A standard chemotherapeutic regimen for recurrent or metastatic ACC has not been previously established. This retrospective analysis evaluated the efficacy of carboplatin plus paclitaxel in a larger number of ACC patients than in previously reports. Moreover, this is the first report to evaluate the prognostic factors for PFS and OS in ACC patients treated with carboplatin plus paclitaxel.
The results of our study indicate a modest efficacy of carboplatin plus paclitaxel for recurrent or metastatic ACC patients. There are a limited number of prospective studies investigating the effects of chemotherapy for ACC. A small prospective trial involving a regimen of cyclophosphamide, doxorubicin, and cisplatin (CAP) on 22 SGC patients, including 12 ACC patients, demonstrated a 25% ORR for the ACC patients [13, 14]. However, this triplet regimen is difficult to administer in an outpatient setting, due to the amount of hydration required for cisplatin administration. Recently, several single-arm prospective phase 2 trials of multi-kinase inhibitors (MKIs), such as sunitinib, sorafenib, axitinib, dasatinib, and lenvatinib, for recurrent or metastatic ACC patients have been conducted [15–20]. In these trials, the number of patients enrolled were 14–40, the ORR were 0–15%, and the median PFS were 4.8–17.5 months. To date, these MKIs are not approved internationally for use in ACC patients. Pembrolizumab, a monoclonal antibody targeting programmed cell death 1 (PD-1), has been approved for metastatic or recurrent programmed cell death ligand 1 (PD-L1) positive cancers, regardless of their primary sites. However, PD-L1 positivity in ACC is reported to be low . In a phase 1b trial of pembrolizumab for various PD-L1 positive solid tumors, an objective response was not observed in ACC patients (0/2), even when PD-L1 positive . In several prospective phase 2 trials, the ORR was 8.6% (4/46) in nivolumab alone, and 6% (2/32) in nivolumab plus ipilimumab, suggesting the limited efficacy of immune checkpoint inhibitors for ACC [23, 24]. Despite being retrospective data, the ORR, PFS and OS of carboplatin plus paclitaxel in our cohort were comparable with the results of these clinical trials. Moreover, a carboplatin-based regimen can be administrated in an outpatient setting because it does not require extensive hydration, and is less expensive than MKIs and immunotherapies. Considering its convenience and cost-effectiveness, carboplatin plus paclitaxel represents a viable therapeutic option for recurrent or metastatic ACC patients.
A large multicenter prospective study (N = 470) for ACC suggested that age, BMI, and lymph node invasion were significant prognostic factors for ACC . Our exploratory analysis of prognostic factors indicated a link between higher TGR or poor ECOG PS and worse PFS and OS. BMI was also a prognostic factor for PFS in our results, which was consistent with the previous study. In the previous cohort, only 18% of the patients underwent chemotherapy and the detailed therapeutic data were excluded from the search for prognostic factors. Therefore, our results can be meaningful as all patients included in the cohort received chemotherapy with the same therapeutic regimen.
The ORR and DCR of our cohort were 11.5% and 76.9%, suggesting that the aim of a carboplatin plus paclitaxel regimen should be disease control, not tumor shrinkage. Patients with lower TGR demonstrated longer OS (median OS; 48.5 months). Therefore, watchful waiting and active surveillance can be an optimal strategy for patients with slow-growing (lower TGR) ACC. Initiation of systemic chemotherapy should be considered when TGR increases up to 6%/month during active surveillance or the patient develops tumor-related symptoms affecting ECOG PS. Patients with massive tumor volumes, aggressive TGR or severe tumor related symptoms might not benefit from carboplatin plus paclitaxel. For these patients, palliative care would be preferable to intensive systemic chemotherapy, which accounts for the patients’ quality of life.
Our study has several limitations. First, this was a retrospective analysis of a small number of patients at a single institute. Due to the rarity of ACC, not more than 46 ACC patients were enrolled in previous prospective studies investigating chemotherapy. Our results should be interpreted in the context of the difficulty of conducting large randomized phase 3 trials for ACC. Second, although the pathological specimens were diagnosed by a pathologist who specializes in head and neck cancers, genetic confirmation with MYB fusion genetic testing could not be performed in the majority of the patients. Third, some patients were excluded by the TGR assessments due to the absence of measurable target lesions. This may cause selection bias. Though we used a cutoff of 6%/month for TGR according to the median value of enrolled patients, the optimal cutoff value was not established. To resolve these limitations, we are now planning a prospective multicenter cohort study.