Keywords

16.1 Introduction

Radical surgery represents the only possibility to cure adrenocortical carcinoma (ACC). Unfortunately, ACC is frequently diagnosed at an advanced stage, in the form of locally advanced or metastatic disease. Furthermore, a significant proportion of patients experience recurrent or metastatic disease after surgery performed with curative intent. Although re-do resection may offer good survival results in these cases, the occurrence of “surgical cure” is anecdotal. In recent years, multimodal approaches integrating systemic and local treatments have emerged, widening the spectrum of integrated treatments for advanced stage, recurrent or oligometastatic patients. We will discuss these approaches in the following pages, well aware that future improvements and the broadening of treatment options will originate from multidisciplinary collaboration.

16.2 Neoadjuvant Chemotherapy Followed by Surgery

Surgery is the cornerstone of therapy and the only treatment modality which may offer a chance of cure; it should be considered in the treatment of all patients and at any stage of disease with the aim of removing the entire tumor bulk (R0). However, while upfront surgery is a clear option in early stages, it may not be the best strategy for patients with locally advanced or metastatic disease, as in these instances the likelihood of recurrence is high. Considering that an objective response can be achieved in 50% of cases using the standard systemic EDP-M scheme (etoposide, doxorubicin, cisplatin plus mitotane) [1, 2], in patients with surgically amenable ENSAT stage III–IV ACC [3] and in those with borderline resectable (BR) ACC the possibility of neoadjuvant chemotherapy followed by surgery should be carefully discussed by the multidisciplinary team.

Neoadjuvant therapy for ACC is a fairly new practice founded on strong theoretical principles. These can be summarized as follows: to reduce tumor size and thus increase the likelihood of R0 resection increasing at the same time the possibility to preserve other organs; to administer nephrotoxic systemic therapy before ipsilateral nephrectomy (if indicated); to select for radical surgery those responding patients who are most likely to achieve the best outcome. In the case of locally advanced disease where radical surgery is not feasible, neoadjuvant chemotherapy is the only option, but this treatment modality should also be considered in patients with BR disease.

BR disease is a multifold definition including anatomical, biological and patient-related criteria. As for the anatomical definition, this applies to patients requiring multi-organ or vascular resections and, in general, those at high risk for a margin-positive resection based on preoperative imaging. The biological definition identifies those patients with suspicion of metastases or potentially resectable oligometastatic disease. Finally, the patient-related definition applies to patients with significant comorbidities contraindicating upfront surgery; among these, poor patient condition, pulmonary embolism and metabolic failure secondary to hormone hyperproduction are the acute conditions more frequently observed.

Some evidence supports the combination of systemic therapy and surgery. A retrospective study analyzed neoadjuvant chemotherapy (mainly EDP-M) in BR ACC [4]. Fifty-three individuals operated on with curative intent were included in the study; of them, 15 (28%) were classified as BR and received neoadjuvant therapy. Despite a more advanced clinical stage at diagnosis and a higher incidence of multi-visceral resections, the rate of margin-positive resections was similar in BR and resectable patients; furthermore, the pathologic size of the tumor was also similar in the study groups, despite larger tumor diameters at diagnosis in the BR group. Median disease-free survival (DFS) for individuals with resected BR ACC was 28 months (95% CI 2.9–not achieved) as opposed to 13 months (95% CI 5.8 to 46.9; p = 0.40) for individuals with resectable disease. Five-year overall survival (OS) showed no significant difference: 65% for the neoadjuvant group (N = 13) versus 50% for the upfront surgery patients (N = 38) (p = 0.72).

Another retrospective Italian study explored the sequence of EDP-M and surgical resection in ACC diagnosed as locally advanced and non-resectable (6 cases) or metastatic [2]. The median progression-free survival (PFS) and OS for the cohort of 58 patients were 10.1 months and 18.7 months, respectively. Surgery was indicated in 26 (45%) responding patients to remove the remaining disease or reduce the tumor bulk: 13 attained a disease-free status and 13 had a residual disease ≤10% (R1 resection in 5 and small lung metastases in 8). Post-chemotherapy surgery provided some important information: the possibility to identify complete responders to chemotherapy (7%) and to reassess Ki67 expression in post-chemotherapy tumor specimens. As expected, responding patients subjected to surgical resection showed better outcomes: median DFS and OS were 13.1 and 29.8 months, respectively.

