EN SERVICES . USA VAINEMENT OF HEALTH & HUMAN
Published in final edited form as: Am Surg. 2019 January 01; 85(1): 23-28.
Operative Management of Recurrent and Metastatic Adrenocortical Carcinoma: A Systematic Review
WINIFRED M. LO, M.D., CHRISTINE M. KARIYA, M.D., JONATHAN M. HERNANDEZ, M.D. Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland
Abstract
Metastatic adrenocortical carcinoma (ACC) is associated with a poor 5-year survival rate and high rate of recurrence. Outcomes after resection for patients with limited disease remain poorly described. We conducted a PubMed search for articles published between 1950 and 2017 using the terms “ACC,” “recurrence,” and “surgery.” Patients with metastatic ACC at any anatomic site who had undergone surgical resection were included. Thirteen studies met the criteria. Patients were grouped according to the recurrence site. Pulmonary metastasectomy was reported in 50 patients with moderate complications and without perioperative mortality. Disease recurrence rates range from 25 to 42 per cent, with median overall survival of 40 to 50 months. Hepatic metastasectomy was reported in 108 patients with a single perioperative mortality. Disease recurrence rates range from 65 to 100 per cent, with median disease-free survival (DFS) and OS of five to nine months and 22 to 76 months. Peritoneal cytoreduction and heated intraperitoneal chemotherapy have been reported for 10 patients with minimal morbidity and without perioperative mortality. The disease recurrence rate was 70 per cent, with DFS of 19 months. For selected patients with recurrent ACC in the lungs, liver, or peritoneum, metastasectomy is safe and can be associated with prolonged survival. However, subsequent disease recurrence is common, and patients should be counseled accordingly.
Adrenocortical Carcinoma (ACC) is a rare and aggressive disease. Whereas current management entails curative resection of the primary tumor with adjuvant systemic therapy, disease recurrence is high (30-80%). Patients with recurrent or advanced disease have a poor prognosis, with estimated 5-year survival of 15 per cent.1,2 Options for systemic therapy include mitotane and multimodal chemotherapy, including etoposide, doxorubicin, and cisplatin (EDP). However, overall survival (OS) remains limited to about 14 months.1 Thus, there remains a need for effective treatment of recurrent and advanced ACC.
Metastasectomy has been associated with survival benefit in other histologies (i.e., renal cell carcinoma and sarcoma3), although the potential for similar benefit remains unclear in patients with metastatic or recurrent ACC. Surgical management of these patients remains sporadic without tangible opportunity for randomized evaluation. Prospective, randomized control trials evaluating this question for recurrent ACC are limited by the availability of patients with oligometastatic, potentially operative disease. When clinical trials are
attempted, the rare incidence of operative disease and appropriate surgical candidates precludes significant accrual. We experienced this during our phase II clinical trial evaluating the efficacy of cytoreduction and heated intraperitoneal chemotherapy (HIPEC) for locally recurrent ACC. Despite our evaluation of 59 patients over three years, target accrual was not achieved.
Given the significant difficulty in evaluating the surgical management of patients with recurrent ACC in a prospective manner, we performed a systematic review of the literature to characterize the safety and efficacy of metastasectomy in patients with recurrent or metastatic ACC.
Methods
A systematic review of the PubMed database was performed after PRISMA guidelines in April 2017.4 The search evaluated articles published between 1950 and 2017 using the search terms “surgery,” “resection,” “ACC,” and “recurrence.” This search query returned 599 articles for review. Articles were selected for further review if they reported on patients who received surgical resection of ACC, if they addressed repeat resection for recurrent disease, and were written in English. Whereas review articles, case series, and case reports were reviewed for potential eligibility, case reports, and case series (less than five patients) were excluded. Articles were not eliminated based on the study type or length of followup. Of these, 19 articles were reviewed in full text by the authors and considered for evaluation. Selected articles for review were published in 1991 to 2017 and comprised retrospective reports from single-institution studies and two international ACC registries. Manual search of these articles’ reference lists was performed to capture additional articles for consideration. Based on full-text review, 13 articles were selected for full-text, in-depth review (Table 1). Safety was assessed by evaluating reported rates of perioperative mortality, perioperative morbidity, and need for reoperation. Efficacy was evaluated by assessing achievement of resection to no evidence of disease (NED), progression-free survival (PFS), and OS, where available.
