Current Management of Adrenal Cortical Carcinoma
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1 Current Management of Adrenal Cortical Carcinoma American Association of Clinical Endocrinologists Texas Chapter of the AACE Annual Meeting And Texas Endocrine Surgery Symposium August 4, 2017 Jeffrey E. Lee, M.D. Professor and Chair Irving and Nadine Mansfield and Robert David Levitt Cancer Research Chair Department of Surgical Oncology
2 DISCLOSURE Nothing to disclose
3 Controversies in the management of known and suspected ACC Role of laparoscopic vs open resection Extent of surgery necessary, including routine LND Role of adjuvant systemic therapy with mitotane Role of adjuvant radiation therapy Potential role for neoadjuvant systemic therapy in selected patients
4 Pearl 1: ACC presentation is almost always non-incidental Incidentaloma = adrenal tumor is totally unexpected Adrenal nodule identified on abdominal imaging performed for unrelated reasons Nonfunctioning adenoma, subclinical Cushing s Anticipated-oma = condition causes search for adrenal tumor Often no symptoms Adrenal metastasis from melanoma, lung cancer Pheochromocytoma in MEN 2A, VHL Non-incidentaloma = adrenal tumor is causing symptoms Signs or symptoms related to adrenal tumor prompt imaging Aldosteronoma, pheo, adrenocortical cancer
5 Pearl 2: Size and imaging characteristics help tell you whether the adrenocortical tumor is ACC ACCs rare & large; adenomas small & common For intermediate-size tumors (4-7 cm), imaging trumps size ACCs typically look like cancers (irregular, inhomogeneous) Adenomas usually low density (<10 HU), contain fat Adenomas wash out promptly (APW >60%, RPW >40%) Radiographically benign adrenal tumors rarely malignant PET avidity not too helpful (pheos =, adenomas PET-avid) Avoid preop FNA unless needed for systemic Rx planning Future: blood-based molecular diagnosis (microrna, DNA, exosomes) Barnett Surgery 2000
6 Optimal surgery for ACC Goal of surgery = complete resection Operative plan should maximize this probability Approach (minimally invasive vs. open) Should be appropriate to the tumor (invasive, soft, easily fractured) Include respect for ACC tumor biology Integrate plan for adjuvant therapy, if indicated Suggested general guidelines for surgery of adrenocortical tumors Preop planning to ensure safe, complete resection Minimally invasive surgery for presumed benign functioning tumors Minimally invasive surgery for presumed benign nonfunctioning tumors of intermediate size ( 4 cm) Open surgery for known or suspected ACC Possible preop therapy for borderline resectable ACC
7 Patient with a L adrenal mass and lung nodules 43 yo woman w/chronic back, abdominal pain 2003: 2.7 cm L adrenal nodule 2009: 4.4 cm L adrenal mass Chest CT: Pulmonary nodules Baseline AM cortisol 9.6, ACTH 6 After 1 mg dex AM cortisol 3.2 UFC 54.7 (normal ) Plasma mets normal Subclinical Cushing s ACC with lung mets? No! Benign adrenal adenoma Minimally invasive adrenalectomy
8 Retroperitoneoscopic adrenalectomy Randomized trial (N=65) of RPA vs. laparoscopic adrenalectomy Both procedures equally safe RPA patients had shorter OR time, less pain, quicker recovery Barczynski, Ann Surg 2014
9 Patient with a right adrenal mass 51 yo woman w/htn, hirsutism CT for? diverticulitis 9-cm R adrenal mass Inhomogeneous, irregular Post-dex cortisol 2 mcg/dl Plasma mets normal Aldosterone 4 ng/dl (3-16) Testosterone 328 (14-76) Dx: ACC Rx: Minimally invasive or open?
