum DHEA-S
• Subclinical cortisol secretion can place patient
  at risk for adrenal insufficiency
  post-operatively
• Endocrinopathy may allow for markers for
  following treatment response
• Need to exclude pheochromocytoma

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Laboratory Evaluation

• Should include
• 24 hour urine free cortisol /- dex suppression
• DHEA-S, 17a-OH progesterone
• 17a-estradiol in men, testosterone,
  androstendione
• Serum aldo and plama renin activity
• 24 hour urine catecholamines /- plasma
  metanephrines

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Imaging

• Size remains best predictor of likelihood of
  malignancy
• Mass gt6cm is 35-98 more likely to be ACC than
  smaller masses
• German registry of ACC demonstrates average tumor
  size 12cm
• CT detects 98 of adrenal carcinomas
• MRI scanning can also provide vascular invasion/
  tumor thrombosis information
• Various features on imaging can help discern
  malignant from benign lesions
• Lower lipid content
• Increased heterogeneity (gt10HU)
• Increased T2 attenuation on MRI
• Local invasion
• Delayed attenuation with CT gt35HU and washout lt50

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Biopsy

• Biopsies are difficult to interpret.
• Case series demonstrates complication rates
  approaching 10 with FNA.
• Large biopsy specimens often difficult to
  distinguish carcinomas from adenomas.

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Biopsy
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Weiss Classification

• 3 or more criteria on specimen is consistent with
  ACC
• Nuclear grade (III or IV)
• Number of mitoses (gt5/50 high-power fields)
• Presence of atypical mitoses
• Percentage of clear cells (gt25 of tumor)
• Diffuse architecture
• Microscopic necrosis
• Venous invasion
• Sinusoidal invasion
• Capsular invasion

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Staging

• Until 2004, no standard TNM classification system
  was widely used
• Most often utilized was Sullivan modification of
  the Macfarlane system

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Staging
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Staging
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Resection

• Surgical resection for stages I-III disease
  remains treatment of choice for long-term
  survival, especially in setting of R0 resection
• Still associated with 10-20 recurrence rates in
  patients with apparent R0 resections
• Some series report up to 85 recurrence rates
• Open resection still TOC for large tumors
• Incomplete surgical resection associated with
  median OS of lt12 mos, and several series document
  5-yr OS of 0

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Role of the medical oncologist- have we made
progress?
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Mitotane

• 1,1- dichloro-2-(o-chlorophenyl) ethane
  (o,p-DDD).
• Chemical relative to DDT
• Initially found to have adrenolytic activity in
  dogs in vivo, selectively destroying the zona
  reticularis and fasciculata.
• Inhibits the intramitochondrial conversion of
  cholesterol to pregnenolone and the conversion of
  11-deoxycortisol to cortisol, producing cortical
  necrosis in both the adrenal tumor and metastases
• First used more than 40 years ago in patients
  with ACC and was noted by Kayhoe in 1966 to be
  associated with a 34 ORR.

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Mitotane

• Large review of 551 cases in 1993 noted ORR of
  35, but responses were transient.
• Occasional anecdotal CRs reported
• Modern reviews seem to demonstrate less ORR

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Mitotane

• Difficult to ascertain true efficacy from these
  retrospective analyses due to lack of
  standardized criteria to measure responses

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Mitotane

• Usually administered in relatively high doses of
  gt3g/d
• Appears that drug levels of gt14mg/L are necessary
  to induce tumor regression.
• ADEs much more common at levels gt20mg/L
• Side effects are very common (up to 80) and are
  often dose-limiting
• GI and CNS are most common
• Others including hepatotoxicity, adrenal
  insufficiency, rash, etc, are often encountered.
• Important that adrenal replacement therapies are
  instituted and often requires high-dose
  glucocorticoids (gt50mg hydrocortisone qd)

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Adjuvant Mitotane

• Previous studies with small numbers of patients
  have not clearly demonstrated a clear benefit to
  mitotane in the adjuvant setting
• One study of 14 patients argued for a detrimental
  effect where all 6 patients who refused therapy
  had favorable outcome and compared the 8 who
  received mitotane

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Adjuvant Mitotane

• Italian group reported in NEJM in 2007 the final
  results of a retrospective analysis of 177
  patients on Germany and Italy
• Patients had undergone radical resection and
  received adjuvant mitotane versus no adjuvant
  therapy
• Primary endpoint was RFS

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Adjuvant Mitotane

• After median F/U of 56.7 mos, mitotane group had
  23 recurrences (48.9), versus 50 (90.9) and 55
  (73.3) recurrences in control groups
• Median RFS in mitotane group was 42 mos versus 10
  and 25 mos in control groups (plt0.001, p0.005)
• Median OS was 110 mos in mitotane group versus 52
  and 67 mos in control groups (p0.01, p0.1)

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Adjuvant Mitotane
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Cytotoxic Therapy

