ESE Treatment Recommendations 

Treatment recommendations are based on whether ACC is localised or advanced.

Localised ACC

Treatment options for localised ACC include both surgery and adjuvant therapy.

Surgery

Open surgery is the standard surgical approach for confirmed/highly suspected ACC (Fassnacht et al., 2018).

  • Open surgery for all tumours with radiological findings suspicious of malignancy and evidence for local invasion is recommended.
  • Laparoscopic adrenalectomy is reasonable for tumours < 6cm without any evidence of local invasion.
  • Routine locoregional lymphadenectomy should be performed with adrenalectomy for highly suspected/confirmed ACC.
  • Perioperative hydrocortisone replacement is recommended in all patients with hypercortisolism who undergo surgery for ACC.


Adjuvant therapy

For adrenal tumours with uncertain malignant potential, adjuvant therapy is not recommended.


Adjuvant mitotane (Fassnacht et al., 2018): 

  • Recommended in patients without macroscopic residual tumour after surgery who have perceived high risk of recurrence.
  • No recommendation for/against for patients at low/moderate risk of recurrence; adjuvant therapy options should be considered on an individual basis.
  • Once the decision for mitotane treatment is established, mitotane should be started as soon as possible after surgery.
  • In patients without recurrence who tolerate mitotane, mitotane should be administered for at least 2 years, but not longer than 5 years.

Other information on adjunctive therapy (Fassnacht et al., 2018):

  • Routine use of radiation therapy in patients with stage I‒II and R0 resection is not recommended.
  • Radiation + mitotane therapy should be considered on an individualised basis therapy in patients with R1 or Rx resection or in stage III.
  • If adjunctive therapy is administered, treatment should be started as soon as possible after surgery.
  • Routine use of cytotoxic drugs in the adjuvant setting is not recommended.
  • Adjuvant chemotherapy should be considered in selected patients with very high-risk recurrence.

The evidence for the efficacy of adjuvant mitotane or radiotherapy is of low quality but does support the recommendation for adjuvant mitotane treatment in those patients without macroscopic residual tumour after surgery but who have a perceived high risk of recurrence. A tumour response in ~20% of patients with advanced disease treated with mitotane was achieved (Fassnacht et al., 2018).

Meta-analysis of recurrence of included studies on adjuvant therapy after radical resection in ACC

Figure 3. Meta-analysis of recurrence of included studies on adjuvant therapy after radical resection in ACC (Fassnacht et al., 2018)

There is also evidence for the efficacy of mitotane on mortality (Fassnacht et al., 2018).

Meta-analysis of mortality of included studies on adjuvant therapy after radical resection in ACC

Figure 4. Meta-analysis of mortality of included studies on adjuvant therapy after radical resection in ACC (Fassnacht et al., 2018).

Treatment recommendations for ACC amenable to complete resection are shown in figure 5.

ACC amenable to surgical resection

Figure 5. ACC amenable to surgical resection (Fassnacht et al., 2018).
ACC: adrenocortical carcinoma: CR: complete response; DFI: disease-free interval; PD: Progression of the disease. PR: partial response; SD: stable disease.

 

  1. All patients with stage I+II and most patients with stage III should be amenable to radical resection. If complete resection is not feasible, consider neo-adjuvant treatment (e.g. mitotane + cisplatin or EDP). In selected patients with single metastases complete resection might be possible as well.
  2. In patients with R2 resection, consider re-surgery by an expert surgeon.
  3. If Ki67 staining is not available, a low (< 20 mitoses/50 high power fields) or a high mitotic rate (> 20 mitoses/50 high power fields) may be used for risk stratification.
  4. Individual decision.
  5. In some patients (Ki67 > 30%. large tumour thrombus in the vena cava, stage IV, or R1 resection) consider additional cytotoxic therapy (4 cycle of cisplatin + etoposide).
  6. After two years the time intervals are gradually extended.
  7. If the disease-free interval is between 6 and 12 months or in patients with DFI > 12, in whom complete resection is not possible, an individual approach is required.

Recurrent and/or advanced ACC

In patients with recurrent and/or advanced ACC there are a number of treatment options.

Surgery +/- mitotane

For patients with limited intra-abdominal metastases, surgical therapy is recommended if complete resection of all lesions seems feasible. Mitotane therapy should then be started as soon as possible. In addition to surgery, other local therapeutic measures are also of value. The routine use of adrenal surgery in case of wide-spread metastatic disease however is not recommended (Fassnacht et al., 2018).

In patients with advanced ACC not qualified for local treatment, either mitotane monotherapy or mitotane + etoposide + doxorubicin + cisplatin (EDP) is recommended. Also, in patients with recurrent disease and a disease-free interval of at least 12 month, in whom a complete resection/ablation is feasible, surgery or other local therapies are recommended (Fassnacht et al., 2018).

