Research ArticleClinical Studies
Open Access

Comparing Injection Site Reactions of Aprepitant and Fosaprepitant in Gynecologic Cancer Chemotherapy

SEIRA NISHIBE-TOYOSATO, YOSUKE ANDO, YUTAKA TORII, RYOKO ICHIKAWA, AKIKO OWAKI, HIRONORI MIYAMURA, EIJI NISHIO, HIDEZO MATSUDA, NAHO TSUJII-FUJII, AKANE SHIMATO-ISOBE, KOTONE MUKAIJI, KAORI ITO, TAKAHIRO HAYASHI, TAKUMA FUJII and SHIGEKI YAMADA
In Vivo September 2024, 38 (5) 2374-2382; DOI: https://doi.org/10.21873/invivo.13704

Abstract

Background/Aim: The frequency rate of injection site reactions (ISR) due to fosaprepitant meglumine (Fos APR) has been shown to vary depending on the types of combined anticancer drug. This study aimed to elucidate the impact of Fos APR on ISR in patients receiving paclitaxel and carboplatin, with and without bevacizumab therapy (TC±Bev). Patients and Methods: This study focused on patients with gynecologic cancer (n=93) who received TC±Bev administration at Fujita Health University Hospital from March 2016 to February 2020, and monitored up to six cycles. The patients were randomly assigned to the Fos APR group (n=47) and the Aprepitant (APR) group (n=46). Using Visual Infusion Phlebitis (VIP) scores, ISR was evaluated by comparing the VIP scores of all cycles using a linear mixed model. The risk factors that contribute to the occurrence of vascular pain throughout all cycles were also examined. Results: The VIP scores of all cycles showed a near significant intergroup difference (p=0.071). Factors that affected the development of vascular pain included Fos APR and age (p=0.027 and 0.049, respectively). Regarding age, patients aged <65 years had a higher risk. Four patients underwent a switch from the originally assigned neurokinin-1 receptor antagonist; in all of these cases, Fos APR was changed to APR for vascular pain. Conclusion: Fos APR may increase the risk for ISR associated with TC±Bev therapy for gynecological cancer.

Key Words:

The number of patients with gynecological cancer has recently been increasing in Japan (1). Treatment options for gynecological cancer include surgery, radiotherapy, and chemotherapy. Among anticancer agents used for ovarian cancer, cisplatin (CDDP) has been considered a key drug since 1980, and CDDP plus cyclophosphamide (CPA) combination therapy has then become a standard treatment regimen. Subsequently McGuire WP et al. (2) reported that CDDP plus paclitaxel (PTX) combination therapy (TP therapy) is superior to CDDP+CPA combination therapy in terms of overall survival, progression-free survival, and complete response rate, and thus the use of TP therapy has gained popularity. In the 2000s, carboplatin (CBDCA) plus PTX combination therapy (TC therapy) was reported to be equally effective as TP therapy, with relatively low toxicity (3, 4). TC therapy has become a standard treatment regimen for ovarian cancer for greater ease of administration, in addition to lower toxicity, compared with TP therapy. Furthermore, for stage III and IV ovarian cancer, the addition of bevacizumab (Bev) has been shown to improve the efficacy of TC therapy, and thus TC therapy +Bev combination therapy has become a recommended option (5).

Notably, TP therapy has been widely used for advanced/recurrent cervical cancer since TP therapy was found to be superior to CDDP monotherapy (6). TC therapy was subsequently reported to be noninferior to TP therapy, and thus TC therapy is currently used as a standard treatment strategy (7). For advanced/recurrent endometrial cancer, doxorubicin plus CDDP combination therapy (AP) has been demonstrated to be effective (8), and thus has been widely used as a standard treatment regimen. Considering that high response rates to TC therapy have been observed in patients with advanced/recurrent endometrial cancer (9, 10), TC therapy is an option through which the regimen to use is chosen based on the efficacy and safety. Therefore, TC therapy is regarded as an indispensable chemotherapy regimen for gynecological cancer.

