Impact of extended R0 resections on oncological outcome of locally advanced adrenocortical carcinoma

This study supports the surgical oncological effectiveness of extended resections of locally advanced ACCs, reporting similar results in terms of locoregional recurrence compared to patients with disease confined to the adrenal gland.

ACC has to be tackled with a limited arsenal of therapeutic options of which surgery remains the first choice [5]. En bloc complete resection of ACC with the peritumoral/periadrenal fat in absence of capsular effraction is considered the most important component of treatment with curative intent, as is the only chance for long-term cure [2, 5, 9]. Indeed, incomplete surgical radicality relates to increased risk of cancer-related death [5].

Application of neoadjuvant treatment to locally advanced ACC to achieve downsizing/downstaging to potentially allow R0 resection is still not standardized [5, 24, 25]. Similarly, efficacy of chemotherapy in the adjuvant setting is still debated, mainly due to ACC poor response to cytotoxic treatment [26, 27]. To date, ESES/ENSAT 2018 recommendations [9] did not reach consensus on this concern, though panelists suggest that they may be considered in selected patients with very high risk for recurrence. To date, mitotane still remains the only medication specifically approved for ACC. Adjuvant early administration of mitotane has been related to improved DFS and OS in advanced disease [3, 11] and it is currently mainly proposed basing on risk factors for disease recurrence, such as Ki-67 ≥ 10%, Rx/R1 resection status and high stage (S-III/IV), balancing them with toxic side effects [4, 11]. Clinical trials such as FIRM-ACT [27] highlighted the efficacy of combination of EDP with mitotane, with a high rate of objective tumor response and a significant increased progression-free survival when compared to combination of streptozocin plus mitotane. However, this trial patients’ cohort only included those ones with diagnosis of ACC not amenable to radical surgical resection [27]. Moreover, ACC has been historically considered a radioresistant disease. Retrospective studies on adjuvant use of radiotherapy in ACC have shown no beneficial effects [26, 28].

As a consequence of the aforementioned considerations, management of locally advanced ACC patients is known to be challenging. Indeed, literature reports suggest that R+ surgery and ENSAT S-III disease represent risk factors for disease recurrence compared to oncological radicality of surgical resection and early ACC stage [5]. Obviously, S-III patients undergoing less than extended surgical resections theoretically present a higher risk of R+ surgery and/or infiltrated margins at pathologic examination.

With regard to the primary endpoint of our study, our results show comparable locoregional recurrence rates between the two groups, with 8 S-I/II and 2 S-III patients developing locoregional disease recurrence (p = 0.420).

However, even though R0 resection has been widely defined as the only effective therapeutic strategy [5, 29], literature data on recurrence rate in locally advanced disease are still lacking. A recent ESES panel [29] expressed against nephrectomy in association to adrenalectomy to achieve oncological favorable results, in absence of pre- and intraoperative evidence of extra-adrenal extension of the disease. On the other hand, they reported encouraging outcomes after extended resections due to ACC infiltration of IVC, although such surgical strategies should be demanded in high-expertise hands and in referral centers with multidisciplinary management of the disease [30].

In this context, in our experience, achieving R0 resection margins and avoiding capsular effraction were deemed to be essential to considerably affect the natural history of the disease. Indeed, intraoperative suspect of extra-adrenal extension guided surgical planning even in case of lack of preoperative evidence of infiltration, as definitive pathologic examination represents the only means to confirm disease stage.

Moreover, to date, there is no clear consensus about the extension of LND in ACC [31]. As a consequence, as long as there is no surgical standard, its exact diagnostic value as well as the oncological effect cannot be still clearly assessed [31]. Discrepant reports regarding lymph node involvement ranging from 4 to 73% [2, 7, 32] suggest that formal regional lymphadenectomy is neither properly performed by surgeons nor accurately assessed or reported by pathologists [9]. Furthermore, retrospective data suggest that regional lymph node involvement in ACC negatively impact on OS and is frequently the cause of locoregional recurrence [6, 12, 14]. Concordantly with such literature evidence, we reported a slightly higher rate of locoregional recurrence in patients who did not undergo LND in association to the index operation, though not statistically significative (as reported in Table 3).

The lack of standardization of lymphadenectomy in ACC may also explain the difference of OS and DFS between S-II and S-III patients, as it can be related to understaging thus to undertreatment of S-III patients in adjuvant setting [12].