• Various cytotoxic chemotherapy agents and
  combinations have been investigated in small
  series, with varying degrees of success
• Results variable, but platinum has demonstrated
  highest degree of efficacy, with little
  improvement with additional agents

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Barriers to cytotoxic therapy

• ACC cells express high levels of mdr-1
• Results in high levels of P-glycoprotein (Pgp)
  which acts as a drug efflux pump
• Various chemicals are known to inhibit this
  mechanism, including mitotane in vitro

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EDP-M

• Berruti et al. reported in 2005 a phase II study
  of mitotane with etoposide, doxorubicin, and
  platinum
• All patients had unresectable LA or metastatic
  disease
• Patients were treated q4wks with
• Cisplatin 40mg/m2 d2, 9
• Etoposide 100mg/m2 d5-7
• Doxorubicin 20mg/m2 d1, 8
• Mitotane 1g/d with increase to max 4g/d
  continuously
• ORR was primary end-point

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EDP-M

• 72 patients were enrolled from 1993-2003
• 35/72 (48.6) had response
• 5/72 (6.9) had clinical CR
• 20/72 (27.8) had SD
• Median TTP and OS of the entire cohort were 9.1
  and 28.5 months respectively (18.2 and 47.7
  months respectively in patients attaining
  response)

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EDP-M Toxicity
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EDP-M

• Only 21 (29.2) patients tolerated 4g/d mitotane
• Due to toxicity with this regimen, Kahn reported
  in 2000 on the use of Streptozocin (Sz)
  Mitotane in the same setting
• Was better tolerated with less Grade 3-4 toxicity
• Had ORR 36 (n22, 1 CR, 7 PR)
• Led consensus group to state that both EDP-M and
  Sz-M are acceptable first-line therapies in
  patients with good PS who can tolerate intensive
  therapy

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FIRM-ACT

• First International Randomized Trial in Locally
  Advanced and Metastatic Adrenocortical
  Treatmement (FIRM-ACT)
• First randomized prospective phase III trial in
  ACC
• Based on consensus that mitotane streptozosin
  (Kahn regimen) as well as M-EDP are acceptable
  regimens for advanced disease in patients with
  good PS
• Target accrural of 300 patients
• Estimated completion date of 2010
• Full protocol can be viewed at www.Firm-ACT.org

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FIRM-ACT
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Tariquidar (XR9576)

• Specific non-competitive inhibitor of Pgp
• Inhibits the basal ATPase activity associated
  with Pgp
• Preclinical studies in cell lines with
  chemotherapeutic resistance demonstrated marked
  reduction of IC50 with use of Tariquidar
• Early dose-finding studies noted no dose-limiting
  toxicities
• Early Phase I study of Tariquidar vinorelbine
  in pts with refractory solid tumors demonstrated
  good tolerability in maximal doses of vinorelbine
  and side effects c/w dosing of vinorelbine

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Tariquidar (XR9576)

• Three Phase II studies have completed
• Combination with Taxol in refractory ovarian
  cancer
• Combination with doxorubicin in refractory solid
  tumors
• Advanced breast cancer with SD or PD during
  anthracycline-based or taxane-based therapy
• Study closed early due to riskbenefit
• Felt that Tariquidar added little to restore
  activity of therapy

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Tariquidar (XR9576)

• Two Phase III studies in NSCLC were closed early
  due to toxicity in Tariquidar arm
• Patients received carbo/taxol or vinorelbine with
  placebo or Tariquidar
• Doses of vinorelbine used were higher than
  previous phase I studies (25 mg/m2 vs 22.5 mg/m2)
• Doses of taxol were higher than that approved by
  the FDA for solid tumors (200 mg/m2 q3wks)
• Growth factors were not allowed
• In ACC, there is currently a Phase II study
  recruiting of Tariquidar with mitotane,
  doxorubicin, etoposide, and vincristine

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Other Targets?

• VEGF-inhibitors
• Current trial of sunitinib in ACC progressing
  after first-line therapy
• Primary endpoint is response rate (defined as
  PFS 12 weeks)
• Phase II study of bevacizumab in first-line
  therapy in non-resectable ACC
• Phase I trial of sorafenib bevacizumab in
  refractory solid tumors

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Other Targets?

• IGF-inhibitors
• IGF-II frequently overexpressed
• IGF inhibitors have demonstrated activity in
  other malignancies in early series
• Combinations of cytotoxic therapies with other
  Pgp inhibitors?
• Thalidomide, quinine, megace, verapamil,
  Valspodar, CSA

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ACC in a Nutshell
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Adrenocortical Carcinoma

• Rare diagnosis
• Surgery is only potentially curative modality
• Recent retrospective analysis in NEJM supports
  role of adjuvant mitotane
• Cytotoxic therapies often have low ORR due to Pgp
• FIRM-ACT study should elucidate standard for
  cytotoxic treatment with EDP-M versus Sz-M

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J.K.

• Followed up in outpatient setting
• Decision was made to initiate Mitotane therapy