Response to Letter to the Editor From Berruti et al: "Cytoreductive Surgery of the Primary Tumor in Metastatic Adrenocortical Carcinoma: Impact on Patients' Survival".

Dear Editor,

We are grateful for the commentary by Berruti et al regarding our paper on cytoreduction of the primary tumor for patients harboring metastatic adrenocortical carcinoma (ACC) (1). We recognize the limitations of our study, mainly related to its retrospective nature and the potential for selection bias, well pointed out by Berruti et al. Taking that into consideration, we found that cytoreduction followed by systemic treatment prolongs survival when compared with systemic treatment alone.

We fully agree that some patients benefit from having neoadjuvant chemotherapy followed by resection of the primary tumor and, if possible, metastatic foci. In our paper, 17.9% of the cytoreduction group received neoadjuvant chemotherapy. We stated that preoperative chemotherapy would help in selecting patients with treatment response who would benefit from a maximal effort approach (ie, chemotherapy followed by surgery). To date, because of the rarity of ACC and the hurdles of patient recruitment, there is a paucity of high-quality data to support what is the ideal treatment for patients with metastatic disease. We concur that the study by Laganà et al, which reported that neoadjuvant chemotherapy might help select patients for surgical treatment, fuels this discussion (2).

On the one hand, it is expected that patients who respond to systemic therapy are the best candidates for a maximum effort approach, including surgery and metastasectomy. Deploying upfront cytoreduction to this group could delay systemic therapy during the convalescence period and worsen their prognosis. On the other hand, most patients with ACC historically have a limited long-term response to chemotherapy, and we do not have good predictors for a response (3). Furthermore, upfront surgery helps control hormonal and local symptoms of bulky tumors and may provide a better quality of life. Hence, performing neoadjuvant or adjuvant treatment is not an obvious choice.

Although the existing data are insufficient to delineate the ideal moment for systemic therapy and we wait for a prospective trial, our efforts should focus on improving patient selection for the different treatment approaches. Currently, we know that tumor grade, patient age, metastasis burden, metastasis location, and hormonal excess are important markers of survival (4). These parameters might tailor an individualized treatment plan to fit patients’ needs and conditions.

In summary, our data suggest that resection of primary tumor should not be overlooked in patients with metastatic ACC if deemed safe and feasible. Nevertheless, some patients who require multiorgan resection are likely to benefit from neoadjuvant chemotherapy that can help in selecting candidates for surgery and may reduce the need for extensive resection in those who respond well to systemic therapy. We strongly believe that the best answer to the neoadjuvant chemotherapy approach should come through collaborative multi-institutional, prospective studies.