Results
ACC frequently metastasizes to the lungs.5 Two reports evaluated pulmonary metastasectomy for recurrent ACC (Table 2), reporting on a total of 50 patients. These patients underwent median sternotomies, thoracotomies, wedge resections, segmental resections, lobectomies, and pneumonectomies. Staged thoracotomies were practiced in both the NCI and German ACC Registry to address disease in bilateral lungs.6, 7
Pulmonary metastasectomy seems safe and feasible to perform in appropriately selected patients with recurrent ACC. A total of 116 operations were performed on the 50 study patients. No perioperative mortality was reported. Perioperative morbidity was estimated at 12 per cent in one study; the specific complications were not specified. No patients required reoperation. 8, 9
For patients selected for pulmonary metastasectomy, OS ranged from 40 to 50.2 months. PFS was reported at four months. Factors associated with survival benefit included repeat
pulmonary metastasectomy, age less than 41 years, time to progression or recurrence greater than 17 months, and T2 versus T3/T4 tumors. Of note, these factors associated with survival benefit were not shared between the reviewed reports. Factors that were not associated with survival benefit included adjuvant chemotherapy, number of pulmonary metastases, lymph node involvement, or resection to NED. Notably, 20 patients who underwent repeat thoracotomy for recurrent disease (after initial pulmonary metastasectomy) exhibited median OS of at least 59 months (range, 59.2 - not yet reached).8, 9
ACC frequently metastasizes to the liver. Four studies reported experiences with treatment of 116 patients with resectable disease (Table 3). The patient cohorts included patients from the NCI, three National Cancer Center Network-affiliated centers, and the German ACC Registry. These patients underwent formal hepatectomy, extended hepatectomy, and single segmentectomy.
A total of 128 operations were performed to treat 116 patients. Perioperative mortality was reported in one patient (0.8%). There were no reported cases requiring return to the operating room during the immediate postoperative period. Perioperative complications included thromboembolic disease, intra-abdominal abscess, wound infection, bile leak, and renal failure with inferior vena cava (IVC) thrombus.
OS was reported to be 22.8 to 76.1 months. PFS was uniformly not reported. Factors associated with survival included disease-free interval greater than six months (after index adrenalectomy), nonfunctional tumor, surgical resection of recurrence, R0 resection, and solitary liver metastasis. Disease-free interval (DFI) ranging 6 to 12 months was found to be associated with survival benefit in three of four reports.10-13 Factors that were not associated with OS included receipt of adjuvant chemotherapy, number of hepatic lesions, or resection to NED.5-18 Of note, resection to NED was successfully achieved in 3 to 70 per cent. 10, 12, 13
Cytoreduction and local chemotherapy for locally advanced disease have not previously been described for ACC. At our institution, we conducted a phase II clinical trial evaluating cytoreduction and HIPEC for locally advanced disease.19 Although this study was conducted from April 2013 to September 2016, the trial failed to accrue the desired number of patients and only 10 patients were enrolled.
Ten patients were enrolled and one patient was retreated for a total of 10 treatments. One patient was unable to be cytoreduced adequately and did not undergo HIPEC. There were no perioperative mortalities. Perioperative morbidity was graded as Clavien-Dindo 2 or 3, and included infectious complications (urinary tract infection, and subcutaneous abscess), hematologic complications (anemia and thrombocytopenia), abdominal pain, and persistent hoarseness after intubation. None of the patients required immediate reoperation.
PFS was 19 months in this cohort. OS cannot be described because median OS has not yet been reached at the time of this analysis (median follow-up 23 months). 19, 20
Discussion
Metastatic ACC is an aggressive disease with few durable treatment options. Systemic therapy, including mitotane and multimodal chemotherapy, has been associated with modest PFS (5.6 months),21, 22 leading patients and treating physicians to attempt alternative treatment options. Surgical treatment of metastatic ACC has been reported intermittently by individual institutions and in highly selected patient cohorts. Although previously demonstrated to be feasible, the safety and efficacy of metastasectomy have been incompletely described using small, heterogeneous patient populations. Here, we sought to critically evaluate the literature describing pulmonary and hepatic metastasectomy for the management of metastatic ACC, in hopes of providing surgeons some clarity for expected outcomes in patients with operable recurrences.
Pulmonary metastasectomy was described in two reports evaluating 116 procedures performed in 50 study patients. It is safe and acceptably comorbid based on the data which are available. Interestingly, while OS in treated patients ranged from 40 to 50 months, PFS was reported at four months. Given that survival with EDP-M chemotherapy is estimated around 14 months, this suggests that there may be a role for pulmonary metastasectomy in achieving longer patient survival, even if the patient is likely to recur very quickly after resection. Furthermore, there may be a role for repeat resection in patients with advanced disease. This is supported by the subgroup analysis of 20 patients who underwent repeat thoracotomy for recurrent disease after initial metastasectomy, who exhibited median OS of at least 59 months. Moreover, repeat pulmonary metastasectomy was associated with prolonged OS.8, 9 Thus, whereas limited data are presently available on pulmonary metastasectomy, it seems that this can be considered a safe and viable adjunct in management of advanced ACC.