Nonetheless, our results concerning 5-years-OS and DFS are similar with literature reports [33, 34], being even superior compared to data reported from other authors’ experience [35], thus underlining R0 resection as the critical prognostic factor.

It may be argued that OS and DSF in S-I/II patients could have been affected by the high rate of minimally-invasive surgeries. However, we reported an equal distribution of locoregional recurrences between open (five cases), converted (two cases) and minimally invasive (three cases) adrenalectomies. Thus, surgical approach did not represent a risk factor for disease locoregional recurrence.

Indeed, although, in the beginning of laparoscopic application to ACC surgery, minimally invasive approach was associated with a higher frequency of R+ surgery and intra-abdominal recurrences, more recently several meta-analyses did not report impaired oncological outcomes after endoscopic treatment [5, 31, 36,37,38]. Hence, the choice of the best surgical approach for ACC or suspected malignant adrenal mass should be tailored on preoperative lesion’s features and evidence of local invasion to achieve a complete resection of the tumoral mass en bloc with the periadrenal fat to avoid tumor or capsular rupture or spillage [2, 5, 9]. Indeed, even if guidelines from two European societies [9, 39] suggest that potentially malignant adrenal tumors < 6 cm without invasion of adjacent organs may be eligible to minimally invasive adrenalectomy, several authors stated that endoscopic approach may not be excluded even in case of preoperative suspect of S-III disease, when surgery is performed in experienced hands and in high-volume centers [40, 41]. Interestingly, more recently Olivero et al. [40] reported clinical outcomes of patients with ACC with venous thrombus extension treated with both open and minimally invasive approaches, without significative differences among the two groups.

Moreover, the most recent ESES expert opinion [9] described robotic platforms as potential surgical alternative to other minimally invasive approaches even for the treatment > 6 cm lesions, due to their superiority in terms of three-dimensional vision, dexterity and stability, thus minimizing the risk of capsular rupture or R+ margins [39, 41], suggesting that RAA may be the preferred technique if a minimally invasive procedure is pursued [41].

Postoperative complications represent one of the main concerns related to extended surgical resections. Our analysis shows comparable results between the two groups (21.4% of S-I/II patients vs 16.7% of S-III patients, p = 0.788), in line with literature data resulting from meta-analysis, ranging from median values of 19.4% to 21.4% [38].

Lastly, we made the effort to try to identify potential risk factors for disease locoregional recurrence, though with the limitation of the relatively small sample size dimension. After univariable analysis, hyperfunctioning lesions were related to locoregional recurrence (p = 0.006; Odds Ratio 11.7 – Interval of Confidence 95%: 2–66.4), in line with literature reports on their association with increased biological aggressiveness [4]. Administration of adjuvant cytotoxic treatments also significantly related to disease locoregional recurrence (p = 0.011; Odds Ratio 8.5 – Interval of Confidence 95%: 1.7–42.8). Such evidence is not surprising, though apparently paradoxical, as it should be explained by the correct identification of preoperative suspicious lesion’s features of those patients who could have benefit adjuvant treatment the most, despite its aforementioned limited efficacy. In this view, adjuvant therapy should be considered as a predictor factor rather than a risk factor for locoregional disease recurrence. These considerations may also explain the higher rate of distant disease recurrence in S-III patients’ group, as a results of increased biological aggressiveness and unresponsiveness to systemic treatments.

The main limitations of the study are due its monocentric and retrospective nature over a long period involving a relative limited number of patients. However, this aspect should be correlated to the rarity of the disease. On the other hand, the strength of our results relies on the high-volume experience of our referral center, with a case volume of 90 adrenalectomies per year, and the multidisciplinary management of the disease. The role of the high volume of the center has been underlined by different societies consensus and recommendations [9, 16, 19, 29]. In this context, more than ten years ago, we reported one of the preliminary experiences in literature concerning the correlation between center’s volume and oncological outcomes [18]. These results have also been reported in larger retrospective series from MD Anderson Cancer Centre and in a Dutch series, with longer OS for S-I/III patients [31, 32, 42, 43].

Moreover, as far as we know, our reported experience represents the first study which compares oncological outcomes of S-III patients, treated with extended surgical resections, with S-I/II patients.

In conclusion, despite the limitations of the lacking effectiveness of systemic treatment in the adjuvant setting, R0 surgical resection seems to relate to improved oncological outcomes of locally advanced ACC.

However, further studies with larger sample size are still necessary to draw definitive conclusions.

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