Abstract
Abstract
Chemotherapy-induced nausea and vomiting (CINV) is one of the most distressing side effects in systemic chemotherapies. Recently, several effective agents have been developed to prevent CINV, and CINV can be prevented in 70%-80% of patients receiving chemotherapies. Conversely, 20%-30% of patients still suffer from CINV despite recommended optimal antiemetic preventions. Refractory emesis is defined as emesis occuring despite the use of antiemetic prophylaxis during the previous cycle of chemotherapy. Salvage treatments for refractory emesis are necessary, but there are few effective treatments at present. We consider medroxyprogesterone acetate to be a potentially promising agent for refractory emesis. We encountered three cases in which medroxyprogesterone acetate was extremely effective for refractory emesis induced by cisplatin-containing chemotherapy.
Introduction
Case Descriptions
Case 1
Case 1 was a 58-year-old man diagnosed with metastatic adenocarcinoma of the lung. He received cisplatin (80 mg/m2 on day 1) plus gemcitabine (1000 mg/m2 on days 1 and 8) every three weeks as first-line chemotherapy with granisetron (3 mg on day 1), aprepitant (125 mg on day 1, 80 mg on days 2 and 3), and dexamethasone (12 mg on day 1, 8 mg on days 2-4). Despite an optimal antiemetic prevention, he exhibited grade 3 nausea and vomiting (CTCAE version 4.0) during the delayed phase in the first cycle of chemotherapy. From the second cycle we substituted oral MPA (900 mg, on days 2-5) for aprepitant and continued granisetron and dexamethasone. Since initiation of MPA, he never exhibited vomiting, and nausea was dramatically reduced. Stable disease was achieved, and the chemotherapy was able to be continued for cumulative six cycles.
Case 2
Case 2 was a 58-year-old woman diagnosed with metastatic biliary tract cancer. She received cisplatin (25 mg/m2 on days 1 and 8) plus gemcitabine (1000 mg/m2 on days 1 and 8) every three weeks as first-line chemotherapy with granisetron (1 mg on day 1) and dexamethasone (8 mg on day 1 and 8, 4 mg on days 2-3, 9-10). Although cisplatin was administered at a split dose, she exhibited grade 3 nausea and vomiting during the delayed phase in the first cycle of chemotherapy. From the second cycle we added aprepitant (125 mg on day 1 and 8, 80 mg on days 2-3, 9-10), but CINV was still uncontrolled. From the third cycle we substituted oral MPA (900 mg, on days 2-5) for aprepitant and continued granisetron and dexamethasone. Since initiation of MPA, she had never vomited, and nausea was well controlled. Chemotherapy was able to be continued for cumulative eight cycles until disease progression.
Case 3
Case 3 was a 67-year-old woman diagnosed with metastatic adenocarcinoma of the lung. She received cisplatin (80 mg/m2 on day 1) plus gemcitabine (1000 mg/m2 on days 1 and 8) every three weeks as first-line chemotherapy with palonosetron (0.75 mg on day 1), aprepitant (125 mg on day 1, 80 mg on days 2 and 3), and dexamethasone (12 mg on day 1, 8 mg on days 2-4). Despite these antiemetic preventions, she exhibited grade 3 nausea and vomiting during both acute and delayed phases in the first cycle of chemotherapy. From the second cycle we added oral MPA (900 mg, on days 1-5). Since addition of MPA she never vomited, and nausea was dramatically reduced. Chemotherapy was continued for four cycles, achieving a partial response.
No apparent adverse events associated with MPA, including thromboembolism, were observed in these three MPA therapeutic cases.
Discussion
In case 1, alternative use of MPA to aprepitant was successful in those who had suffered from CINV in prior chemotherapy. In case 2, despite a split dose of cisplatin, CINV occurred in the first cycle of chemotherapy. In the second cycle, aprepitant was added, but CINV still occurred. Finally, substituting MPA for aprepitant was effective for this refractory emesis. In case 3, a three-drug combination consisting of dexamethasone, aprepitant, and palonosetron failed to prevent CINV. Palonosetron is a long-acting 5-HT3-RA and effective for delayed emesis. This three-drug combination has demonstrated a remarkable effect for CINV, with rates of complete response (no vomiting and rescue drugs) of 97.7% (acute phase), and 72.5% (delayed phase). 8 Although CINV occurred despite using these three drugs, CINV was markedly improved after the addition of MPA to this combination.