Chemotherapy-induced nausea and vomiting (CINV) is one of the most painful adverse events experienced by patients receiving chemotherapy, and it was reported to impair patients’ quality of life (QOL) and daily life functioning (11). In the National Comprehensive Cancer Network (NCCN) guidelines, CBDCA-based regimens [area under the curve (AUC) ≥4] were classified as regimens with a high emetic risk, and the concomitant use of neurokinin-1 (NK-1) receptor antagonists was recommended (12). Aprepitant (APR), which is classified as an NK-1 receptor antagonist, is an oral agent developed for prevention of CINV and has been approved for manufacturing and sale in Japan in October 2009. In Japan, where the aging of cancer patients is progressing (13), measures are needed for patients experiencing difficulties with oral intake or medication forgetfulness due to factors, such as swallowing and cognitive function decline and polypharmacy. Fosaprepitant Meglumine (Fos APR), an intravenous administration formulation of the prodrug of APR that obtained manufacturing and marketing approval in Japan in September 2011, serves as a solution for such cases. Typically, APR is administered for three days (at a dose of 125 mg on Day 1 of anticancer agent administration and at 80 mg once daily on Days 2 and 3), and Fos APR was administered once at a dose of 150 mg (on day 1 of anticancer agent administration). No differences in the efficacy were observed in a study comparing oral APR therapy for three days and administration of Fos APR as a single dose of 150 mg in patients with lung, gastrointestinal, or other cancers receiving CDDP therapy. However, Fos APR had a higher frequency of injection site reaction (ISR) presenting with erythema, induration, or pain as a symptom than APR (14). In the study comparing the frequency of ISR between oral APR therapy for three days and single-dose Fos APR in patients with breast, lung, or other cancers receiving CDDP- or anthracycline-based anticancer regimens, no intergroup differences were found in patients receiving the CDDP-based regimens, whereas the two groups of patients treated with the anthracycline-based anticancer regimens showed differences in the ISR frequency (15). Therefore, reported clinical studies on ISR frequency with Fos APR and APR were inconsistent, suggesting that the occurrence rate of ISR caused by Fos APR varies with the types of combined anticancer drugs.

To the best of our knowledge, there have been no reported studies comparing the frequency of ISR associated with CBDCA-based regimens between Fos APR and APR in gynecologic cancers exclusively affecting women, where a high frequency of ISR occurrence is noted (16). Therefore, this clinical study aimed to compare the effects of APR and Fos APR on the frequency of ISR in patients with gynecological cancer receiving paclitaxel+carboplatin with and without bevacizumab (TC±Bev) therapy at Fujita Health University Hospital.

Patients and Methods

Participants. Among patients aged ≥20 years who received chemotherapy for the first time at Fujita Health University Hospital between March 2016 and February 2020, we included patients who were scheduled to receive TC±Bev therapy for gynecological cancer and consented to participate in this study. Patients who experienced ISR-like symptoms or nausea/vomiting within 24 hours before starting chemotherapy and patients who received TC±Bev via a central venous line were excluded.

Study design and chemotherapy regimens. In this single-center randomized open-label pilot study, the primary endpoint was a comparison of the effects of APR and Fos APR on ISR frequency. The secondary endpoint was a comparison of the effects of APR and Fos APR on the frequency of nausea/vomiting. The target number of participants was 100 patients, with 50 patients each in the respective groups. Regarding the number of cases, although this was a pilot study, we collected a large number of cases to increase the reliability of the results. Fujita Health University Center for Clinical Trial and Research Support assigned the patients to either of the groups using the central registration and allocation method. The observation period was set to a maximum of six cycles. The observation period was discontinued when the originally assigned NK-1 receptor antagonist was changed (from Fos APR to APR, or from APR to Fos APR) or the chemotherapy regimen was changed during the observation period.

In the Fos APR group, 150 mg of Fos APR (dissolved in 250 ml of physiological saline) was administered on day 1 via intravenous drip infusion for 30 min. In the APR group, APR was administered orally at a dose of 125 mg on day 1 and at a dose of 80 mg on days 2 and 3. As antiemetics other than NK-1 receptor antagonists, 1 mg of granisetron (Gra), which is a 5-HT3 receptor antagonist, and 19.8 mg of dexamethasone (DEX) were administered via intravenous drip infusion on Day 1, and 4 mg of DEX was administered orally on Days 2-4 in cycle 1 in both groups. Other antiemetics could be used as a single dose only when patients experienced symptoms of nausea/vomiting, and the use of a drip infusion of the 5-HT3 receptor antagonist palonosetron (Paro) at a dose of 0.75 mg or Gra at 1 mg and DEX at 19.8 mg was required on day 1 from cycle 2 onwards; antiemetics other than these could be used at the physician’s discretion. The same volume of the diluent was used to dilute the intravenous infusion for all patients. The chemotherapy regimen consisted of PTX at 175 mg/m2 and CBDCA (AUC: 5.5) on day 1 of each cycle, with and without Bev at 15 mg/kg, and 1 cycle was defined as 21 days. Longer dosing intervals and lower chemotherapy doses could be used as needed depending on the patient’s condition at the discretion of the physician. When ISR symptoms were observed during chemotherapy, hot compress was provided as needed based on the patient’s complaint.

