Introduction

During the past two decades, there have been dramatic advances in the management of chemotherapy-induced nausea and vomiting (CINV) [5]. Chemotherapy agents are currently classified according to their potential for inducing nausea and vomiting. Drugs such as cisplatin routinely produce CINV when given without antiemetic protection. By contrast, Vinca alkaloids and bleomycin have low emetic potential [8]. The Hesketh classification was recently updated at the 2004 Perugia Antiemetic Consensus Meeting. This included new intravenous agents and oral agents [6]. Drugs were categorized as having high (>90%), moderate (30–90%), low (10–30%), or minimal (<10%) emetogenic potential (the figures in parentheses represent the percentage of patients having emetic episode/s when no prophylactic antiemetic protection provided). In this revised classification, intravenous etoposide was labeled as having low emetogenic potential. However, oral etoposide was classified as moderate, implying that there is a 30–90% incidence of emesis [7].

CINV is best managed by prophylactic antiemetics. Success during actual emesis is poor. Drugs classified as having high or moderate emetogenic potential require prophylactic antiemetics with a 5-hydroxytryptamine-3 (5-HT3) antagonist plus dexamethasone [7]. Furthermore, patients who receive moderately emetogenic chemotherapy known to be associated with a significant incidence of delayed nausea and vomiting should receive antiemetic prophylaxis for delayed emesis with agents such as oral dexamethasone [10].

Etoposide inhibits topoisomerase II [11]. This drug has been a standard intravenous agent, combined with cisplatin, in small cell lung cancer and testicular cancer. Etoposide is more effective over several days than as a single-day treatment. Studies using daily oral etoposide have been performed at Indiana University to try to exploit the schedule dependency. We have demonstrated activity of daily oral etoposide germ cell tumor patients who have progressed during intravenous etoposide [9].

Advanced testicular cancer patients are treated initially with bleomycin + etoposide (intravenously) + cisplatin (BEP). Approximately 75% of metastatic patients are cured. Salvage (second-line) therapy with high-dose carboplatin + etoposide with peripheral blood stem cell transplant can cure 50% of those not cured with BEP [4]. We currently employ maintenance daily oral etoposide after high-dose salvage therapy to try to decrease the probability of relapse [2]. During our extensive experience with daily oral etoposide, we have not felt that this oral agent has significant emetic potential. A moderately emetogenic drug would require prophylactic antiemetics with a 5-HT3 antagonist + dexamethasone. We, therefore, designed this prospective study of testicular cancer patients receiving daily oral etoposide to determine its emetic potential.

Materials and methods

Eligible patients were male patients with a diagnosis of germ cell tumor. All patients were pretreated with initial chemotherapy for metastatic disease with bleomycin + etoposide + cisplatin (BEP) or a similar cisplatin + etoposide-based regimen. In addition, all patients also received salvage chemotherapy for relapsed and/or progressive germ cell tumor with high-dose chemotherapy with carboplatin 700 mg/M2×3 + etoposide 750 mg/M2 (intravenously) for three consecutive days with peripheral blood stem cell tandem transplant [1]. The second course was given 3–5 weeks later after hematopoietic recovery. Several patients also received other salvage chemotherapy before tandem transplant. Daily oral etoposide was given in this study to post-tandem transplant patients as maintenance therapy for those patients in complete or excellent partial remission [2]. Oral etoposide started 4–6 weeks after second and final course of high-dose carboplatin + etoposide after hematopoietic reconstitution. The dosage was 50 mg/M2 orally for 21 consecutive days. The 50 mg capsule was rounded off to the nearest 25-mg dosage. Complete blood counts were obtained twice weekly. The etoposide was discontinued if the absolute granulocyte count was <500/mm3 and/or platelets <50,000/mm3. All patients received at least 15 days of the planned 21 days of daily oral etoposide. A second and third course of daily oral etoposide was given after seven or more days off therapy after hematologic recovery. Emetic data was collected only for the first course. A six-question questionnaire based upon the Multinational Association of Supportive Care in Cancer (MASCC) antiemetic tool (MAT) was filled out daily by the patients during the first course of daily oral etoposide.

