This study firstly demonstrated the efficacy of combining cooling and oral Dex for primary prevention of PLD-induced HFS. The combination therapy of cooling and oral Dex led to a lower incidence of HFS (HFS ≥ Grade 2, 7.6% and HFS ≥ Grade 3, 1.5%) compared with cooling alone. The results of this study support the usefulness of cooling + oral Dex as primary prevention for HFS in ovarian cancer patients receiving PLD monotherapy or PLD + Bev therapy.
In the current study, cooling + Dex therapy demonstrated a sufficient prevention of HFS associated to PLD regardless of the PLD dose; HFS ≥ Grade 2 occurred in 5.9% and 9.4% of patients receiving 40 mg/m2 and 50 mg/m2 of PLD, respectively, and HFS ≥ Grade 3 occurred in 0.0% and 3.1% of patients receiving 40 mg/m2 and 50 mg/m2 of PLD, respectively. Considering that the preventive efficacy of cooling alone was controversial in previous reports (up to 30% and 17% of incidence for HFS ≥ Grade 2 and ≥ Grade 3, respectively), these results indicate that at least part of the observed preferable preventive efficacy is attributed to the addition of 7 days of oral Dex to the regional cooling. Previously, we had used a combination therapy of cooling and 2 days of oral Dex (8 mg/day on days 1 and 2) for six patients prior to the current postulated protocol. Among these six patients, two (33%) each experienced Grade 2 and Grade 3 HFS, indicating that 2 days of oral Dex might be less effective in preventing HFS compared with 7 days of oral Dex. These observations seem reasonable considering the long t1/2 of PLD (approximately 80 h). Although cooling alone is effective in preventing HFS by reducing the distribution of PLD into hands and feet, PLD can remain in the body for a long period and induce inflammatory reaction. Therefore, it would be beneficial to maintain the anti-inflammatory effect by administrating Dex for a period well beyond the t1/2 of PLD.
Regarding AEs other than HFS, previous prospective studies have reported nausea + vomiting ≥ Grade 2 and ≥ Grade 3 at frequencies of 15-20% and 5-10% [5, 7, 8, 14-16], respectively, whereas in our study, the incidences of nausea + vomiting ≥ Grade 2 and ≥ Grade 3 were 10.8% (8/74) and 0.0% (0/74), respectively (Table 2): the incidence of nausea + vomiting tended to be lower than those previously reported in the literature. This observation seems reasonable considering that Dex is an established anti-emetic agent and is used with many cancer chemotherapies. In contrast, in our study population, mucositis ≥ Grade 2 and Grade 3 occurred in 36.5% (22/74) and 6.8% (5/74) of patients, respectively. Particularly, in patients receiving 50 mg/m2 of PLD, mucositis ≥ Grade 2 occurred in 56.3% (18/32). Consequently, mucositis was the leading cause of dose reduction instead of HFS. The incidences of Grade 2 and 3 mucositis were relatively higher than those previously reported in the literature (incidences of mucositis ≥ Grade 2 and Grade 3 were 15-30% and 5-10%, respectively) [5, 7, 8, 14-16].
The high incidence of mucositis might be attributed to the ambivalent effect of oral Dex. Similar to HFS, mucositis is considered to be caused by free radicals and inflammatory cytokines from anticancer agents that destroy the organization of the oral mucosa [29]. However, different from HFS, secondary infection with oral bacteria, which can be exacerbated by chemotherapy-induced neutropenia, augments mucositis [29]. Oral Dex may reduce the production of free radicals, inflammatory cytokines, and subsequent mucosal injuries [27]; however, bacterial infection may be worsened due to steroid therapy. In addition, steroid therapy sometimes causes not only mucositis but also other AEs including insomnia and hyperglycemia. Most especially, AEs are more likely to occur when patients take a long course of oral steroids. Therefore, optimal duration of oral Dex should be further investigated in the future prospective studies.
This study has several limitations. First, this is a retrospective and observational study. There might be some missing data, and assessment of AEs can vary between physicians. Those limitations may have led to an underestimation of the incidences of AEs. Second, this study is not a case-control study. We only compared the incidence of HFS in our cohort with those in previous reports. Direct comparison is needed to confirm the preventive effect against HFS. Third, in this study, AEs of seven-day oral Dex were not sufficiently assessed. Oral steroids may cause hyperglycemia, insomnia, osteopenia, and bacterial infection. Further prospective controlled studies to assess the efficacy and safety of oral Dex as primary prevention of HFS are warranted. Despite these limitations, this study is the first to demonstrate the preventive effect of cooling + oral Dex on PLD-induced HFS.
In conclusion, we demonstrated the efficacy of the combination therapy of cooling and oral Dex as primary prevention for PLD-induced HFS. This combination therapy can be considered as primary prevention for HFS in ovarian cancer patients who are administered PLD.