Assessment. The following information was collected from electronic medical records or through interviews with the patients: patient’s age at the introduction of TC±Bev therapy, body mass index (BMI), performance status (PS), cancer types, number of TC±Bev therapy cycles, any history of diabetes, use/non-use of opioids, and antiemetic usage during Days 1-7 of cycle 1. Information regarding whether the patients had a history of motion sickness, a history of hyperemesis gravidarum, and drinking habits was obtained by interviewing the patients at the time of patient enrollment. The occurrence of ISR and nausea/vomiting was surveyed using the treatment diary recorded by patients during this study. The episodes of ISR were evaluated using the visual infusion phlebitis (VIP) score determined based on patients’ records on whether they had pain, erythema, swelling, induration, palpable venous cord, and pyrexia (17). The episodes of nausea/vomiting were surveyed in detail only for those occurring during Days 1-7 of cycle 1. In accordance with previous reports (18, 19), the outcomes were defined as follows: the complete response (CR) rate, the proportion of patients who did not experience vomiting and did not receive additional antiemetic therapy; the complete control (CC) rate, the proportion of patients who did not experience vomiting, did not receive additional antiemetic therapy, and had mild nausea [5 mm ≤visual analogue scale (VAS) <25 mm] or did not have nausea; and the total control (TC) rate, the proportion of patients who did not experience vomiting, did not receive additional antiemetic therapy, and did not have nausea (VAS <5 mm). For nausea, the mean VAS and the median of maximum VAS in each group were calculated. For vomiting, the frequency of vomiting in each group was calculated.

Statistical analysis. Intergroup comparison of patient baseline characteristics was performed using the Mann-Whitney U-test or the chi-square test. In the ISR assessment, the VIP scores of all cycles were compared intergroup using a linear mixed model. Furthermore, the frequency rates of symptoms related to phlebitis in all cycles were compared between the two groups using the chi-square test, and logistic regression analysis was used to explore risk factors that affected the frequency of vascular pain in all cycles. Regarding values that showed a significant association with vascular pain, receiver operating characteristic (ROC) curve analysis was performed to determine the cutoff value using the Youden’s index. The maximum VAS and mean VAS of nausea were compared using the Mann-Whitney U-test, whereas the rates of CR, CC, TC, and occurrence of vomiting were compared using the chi-square test. EZR Version 1.55 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) was used to calculate the cutoff value from the ROC curve. All other statistical analyses were performed using SPSS Ver.22.0 (IBM Corporation, Armonk, NY, USA).

Ethical considerations. This study was performed in accordance with the Declaration of Helsinki. Patient consent was obtained, and the study was approved by the Ethical Review Board of the Fujita Health University (date, 28 May 2022; approval number: HM22-045).

Results

Patient baseline characteristics. Patients were randomly assigned to receive Fos APR (n=50 patients) or APR (n=50 patients) administration. Due to reasons such as the loss of diaries, treatment changes before the start of the trial, transfers to other facilities, meeting exclusion criteria, and allergies, it was not possible to collect the necessary diaries from seven patients for analysis. Therefore, 93 patients from the Fos APR (n=47 patients) group and the APR (n=46 patients) group were included in the analysis (Figure 1). No variables related to patient baseline characteristics showed significant intergroup differences (Table I and Table II).

Figure 1.
Figure 1.

Inclusion criteria.

View this table:
Table I.

Patient baseline characteristics.

View this table:
Table II.

Additional patient baseline characteristics.