In the absence of a randomized clinical study, from these papers we cannot conclude that the association of chemotherapy and surgery is per se more efficacious than surgery, since the patients operated on were selected among responders, who already benefit from survival advantages. Considering that the disease’s biologic behavior is the main determinant of the long-term success of surgery, neoadjuvant chemotherapy is therefore helpful in selecting for surgery those patients with either an indolent primary or affected by a disease which has been made indolent by chemotherapy. Therefore, neoadjuvant therapy is a valid option for patients with BR or unresectable disease at diagnosis. Moreover, potentially resectable patients who demonstrate aggressive disease, such as those displaying a significant volume increase in two imaging procedures performed sequentially within a short period of time, or patients who have already undergone surgery but have developed an early recurrence, are also eligible. Considering these premises, it is necessary for a multidisciplinary team to carefully discuss any patient with ACC. The Brescia experience shows that an aggressive multimodal and staged treatment offers interesting results, permitting long-term disease-free status to be obtained in a non-negligible percentage of cases.

16.3 Adrenalectomy: Upfront or After Primary Chemotherapy in the Metastatic Setting?

Surgical excision of the primary tumor is effective in improving survival in some metastatic malignancies. This strategy may therefore be an option in patients with metastatic ACC. The role of non-curative surgical debulking was explored in a retrospective cohort of 239 metastatic patients by the American-Australian-Asian collaborative group [5]. A propensity score analysis using as matching criteria the patients’ age and the number of metastatic organs (2 or >2) investigated OS in patients treated with or without resection of the adrenal primary. Patients in the surgery group had a median OS of 25.2 months (95% CI 21.0–29.5) as opposed to those in the no-resection group, whose median OS was 9.0 months (95% CI 6.7–11.3). From this analysis, age (HR [hazard ratio] 1.02; 95% CI 1.00–1.03), hormone excess (HR 2.56; 95% CI 1.66–3.92) and local treatment of metastasis (HR 0.41; 95% CI 0.47–0.65) also emerged as independent predictors of survival.

A multivariate analysis of 202 patients with synchronous metastatic ACC identified from the SEER (Surveillance, Epidemiology, and End Results) database [3], showed that those 76 (37.6%) patients who underwent adrenal surgery had better survival as compared to non-surgical patients (median OS: 13 vs 4 months, p < 0.001). Besides, adrenalectomy (HR 0.64; 95% CI 0.45–0.92; p = 0.017), metastasectomy (HR 0.48; 95% CI 0.26–0.86; P = 0.013) and chemotherapy (HR 0.59; 95% CI 0.42–0.82; p = 0.002) were also associated with improved survival.

Based on these data, surgical removal of the adrenal primary should always be considered in metastatic ACC, especially in the oligometastatic status. The critical point is whether to perform surgery upfront or after chemotherapy. The position of the multidisciplinary group in Brescia is that all patients should undergo an upfront systemic treatment and that the surgical indication should be discussed on the basis of a computed tomography (CT) re-evaluation after chemotherapy [6]. Generally, surgery should be offered only to those who attain disease response or stabilization. This approach has several advantages: (1) patients not progressing after systemic treatment are selected as having a more indolent disease either spontaneously or after systemic treatment, (2) surgery after chemotherapy has the opportunity to identify any complete pathological response which represents undisputed evidence of treatment efficacy and a powerful prognostic parameter, (3) surgery after chemotherapy provides the unique opportunity to reassess the tumor biology and obtain useful information for planning the next treatment. On this subject, the Brescia experience has shown that proliferation activity assessed by Ki67 in post-chemotherapy residual tumor has a stronger prognostic role than Ki67 evaluated under baseline conditions [2].

In metastatic patients, the surgical treatment of metastases should be considered. Metastasectomy in the synchronous setting should be indicated in selected cases, at completion of removal of the primary, if R0 status is anticipated on preoperative cross-sectional imaging and in the case of favorable biological behavior [7,8,9]. The same criteria should also be adopted, in association with mitotane, in patients with metachronous metastatic disease [10, 11].

16.4 Cytoreduction and Hyperthermic Intra-peritoneal Chemotherapy

In the major referral centers, cytoreductive surgery completed by hyperthermic intraperitoneal chemotherapy (HIPEC) is now part of the toolbox for the multimodal management of different primaries with peritoneal involvement. This strategy pursues the optimization of local control through an aggressive surgical strategy aimed to maximal cytoreduction of the neoplastic bulk and the synergistic effect of chemotherapy and hyperthermia on low-volume (≤2 mm) or microscopic neoplastic remnants.