Hepatic metastasectomy was safely performed with only one mortality reported in more than 120 operations. Disease-free interval was reported to range from 5 to 9.1 months.8, 11-13 It is important to note that of the patients who underwent hepatic metastasectomy, around 40 per cent did not undergo complete extirpation of all disease. In one study, 42 per cent of patients were not rendered disease free. This was due to the presence of extrahepatic disease or more than one lesion at the time of hepatic resection.8 Furthermore, patients who were not rendered disease free experienced PFS similar to patients who were treated with systemic chemotherapy (5.1 months) versus lengthened disease-free interval after resection to NED (9 months).8 Thus, the reported disease-free intervals associated with hepatic metastasectomy are likely an underestimation of potential benefit because these analyses include patients regardless of whether they were resected to NED. The impact of not resecting all diseases is reflected in the higher rates of recurrence for patients undergoing hepatic metastasectomy- disease recurrence rates ranged from 65 to 100 per cent in this cohort.
Cytoreduction and HIPEC may enable prolonged PFS and OS for patients with locally advanced disease restricted to the peritoneum. In our institution’s phase II clinical trial, peritoneal PFS reached 19 months, as compared to 5 months with systemic chemotherapy and 5 to 9.1 months in patients with resection of hepatic disease.19 HIPEC facilitates the local distribution of chemotherapy at higher concentrations than would otherwise be
systemically tolerated. This procedure is safe, tolerable, and is associated with perioperative complications within the range of what has previously been described in other cytoreduction and HIPEC studies. It seems that whereas the addition of local chemotherapy achieves longer PFS compared with metastasectomy alone, recurrent disease remains a persistent issue. Seventy per cent of patients experienced disease recurrence, with 75 per cent of patients experiencing disease recurrence in the peritoneum. Despite this, OS in this study has not yet been reached (median follow-up 23 months).19 This suggests that although local control is difficult to attain in advanced ACC, it may not be the only determinant for OS. Furthermore, the prolongation of PFS with local chemotherapy may increase the patient’s likelihood of eligibility for future metastasectomy. These early findings suggest that in carefully selected patients, cytoreduction and HIPEC may be considered as an adjunct in multimodal therapy for treatment of advanced disease.
Patient and tumor prognostic factors evaluated for association with survival have not yielded any helpful metrics to improve patient selection for metastasectomy. Surprisingly, the number of metastastic lesions, receipt of adjuvant systemic therapy, and resection to NED were not associated with survival. The only shared prognostic factor across multiple studies was the disease-free interval between index adrenalectomy and initial recurrence (DFI >6 months). 10, 12, 13 This paradox suggests two potential problems. First, examining traditional metrics to determine a patient’s candidacy may not be appropriate in this disease-instead, evaluation for tumor mutations (i.e., TP53, CTNNB1, etc.) and protein expression may be more constructive for distinguishing patients. For example, Ki67 index over 7 per cent has been previously associated with significantly worse clinical outcomes in ACC and is already evaluated as part of the histologic evaluation of ACC.23 Second, it is possible that despite all therapies offered to patients, individuals who survived longer had more indolent tumor biology and might have survived longer than their peers, regardless of therapy received. Thus, there remains a need for evaluation of nontraditional tumor characteristics for better patient selection.
Limitations to this analysis include significant potential for selection bias, heterogeneous data reporting across studies, the broad range of time during which patients were aggregated, and the limitations of using retrospective cohort studies for data. Patients who were selected for evaluation in these studies represent a highly selected cohort with likely less aggressive tumor biology, potentially better overall health, and metastatic tumor that was anatomically amenable to resection. True comparison to medical management cannot be made based on the data aggregated in these studies. In addition, given the low annual incidence of disease, most included cohorts evaluated a tiny number of patients who were treated across several decades. Given the significant advancements in preoperative imaging, perioperative critical care, and the more recent association of mitotane and EDP chemotherapy with survival benefit, these populations do not accurately reflect the current management strategies for patients with recurrent ACC. This will likely remain an ongoing issue limiting progress in the field unless a large, international consortium is created to aggregate multiple institutions’ data for deeper analysis.