The patient’s name, date, treatment day, and dosage of oral etoposide were recorded. Six separate questions were asked on the MAT. Patients were asked to respond whether they had any nausea in the past 24 h and to encircle the number corresponding to the intensity of the nausea (0 = none and 10 = as much as possible). They were asked to quantify the duration of nausea. They were also asked whether they had any vomiting in the last 24 h and the number of emetic episodes. Finally, they were asked to document any antinauseant medications (rescue medications) that they took during the duration of the study.

Median patient age was 33 years (range 14 to 54). No patient received prophylactic antiemetics.

All patients gave informed consent, and the study was approved by the Institutional Review Board of Indiana University Cancer Center. Patient contact was made by phone (MJB) to ensure patient compliance and understanding of the MAT.

Statistical methods

This was a registration trial to investigate the incidence of CINV among patients receiving daily oral etoposide. Objectives were to determine whether the proportion of patients with emesis or significant nausea was 30–90%. A patient reporting any occurrence of emesis during the 21 days of oral etoposide would be counted as experiencing vomiting. Nausea incidence, severity, and duration were measured.

Results

Sixteen patients were treated with oral etoposide 50 mg/M2 daily for 21 consecutive days. The median number of days of therapy was 20 (range 15 to 21). All patients previously received BEP or similar first-line chemotherapy for metastatic disease and salvage therapy with tandem transplant with high-dose chemotherapy with carboplatin + etoposide (intravenously). All 16 patients completed the MAT.

Overall, 11 of 16 (70%) patients had no nausea or vomiting. Two patients had a single emetic episode on just a single day of their oral etoposide. One patient had moderately severe nausea on days 9–20 with a MAT rating ranging from 3 to 6 on the days of nausea. One patient had persistent mild nausea for all 21 days (MAT rating of 1–3). Two additional patients had a MAT rating of 1 for brief nausea. Only two of these 16 patients (12%) required any form of antiemetic support.

Discussion

CINV is a serious side effect of many cytolytic agents. This is especially true for highly emetogenic agents such as cisplatin. The introduction of the 5-HT3 antagonists has greatly mitigated this adverse effect [3]. The primary value of antiemetics is to prevent CINV. No therapeutic agent is of major value in ameliorating CINV during an acute episode.

Hesketh [8] originally classified intravenous chemotherapy agents according to their frequency of causing emesis. An updated classification also included oral cytolytic agents such as oral etoposide [6]. Although intravenous etoposide was listed as having low emetogenic potential, oral etoposide was categorized as having moderate severity. Moderate emetogenicity is defined as a 30–90% incidence of vomiting if prophylactic antiemetics are not administered. The consensus recommendation for moderately emetogenic drugs was the prophylactic administration of a 5-HT3 plus dexamethasone 8 mg orally. It was recognized that daily oral chemotherapy had different challenges than intermittent intravenous chemotherapy, but the general consensus was to at least employ a daily oral 5-HT3 antagonist [7]. However, these agents are expensive and can cause constipation and headaches. Dexamethasone, although less expensive, has a myriad of adverse events that would be increased in incidence and severity if given for multiple days such as 21 consecutive days of oral etoposide [12].

We have utilized daily oral etoposide in patients with germ cell tumors for the past 15–20 years [2, 9]. Although CINV was not previously prospectively recorded, it was our impression that this was only a minor problem in this patient population. We had never administered prophylactic antiemetics to patients receiving oral etoposide. Our prospective data collaborates and confirms our impression. These patients would be expected to have some degree of CINV with any agent since they were primed with highly emetogenic regimens with BEP and high-dose carboplatin. Nevertheless, 11 of 16 patients (70%) had no nausea or vomiting whatsoever with their daily oral etoposide. Furthermore, only two of 16 patients (12%) had emesis and both just had a single emetic episode on 1 day only of the oral etoposide. The severity of nausea for those patients experiencing this adverse event was mild on the linear analogue scale as part of the MAT. Only two patients required antiemetic rescue. Lorazepam and lorazepam + prochlorperazine was used for these two patients. Technically, five of these 16 patients (31%) did have some degree of CINV, so oral etoposide could still be considered a ‘‘moderate’’ emetogenic agent. However, only two of 16 patients required any antiemetic support and the degree of CINV was mild. Thus, we feel that this agent is more correctly classified as having low rather than moderate probability of inducing CINV.

In conclusion, daily oral etoposide in the dose and schedule utilized in this study, only has a low probability of producing CINV. Prophylactic antiemetics can thus be avoided in this patient population.