As far as ACC is concerned, the literature is scarce, consisting of a few case reports, and the first paper reporting on the value of HIPEC was published by Hughes et al. in 2018 [12]. In a selected series of 10 patients who developed local and/or peritoneal ACC recurrence at least 12 months after adrenalectomy a complete cytoreduction (CCR = 0) was achieved. HIPEC was carried out using cisplatin (250 mg/m2/L of perfusate) at 40 °C for 90 min. The complication rate was 40% with complications graded 2 or 3 according to the Clavien-Dindo scale. At a median follow-up of 23 months, median DFS was 19 months while median OS was not reached.

A second paper was published by our group in 2020 [13]. HIPEC was conducted in a different way, using cisplatin (25 mg/m2/L) and doxorubicin (4.5 mg/m2/L) at 42 °C for 60 min. We analyzed a small cohort of 14 patients presenting local or peritoneal recurrence of ACC, responsive or stable after chemotherapy (EDP-M or mitotane alone). The morbidity rate reached 77%, due to extended (often multi-organ) resections required by the recurrent neoplastic bulk; grade 3 and 4 complications were observed in 12% and 6% of cases, respectively. Mortality was nil. After a median follow-up of 30 months, patients with recurrence showed a median local/peritoneal DFS of 12 months while median OS was not reached. Interestingly and for the first time, in the same paper, we also presented data concerning a cohort of 13 BR ACC patients subjected to cytoreductive surgery and HIPEC with prophylactic intent. In this setting, the 90-day morbidity rate was 46% with grade 3 and 4 complications accounting for 15% and 8%, respectively. After a median follow-up of 25 months, both median DFS and OS was not attained.

For this monograph, we revised our database. Twenty-three patients received 26 cytoreductive procedures and HIPEC for the management of recurrent ACC. All but one patient received chemotherapy (EDP-M or mitotane alone) after the diagnosis of recurrence. Twenty percent of our patients were alive and disease-free 5 years after the procedure. We were also able to confirm the results reported by Hughes et al.: in those patients (n = 10) who recurred ≥12 months after adrenal surgery, median local/peritoneal DFS was 19 months and, after a median follow-up of 27 months, median OS was not attained. Considering the prophylactic setting, in a cohort of 26 patients presenting with stage II and III ACC, we made a comparison between a group of 11 patients subjected to regional adrenalectomy completed by HIPEC and a group of 15 patients subjected only to regional adrenalectomy. After a median follow-up of 25 and 34 months, respectively, the median local/peritoneal DFS and OS was not reached in either group. Albeit not significant, Kaplan-Meyer survival curves show an advantage of 20% in terms of local/peritoneal DFS at 2 years, which is replicated in the 3-year OS (Fig. 16.1).

Fig. 16.1
2 line graphs of local slash peritoneal disease-free survival versus months and overall survival versus months plotted for locoregional surgery + H I P E C and adrenalectomy. The disease-free survival and overall survival rates are better for locoregional surgery + H I P E C compared to adrenalectomy.

Local/peritoneal disease-free survival and overall survival in stage II & III adrenocortical carcinoma. Effect of HIPEC (cytoreduction and hyperthermic intraperitoneal chemotherapy) at completion of regional surgery

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16.4.1 Alternative Locoregional Treatments

Control of the tumor bulk by means of local treatments supports systemic therapy and exerts a paramount prognostic role in the management of metastatic ACC. The multidisciplinary team may choose among different options such as radiation therapy, radiofrequency or microwave ablation, cryoablation and transcatheter arterial chemoembolization. Unfortunately, due to the rarity of the disease, the specific literature is scarce. For this reason, besides general selection criteria, the choice of the technique is influenced by the experience of the local team. Interestingly, the combination of locoregional treatment and mitotane allowed, in a selected case series, the start of chemotherapy to be significantly delayed in patients with metachronous oligometastatic disease [14].

Small series studied the ablative treatment of hepatic metastases employing radiofrequency or microwave ablation [15, 16]. These techniques show particular value in cases of oligometastatic disease and diameter of the metastases ≤3 cm, in particular if employed in combination with systemic treatments [17]. Transcatheter arterial chemoembolization (TACE) has also been reported in the management of metastatic ACC. As for other primaries, it may be instrumental in controlling or stabilizing hepatic metastases. Cisplatin, doxorubicin, and/or mitomycin or lipiodol alone have been selectively injected in the arterial branches directed to the metastatic lesions [10].