ISR occurrence. No significant intergroup difference was observed in terms of the changes in VIP score over time; however, the VIP score in the Fos APR group tended to remain higher than that in the APR group over time (p=0.071) (Figure 2). The proportions of patients who experienced pain, swelling, induration, and pyrexia—symptoms related to phlebitis—in all cycles were significantly higher in the Fos APR group (p=0.034, 0.016, 0.001, and 0.003, respectively) (Table III). Fos APR administration, age, BMI, PS, number of cycles of TC±Bev administration, and history of diabetes were considered factors that affected the onset of vascular pain in all cycles; thus, a univariate analysis of these factors was performed. Furthermore, a multivariate analysis of factors with p<0.1 in the univariate analysis showed that Fos APR use and age affected the occurrence of vascular pain (p=0.027 and 0.049, respectively) (Table IV). The age at higher risk of developing vascular pain as calculated from the ROC curve was <65 years (specificity, 0.556; sensitivity, 0.697), AUC and 95%CI of age were 0.617 and 0.495-0.739, respectively (Figure 3). Four patients underwent an NK-1 receptor antagonist switch from the originally assigned one; in all of these cases, Fos APR was changed to APR, and the reason for the change was vascular pain (Table V).

Figure 2.
Figure 2.

Visual infusion phlebitis (VIP) score (mean±SD) changes over time. SD, Standard deviation.

View this table:
Table III.

Incidence rates of visual infusion phlebitis score-related symptoms among all cycles.

View this table:
Table IV.

Factors associated with the occurrence of vascular pain among all cycles.

Figure 3.
Figure 3.

Receiver operating characteristic curve to calculate sensitivity and specificity at cutoff values.

View this table:
Table V.

List of patients who underwent an NK-1 receptor antagonist switch.

Occurrence of nausea and vomiting. For episodes of nausea and vomiting during days 1-7 of cycle 1, the CR rate was 70.2% in the Fos APR group and 63.0% in the APR group; the CC rate was 61.7% in the Fos APR group and 60.9% in the APR group; and the TC rate was 44.7% in the Fos APR group and 45.7% in the APR group. None of these showed significant intergroup differences (p=0.463, 0.934, and 0.925, respectively). Furthermore, the maximum and mean VAS values of nausea and the frequency of vomiting did not show significant intergroup differences (p=0.579, 0.508, and 0.813, respectively) (Table VI).

View this table:
Table VI.

Occurrence of nausea and vomiting.

Discussion

In this study, we compared the effects of APR and Fos APR on ISR in patients receiving TC±Bev therapy for gynecological cancer. Regarding ISR occurrence, the VIP scores in the Fos APR group tended to remain higher than the APR group over time, and the frequency rates of pain, swelling, induration, and pyrexia—which are related to the VIP score—were significantly higher in the Fos APR group. Furthermore, factors associated with the development of vascular pain included Fos APR administration and age. Moreover, in all patients who underwent an NK-1 receptor antagonist switch, the switch was from Fos APR to APR because of vascular pain. These results suggested that the use of Fos APR may increase the frequency of ISR associated with TC±Bev therapy for gynecological cancer. Therefore, patients should be provided with an explanation regarding the possibility of ISR and treatment options available for ISR before they start receiving Fos APR concomitantly with TC±Bev therapy for gynecological cancer. In particular, when Fos APR is selected in patients younger than 65 years, they should be carefully monitored for ISR, and administration via a large blood vessel, including a central venous line, may be a valid option in some cases.

Drug-induced phlebitis is attributable to intimal damage caused by pH or osmotic changes associated with drug infusion (20). A solution prepared by dissolving Fos APR in 250 ml of physiological saline reportedly has a pH of 8.55 immediately after dissolution (21). The alkalinity of Fos APR can be brought closer to neutral by mixing with 5-HT3 receptor antagonists (22); this is not a viable option in clinical settings as the Fos APR degradation products reportedly formed precipitates when Fos APR was mixed with 5-HT3 receptor antagonists (23). The infusion of Fos APR over an extended time period was reported to contribute to the alleviation of ISR (24), suggesting that administration of Fos APR at a reduced rate can be effective.

A previous study showed that Fos APR did not affect the frequency of ISR in patients treated with CDDP-based regimens, whereas Fos APR affected the frequency of ISR in patients treated with anthracycline-based anticancer regimens (15). In the present study, the comparisons were made in patients treated with a platinum-based regimen similar to that used in the previous report; however, our results were different from those reported in the previous study. Differences in the study backgrounds between the previous and present studies included the absence of restrictions to the anticancer agents that were concomitantly administered with CDDP and the number of anticancer regimens used before CDDP-based regimen. Furthermore, although a previous study included male participants, the present study was performed with female participants. A different previous study (16) reported that the frequency of ISR in women was higher than that in men; because our study only included female patients, a higher risk of developing ISR in our study population may partly explain why the results were different between the two studies. Furthermore, the same chemotherapy regimen was used to treat chemotherapy-naïve female patients in the present study, and thus the effects of Fos APR on the occurrence of ISR in our study were clearer than those in the previous study.