Conclusion
ACC is a rare and challenging disease with few durable systemic options. Surgical metastasectomy is a safe and feasible option; patients with disease-free intervals greater than six months and who undergo multiple resections may experience prolonged survival. Patients should be counseled on the high rate of recurrence and likely need for adjunct therapies. Additional metrics, such as TP53 mutation status or Ki67 index, should be considered for stratification of surgical candidates. Finally, additional novel therapies and multimodal treatment strategies should be considered to achieve improved survival.
Acknowledgements
The authors gratefully acknowledge the assistance of Judith Welch in searching and identifying candidate articles for evaluation.
This report was funded by the Intramural Research Program at the National Institutes of Health.
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| Author | Year | Number of Institutions | Patients Reported | Length of Follow-Up | Outcomes Measured |
|---|---|---|---|---|---|
| Jensen | 1991 | NCI | 15 | 23+ years | OS |
| Bellantone | 1997 | Italian Registry for ACC | 20 | Not reported | Survival Disease-free interval |
| Schulick | 1999 | MSKCC | 49 | Not reported | Survival |
| Ripley | 2011 | NCI | 27 | 6.2 years | OS Disease-free interval |
| Kemp | 2011 | NCI | 26 | 165 months | OS Recurrence-free survival |
| Datrice | 2012 | NCI | 57 | Not reported | OS DFS or PFS |
| Gaujoux | 2012 | MSKCC | 36 | 28 months | Disease-free survival OS |
| Op den Winkel | 2012 | German ACC Registry | 24 | 109 months | OS |
| Erdogan | 2013 | German ACC Registry | 101 | 30 to 297 months | PFS OS |
| Dy | 2013 | Mayo Clinic | 67 | Not reported | Survival DFI |
| Dy | 2015 | Mayo Clinic, MDACC | 27 | Not reported | Recurrence-free survival OS Disease-free interval |
| Simon | 2017 | 61 | 69 months | OS | |
| Baur | 2017 | German ACC Registry | 43 | Not reported | OS DFS |
| Hughes | 2018 | NCI | 10 | 23 months | Intraperitoneal PFS OS |
MSKCC, Memorial Sloan Kettering Cancer Center; MDACC, MD Anderson Cancer Center.
| Author | Year | Patients | Types of Resection | Number of Resections | Deaths (n, %) | Complications | Resected to NED | Median DFI (months) | PFS | OS (months) | Recurrence Rate | Factors Associated with Survival |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Kemp8 | 2011 | 26 | Pulmonary metastasectomy | 60 | 0 (0%) | 12% | 14 (54%) | 7 | 4 months | 40 | 25% | Time to first recurrence; T stage of primary tumor |
| Op den Winkel9 | 2012 | 24 | Wedge resection (83.9%) | 47 | 0 (0%) | Not described | 20 (83%) | 28.4 | Not reported | 50.2 | 41.7% | Age >41 years at time of metastasectomy |
| Segmental resection (5.4%) | 3 | |||||||||||
| Lobectomy/ bilobectomy (8.9%) | 5 | |||||||||||
| Pneumonectomy (1.8%) | 1 |
| Author | Year | Patients | Types of Resection | Number of Resections | Deaths (n, %) | Complications | Resection to NED | DFI (months) | PFS | OS | Recurrence Rate | Factors Associated with Survival |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Ripley10 | 2011 | 19 | Liver resection | 19 | 0 (0%) | Thromboembolic disease (26%), intra- abdominal abscess (11%), wound infection (5%), bile leak (5%), renal failure (5%) | 58% | 5 months | Not reported | 1.9 years | 65% | DFI >9 months after primary adrenalectomy |
| Gaujoux11 | 2012 | 28 | Major hepatectomy | 39 | 0 | 55% (details not specified) | Not reported | 7 months | Not reported | 5-year survival 39% | 100% | Non-functional tumor; surgical resection of recurrence |
| Dy12 | 2015 | 18 | Liver resection (67%) | 27 | 1 (3.7%) | Not reported | 9/27 (33%) | Not reported | Not reported | Not reported | Not reported | R0 resection; DFI >6 months |
| Baur13 | 2017 | 43 | Single or multiple segmentectomy | 29 | Not reported | Not reported | 30/43 (69.8%) | 9.1 months | Not reported | 76.1 months | 88.40% | Time to first recurrence >12 |
| Formal hepatectomy | 7 | months; solitary liver metastases | ||||||||||
| Extended hepatectomy | 3 | |||||||||||
| Atypical resection | 2 | |||||||||||
| Unknown | 2 |