구토

The herbal medicine rikkunshito has the potential to improve chemotherapy-induced nausea and vomiting (CINV) by stimulating ghrelin secretion. We aimed to evaluate the efficacy and safety of rikkunshito in preventing CINV for patients with lung cancer. Two separate prospective, randomized, phase II parallel design studies were conducted in patients with lung cancer. Fifty-eight and sixty-two patients scheduled to receive highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC), respectively, were randomized 1:1 to receive either standard antiemetic therapy in accordance with international guidelines (S group) or standard antiemetic therapy plus oral rikkunshito (R group). The primary endpoint was overall complete response (CR)—that is, no emesis and rescue medication in the first 120 h post-chemotherapy. Secondary endpoints included CR in the acute (0–24 h) and delayed (>24–120 h) phases and safety. Fifty-seven patients (S group, 28; R group, 29) receiving HEC and sixty-two patients (S group, 30; R group, 32) receiving MEC with comparable characteristics were evaluated. The CR rates were similar across the S and R groups for the HEC study in the overall (67.9% vs. 62.1%), acute (96.4% vs. 89.6%), and delayed (67.9% vs. 62.1%) phases, respectively, and for the MEC study in the overall (83.3% vs. 84.4%), acute (100% vs. 100%), and delayed (83.3% vs. 84.4%) phases, respectively. No severe adverse events were observed. Although rikkunshito was well tolerated, it did not demonstrate an additional preventative effect against CINV in lung cancer patients receiving HEC or MEC.

Clinical Trial Registry Information: This study is registered with the University Hospital Medical Information Network (UMIN) Clinical Trial Registry1, identification numbers UMIN 000014239 and UMIN 000014240.

Patient Characteristics: Between July 2014 and January 2016, 58 patients who received HEC (29 each in the S and R groups) and 62 patients who received MEC (30 in the S group and 32 in the R group) were enrolled. One patient from the S group of the HEC study was excluded because of disease progression before the antiemetic treatment; hence, only 57 patients who received HEC were evaluable (Figures 1, 2). All patients enrolled in the two phase II studies had a good nutritional status, and had neither muscle wasting nor weight loss. The patients’ characteristics are summarized in Table 1. The baseline characteristics of the study subjects were similar between the groups in both the HEC and MEC studies. In the HEC study, the median patient age was 65 years (range 46–76 years), of whom 77.2% were men and most (96.5%) had a good ECOG PS (0–1). The most common histology was adenocarcinoma (54.4%), followed by small cell carcinoma (24.6%), and squamous cell carcinoma (14.0%). Most of the patients (87.7%) were treated with palliative chemotherapy. The combined chemotherapeutic agents with CDDP were as follows: pemetrexed (29.8%), pemetrexed plus bevacizumab (22.8%), etoposide (14.0%), vinorelbine (8.8%), irinotecan (12.3%), gemcitabine (8.8%), docetaxel (1.8%), and S-1 (1.8%). As for the MEC study, the median patient age was 70 years (range 45–89 years); 77.4% were men and most (95.2%) had a good ECOG PS of 0–1. The most common histology was adenocarcinoma (46.8%), followed by squamous cell carcinoma (30.6%) and small cell carcinoma (12.9%). Most of the patients (95.2%) were treated with palliative chemotherapy. The combined chemotherapeutic agents with carboplatin were as follows: pemetrexed (29.0%), nab-paclitaxel (27.4%), etoposide (17.7%), S-1 (9.7%), paclitaxel plus bevacizumab (6.5%), pemetrexed plus bevacizumab (3.2%), gemcitabine (3.2%), paclitaxel (1.6%), and amrubicin (1.6%).

Efficacy: In the HEC study, the CR rates in the overall phase were 67.9% (95% confidence interval [CI], 47.7–84.1) in S group and 62.1% (95% CI, 42.3–79.3) in R group (P = 0.65), which did not meet the primary endpoint. In the MEC study, the CR rates in the overall phase were 83.3% (95% CI, 65.3–94.4) in S group and 84.4% (95% CI, 67.2–94.7) in R group (P = 0.59), which met the primary endpoint (Table 2). In the HEC and MEC studies, rikkunshito did not exhibit additional improvement on CR rates in the overall phase. Furthermore, rikkunshito did not improve CR rates for the acute and delayed phases in either the HEC or MEC study. Rikkunshito administration also did not improve CP or TC rates in the acute, delayed, or overall phases in the HEC and MEC study. The median dietary intakes were also similar between the S and R groups (89 and 89 mm in the HEC study, and 90 and 91 mm in the MEC study, respectively). Subgroup analyses according to sex, age, alcohol intake, smoking status, ECOG PS, body mass index, motion sickness, dexamethasone dose, treatment line, histology, CDDP, or CBDCA dose, and combined drugs revealed no additional benefit for rikkunshito administration on CR rates in the acute, delayed, or overall phases (data not shown).

Safety: Rikkunshito was well tolerated, with frequencies of treatment-related adverse events similar to those reported in the S groups. Most adverse events were mild and were associated with the patients’ cancer and/or chemotherapy treatment. The most common treatment-related adverse events were constipation, diarrhea, and hiccups. No severe adverse events attributed to antiemetic treatments were reported in either study (Table 3).