  • Mitotane should be started as soon as possible after the intervention.
  • EDP-M is recommended as a first line treatment if the time interval between last surgery/loco-regional therapy and recurrence is less than 6 months.

In patients who progress under mitotane monotherapy, EDP should be added and if they respond to treatment, local measure should also be considered (Optimal timing of mitotane therapy is currently unknown).

Treatment recommendations for ACC not amenable to radical resection are shown in figure 6.

Advanced ACC not amenable to resection

Figure 6. Advanced ACC not amenable to resection (Fassnacht et al., 2018).
EDP, etoposide, doxirubin and cisplatin.

  1. Only in selected patients (with severe hormone excess).
  2. The following factors might guide the decision: site of disease involvement, tumour burden, symptoms, tumour grade/Ki67 index.
  3. The following factors might guide the decision: site of disease involvement, tumour burden, symptoms, tumour grade/Ki67 index, and importantly kinetics of tumour growth.
  4. Radiotherapy, radiofrequency ablation, cryo ablation, microwave ablation, (chemo-) embolization.
  5. Few panellists favoured cisplatin + etoposide.
  6. Contact specialised centre.


Systemic therapies

Although surgery and other local measures are the first consideration mitotane monotherapy should be started as soon as possible after the intervention (Fassnacht et al., 2018). The recommended treatment is as follows:

  • Etoposide, doxirubin and cisplatin (EDP) + mitotane (30) every 28 days.
  • Day 1: 40 mg/m2 doxorubicin (D).
  • Day 2: 100 mg/m2 etoposide (E).
  • Day 3+4: 100 mg/m2 etoposide (E) + 40 mg/m2 cisplatin (C).
  • Plus oral mitotane aiming at blood level between 14‒20 mg/m2.

In patients unfit for the EDP-M-regimen (E) P-M may constitute a reasonable alternative every 28 days:

  • Day 1: 100 mg/m2 etoposide (E).
  • Day 2+3: 100 mg/m2 etoposide (E ) + 40 mg/m2 cisplatin (P).

Additional therapeutic options include:

  • Enrolling patient in a clinical trial.
  • Using loco-regional therapies.
  • Gemcitabine plus capecitabine. If so this would be:
    • 800 mg/mgemcitabine on day 1 and 8 (repeated every 3 weeks).
    • 1,500 mg/m2 etoposide (E).
    • Mitotane can be continued on an individualised decision.
  • Streptozotocin plus mitotane can also be used:
    • Induction on day 1: 1‒5: 1 g (Sz/d).
    • Afterwards 2 g/d Sz/d every 21 days.
    • Plus oral mitotane aiming at a blood level between 14‒20 mg/L.


Mitotane treatment

Mitotane treatment should be started as soon after surgery as possible (Fassnachet et al., 2018). It needs to be done in an escalating regimen depending on response and tolerability. It is also important to monitor the blood concentration of mitotane. In addition glucocorticoid replacement with hydrocortisone/cortisone acetate (at twice the standard dose) is advised in all patients treated with mitotane (except those with ongoing cortisol excess).

Remember that regular monitoring of mitotane-induced adverse events is required and to increase tolerability, supportive therapy should be started before toxicity occurs. There may also be some drug interactions with mitotane. All concomitant medication should be checked for CYP3A4 interactions and other care providers should not initiate other therapies without consultation (Fassnacht et al., 2018).

Mitotane treatment is associated with adverse events (table 6).

Table 6. Mitotane adverse events (Fassnacht et al., 2018).

Frequency is defined according to the following convention: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), Not known (cannot be estimated from the available data).

Mitotane adverse events

CBG, corticosteroid binding globulin; CNS, central nervous system; GT, glutamyl transferase; SHBG, sex hormone binding globulin; TBG, thyroxine binding globulin; T4, thyroxine; TSH, thyroxine stimulating hormone.

Recommendations for mitotane monitoring are shown in table 7.

Monitoring during mitotane treatment

CBG, corticosteroid binding globulin; CNS, central nervous system; GT, glutamyl transferase; SHBG, sex hormone binding globulin; TBG, thyroxine binding globulin; T4, thyroxine; TSH, thyroxine stimulating hormone.

Other supporting therapies

Medical therapy is recommended to control hormone excess in all patients with clinically relevant hormone-producing ACC. Anti-resorptive treatments are recommended in patients with bone metastasis. Palliative radiation is also recommended in advanced/metastatic patients, but palliative care should be integrated into standard oncology care for all patients with advanced ACC. If you have a patient recommended for fertility protection who is at a reproductive age counselling is recommended especially if they decided to embark on mitotane therapy (Fassnacht et al., 2018).

References

 

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