10 Potential problem with laparoscopic resection of ACC 43 year old woman presents with Cushing s syndrome 6 cm irregular L adrenal mass Laparoscopic adrenalectomy performed Capsular disruption, fragmentation of soft tumor; removed piecemeal Recurrence of Cushing s 7 months postop CT reveals carcinomatosis Gonzalez Surgery 2005
11 Laparoscopic resection of ACC Laparoscopic approach preferred for benign adrenal tumors Randomized trials in colon cancer: Laparoscopic resection in selected patients does not compromise oncologic outcomes No equivalent data for ACC (too rare) Outcomes reported at experienced centers for laparoscopic R0 resection of small ( 8cm) ACCs in selected patients have been similar those of larger ACCs done open BUT high rates of recurrence reported when laparoscopic resection of ACC is performed pre-referral What are the oncologic outcomes for patients with ACC who undergo laparoscopic vs. open resection? Lombardi Surgery 2012 Donatini Ann Surg Oncol 2014
12 Local-peritoneal recurrence: Laparoscopic vs open (U Michigan) Miller Surgery 2012
13 Survival: Laparoscopic vs open 44 consecutive patients who had surgery at one institution 18 laparoscopic, 26 open Open adrenalectomy ACCs were larger, more advanced stage Overall + recurrence-free survival trends favored open surgery (not significant) (Cleveland Clinic) Mir Ann Surg Oncol 2013
14 Pattern of recurrence: Laparoscopic vs open MDACC pts have better DFS than Outside pts (open or laparoscopic) Referral bias at work here (UTMDACC) Laparoscopic pts are at high risk for early peritoneal recurrence Stage-specific survival of laparoscopic patients also worse Cooper Surg Endosc 2013
15 Minimally invasive surgery for ACC: Recent data NCDB, 423 ACC patients stages I-III 137 MIS, 286 open MIS = smaller tumors, lower stage MIS associated with OS (stageadjusted, MV analysis) Multi-institutional study; 201 patients 13 centers; 47 MIS (9 converted to open), 154 open MIS = smaller tumors, lower stage No difference in DFS, OS based on approach BUT Be careful about your conclusions! Huynh, J Am Coll Surg 2017 Lee, J Gastrointest Surg 2017
16 LND for ACC German ACC Registry 47 of 283 patients (17%) had 5 LNs identified on path ( LND ) 5 LNs associated with larger ACC, multi-organ resection Overall 9% LN+ rate (25/283) 5 LNs resected associated with improved outcomes Caveats: LND likely a surrogate for surgical quality Nodes probably rarely + when normal on imaging and outside of surgical resection field Isolated failure in regional nodes appears to be rare Reibetanz Ann Surg 2012
17 Patient with a right adrenal mass 51 yo woman w/htn, hirsutism CT for? diverticulitis 9-cm R adrenal mass Inhomogeneous, irregular Post-dex cortisol 2 mcg/dl Plasma mets normal Aldosterone 4 ng/dl (3-16) Testosterone 328 (14-76) Dx: ACC Rx: Open resection Rx: Routine LND?
18 Patient with a right adrenal mass Open resection Total R adrenalectomy No liver, kidney, vena cava involvement Final path 10 cm ACC Margins free (R0) Nuclear pleomorphism Frequent mitotses Lymphvascular invasion Adjuvant mitotane (o,p -DDD)?
19 Adjuvant mitotane for ACC NEJM = 177 patients, median F/U 55 months MDACC = 218 patients, median F/U 88 months DFS MDACC (without mitotane) NEJM mitotane group DFS Referred NEJM control groups Quality and completeness of surgery is important; mitotane may help Terzolo New Engl J Med 2007 Grubbs Ann Surg Oncol 2010
20 Is adjuvant mitotane harmful? US Adrenocortical Carcinoma Group (13 institutions) 207 ACC patients treated ; 43% received mitotane Univariate analysis: Mitotane associated with poorer outcomes Multivariable analysis: Mitotane neither helpful nor harmful Only 17% with documented therapeutic mitotane level; short median Rx (6 months) Postlewait J Am Coll Surg 2016
21 Should we consider adjuvant XRT? Single institution study (U Michigan) 20 R0/R1 ACC patients who received XRT matched with 20 who did not Median XRT dose 55 Gy (45-60) Median F/U 34 months Local recurrence 1 vs 12 (P=0.0005) RFS, OS similar Sabolch Int J Rad Oncol Biol Physics 2015