There is no standard treatment for refractory emesis, and salvage treatments are given on demand in each case. Several approaches have been utilized, including switching to a different 5-HT3RA, or adding other agents such as dopamine antagonists or benzodiazepines according to several guidelines.3,4 However, the efficacy of these agents seems to be limited, and more effective drugs are desired.
MPA for palliation of nausea and vomiting in cancer patients was already proven in a placebo-controlled randomized trial. 6 In the trial, MPA was additionally effective for appetite and weight loss. Efficacy of MPA and MA were also suggested for cancer related cachexia in some studies.7,9 Although these results would imply the efficacy of MPA and MA for CINV, little evidence was shown before Zang and colleagues reported the efficacy of MA for CINV. 10 They have documented antiemetic activity of MA in patients receiving chemotherapy. Zang and colleagues and our cases demonstrate the efficacy of synthetic progestagens such as MPA and MA for CINV.
Although the mechanism of MPA for suppressing CINV is unclear, a similar mechanism to that observed in corticosteroids such as dexamethasone is postulated. 10 In our present cases we administered initial dexamethasone at recommended dosages according to several guidelines.2,3,4 If MPA works via mechanisms similar to dexamethasone, a dose-escalated dexamethasone might have been effective instead of additional MPA. In a separate dose-ranging study where doses of 4, 8, 12, or 20 mg dexamethasone were administered before cisplatin-induced chemotherapy, the 20-mg dose was shown to be most efficacious for prevention of acute emesis. Complete protection from acute vomiting and nausea was achieved by 69.2% and 60.9% of patients, respectively, who received 4 mg of dexamethasone; by 69.1% and 61.0% of those who received 8 mg; by 78.5% and 66.9% of those who received 12 mg; and by 83.2% and 71.0% of those who received 20 mg. 11 Their data demonstrated the higher dose of dexamethasone to be the more effective to prevent CINV. On the other hand, Mantovani and colleaues demonstrated that MPA reduces the in vitro production of cytokines and serotonin in peripheral blood mononuclear cells of cancer patients. 12 MPA is thus potentially more than just another corticosteroid, and the addition of MPA to dexamethasone can exert greater effect than an increased dose of dexamethasone alone.
As with its efficacy for refractory CINV, MPA can also be applied to nonchemotherapy-induced refractory emeses, such as opioid-induced emesis, radiation-induced emesis, unknown-, or multiple-caused emesis. We experienced some cases in which MPA was effective for these refractory emeses. However, little is still known about the effcicacy of MPA for these refractory emeses, and further investigations are needed.
To palliate cancer-related emeses, MPA is potentially a good alternative in patients with contraindications for corticosteroids. Corticosteroids can induce metabolic abnormalities, central nervous system effects, glaucoma, cataracts, impaired wound healing, dyspepsia, myopathy, hypertension, increased risk of infection, hypothalamic-pituitary-adrenal axis suppression, osteoporosis, or osteonecrosis. MPA can be used in patients with these comorbidities instead of dexamethasone. Meanwhile, thromboembolism is known as a relatively frequent and severe side effect of MPA, and thus MPA is considered a contraindication in patients with thromboembolism. In our present cases no apparent symptoms associated with thromboembolism were observed. We can then safely administer MPA in short duration.
Currently, CINV can be prevented by optimal antiemetic medications in a large portion of patients receiving chemotherapy, even in highly emetogenic agents such as cisplatin. However, symptoms are occasionally still intolerable in refractory emesis cases. Therefore, we should explore salvage treatments for refractory emesis despite optimal antiemetic preventions. We consider MPA to be a potentially promising agent for refractory emesis. Furthermore, MPA can be applied to nonchemotherapy induced refractory emeses, and can be a good alternative in patients with contraindications for corticosteroids. As our data was based on only a few cases, further studies are warranted to confirm the efficacy of MPA for refractory emesis.
Footnotes
Acknowledgments
We thank Mr. David Martin for writing support.
Author Disclosure Statement
The authors declare no conflicts of interest. No financial support was provided for this study.