22 Systemic therapy for advanced ACC Aggressive malignancy Some progress defining role of systemic therapy Mitotane ± as adjuvant therapy Therapy for advanced disease FIRM-ACT trial defined EDP+mitotane as standard 23.2% response rate Targeted therapies so far disappointing Ongoing evaluation of targeted Rx, immunotherapy For resectable patients, complete surgical removal remains the most important single treatment Fassnacht New Engl J Med 2012 Terzolo New Engl J Med 2007 Grubbs, Ann Surg Oncol 2010
23 Preoperative systemic therapy for ACC ACC patients may present with characteristics arguing against immediate surgery Unacceptably high risk for incomplete resection or early recurrence Unacceptably high risk for morbidity or mortality Preoperative therapy (e.g., mitotane) may be helpful in patients with recurrent ACC prior to reoperation Potential role for preoperative therapy followed by surgery in selected patients with primary ACC Gonzalez Surgery 2007
24 Patient with BRACC 19 year old woman Progressive right abdominal pain, SOB Right abdominal fullness No clinical Cushing s Laboratory evaluation Anemic Random cortisol 29.5 ( ) ACTH 5 ( 46) Testosterone 151 (14-76) DHEAS 897 (44-332) 24 hour UFC 1371 (3.5-45) CT demonstrates large R adrenal mass, multiple PEs
25 Patient with BRACC
26 Methods Retrospective evaluation of patients with ACC considered for primary surgery at MDACC 3 categories of patients identified as having borderline resectable ACC treated with preoperative therapy Group A = Multiorgan/vascular resection required Group B = Potentially resectable oligometastases Group C = Poor performance status/comorbidity Demographics, response, outcomes of preop Rx group compared to those treated with surgery first Bednarski World J Surg 2014
27 Demographics Patient Characteristics (n=53) Neoadj+Surg/ BRACC (n=15) Initial Surgery (n=38) p-value Gender, n (%) Male Female 6 (40.0) 9 (60.0) 16 (42.1) 22 (57.9) 1.00 Median Age, yrs (Range) 40 ( ) 55.5 ( ) Median Size, cm (Range) 14 ( ) 10.5 ( ) Stage, n (%) I II III IV 0 (0.0) 2 (13.3) 7 (46.7) 6 (40.0) 3 (7.9) 17 (44.7) 17 (44.7) 1 (2.6) <0.001 Bednarski World J Surg 2014
28 Characteristics of 15 BRACC pts treated with preop Rx Response of vena cava tumor in 6/7 (86%)
29 Preoperative systemic therapy for BRACC Anticoagulated EDP+mitotane x 5 cycles Emboli resolve Pain improves Tumor responds (12 7 cm) Tumor thrombus in IVC shrinks
30 BRACC after preoperative therapy
31 Resection of BRACC following preoperative Rx Path: ACC, 8.0 cm; extensive necrosis and treatment effect; vena cava wall invaded; margins free (R0)
32 Outcomes of ACC patients Surgical Outcomes (n=36) Neoadj+Surg/BRACC (n=13) Initial Surgery (n=38) p-value Multivisceral Rsxn, n (%) 11 (84.6) 20 (52.6) 0.05 Neg. Path. Margin, n (%) 12 (92.3) 33 (86.8) Postoperative mitotane 7 (53.8) 11 (30.6) 0.18 Median DFS, mos (95%CI) 27.6 (2.9 - NA) 12.6 ( ) yr OS 65% 50% 0.35 (Median follow-up 49.9 months)
33 Patient with borderline resectable ACC (BRACC) 23 year old woman Amenorrhea, leg swelling, thinning hair Elevated testosterone, cortisol Large L adrenal tumor L adrenal vein tumor thrombus extending into retrohepatic vena cava At least 2 liver metastases
34 Patient with borderline resectable ACC (BRACC) EDP+ mitotane x 9 cycles (!) Response at all sites Improved performance status Open resection of primary tumor and thrombus Partial hepatectomy x1, RFA x 2 NED 5 years from dx, 4 years from surgery
35 Patient with borderline resectable ACC (BRACC) 44 year old woman Amenorrhea, weight gain, hirsutism, fatigue, hypertension, edema Elevated testosterone, cortisol Large L adrenal tumor, two small liver mets Pulmonary emboli Medical management of pulmonary emboli and Cushing s EDP+mitotane with response Surgery following systemic Rx NED 8 months postop
36 Treatment of known or suspected ACC Goal is complete resection Operative plan should maximize this probability Remove tumor intact No fragmentation or capsular disruption Approach (minimally invasive vs. open) Should be appropriate to the tumor (invasive, often soft and easy to fracture) You never have a second chance to make a first impression : Recognize that there are no do overs Adjuvant/neoadjuvant therapy deserves consideration Bednarski World J Surg 2014
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