The frequency of CINV did not differ between the Fos APR and APR groups. Furthermore, no intergroup differences were observed in terms of opioid usage, history of motion sickness, history of hyperemesis gravidarum, and drinking habit, which have been reported to be risk factors for CINV (25). These findings suggested that Fos APR and APR had no differences in terms of efficacy for CINV associated with TC±Bev therapy for gynecological cancer as far as Japanese women are concerned. The emetic effects of Fos APR and APR were reported to be similar in patients receiving monthly CBDCA (AUC, 6) and weekly PTX 80 mg/m2 for the treatment of gynecologic cancer (26). However, the relevant study is based on a very small number of cases, and in other previous studies, the delayed-phase CR rate in Japanese patients who received regimens including CDDP was shown to be 73% with APR (27) compared to 64.7% with Fos APR (28). Therefore, evidence regarding the antiemetic effects of Fos APR and APR in Japanese patients undergoing TC therapy for gynecologic cancer was limited. Hence, the comparative results of the antiemetic effects of Fos APR and APR in this study are considered to be very valuable.

In addition to Fos APR and APR, a new NK-1 receptor antagonist, fosnetupitant (Pro-NETU), has recently been approved for manufacturing and sale in Japan in March 2022. Pro-NETU has been shown to be noninferior to Fos APR in terms of the CR rate in patients undergoing CDDP-based regimens with a high emetic risk. In the same study, the frequency of injection site pain in the Pro-NETU group was 1 out of 392 patients (0.3%), which was lower than 11 out of 393 patients (2.8%) in the Fos APR group (29). Moreover, injection site pain associated with anthracycline-based anticancer regimens occurred in 0 out of 52 patients (0%) in the Pro-NETU group, compared to 4 out of 50 patients (8.0%) in the Fos APR group (30). These data suggest that Pro-NETU is as effective as Fos APR with a lower frequency of injection site pain and could be an option to consider for patients in whom APR is contraindicated and for patients with the risk of forgetting to take their drugs.

Study limitations. First, we were unable to elucidate the mechanism for ISR in patients receiving Fos APR concomitantly with TC±Bev therapy and identify which of PTX, CBDCA, and Bev was responsible for the occurrence of ISR in these patients. Second, as body weight and body surface area were not measured at every cycle of TC±Bev therapy, we could not examine the relations of the doses of PTX, CBDCA, and Bev per body weight or body surface area and the occurrence of ISR. Therefore, we cannot be certain whether the findings of this study are applicable to treatment when using the same regimen at different doses. Additionally, vascular pain-like symptoms associated with oxaliplatin were reported to reduce when nonsteroidal anti-inflammatory drugs (NSAIDs) were used concomitantly (31). In the present study, we surveyed the use/non-use of opioids, but did not survey whether NSAIDs were used; thus, we consider this as another limitation of the study.

Nevertheless, this was possibly the first study to investigate whether Fos APR administration carries the risk for ISR in patients receiving TC±Bev therapy for gynecological cancer. Findings of this study indicated that concomitant use of APR was more desirable for patients receiving TC±Bev therapy, and patient age was a factor that should be accounted for when using Fos APR.

Conclusion

Fos APR may increase the risk for ISR associated with TC±Bev therapy for gynecological cancer.

Acknowledgements

The Authors would like to thank the participating patients for their contribution to this study.

Footnotes

  • Authors’ Contributions

    SN-T, YA designed the study. TF, SY supervised the study. SN-T, YA, YT, RI, AO, HM, EN, HM, NT-F, AS-I, KM, KI contributed to data acquisition. SN-T, YA analyzed and interpreted the data. SN-T, YA drafted the manuscript. All Authors substantively revised the manuscript. All Authors read and approved the final manuscript.

  • Funding

    The Authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

  • Conflicts of Interest

    The Authors declare that there are no actual or potential conflicts of interest associated with this work. While some authors have received research funding, honoraria, or scholarship donations from diverse pharmaceutical companies and external organizations, these activities are unrelated to the submitted work and do not constitute actual or potential conflicts of interest.

  • Received April 23, 2024.
  • Revision received May 21, 2024.
  • Accepted May 22, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Comparing Injection Site Reactions of Aprepitant and Fosaprepitant in Gynecologic Cancer Chemotherapy
SEIRA NISHIBE-TOYOSATO, YOSUKE ANDO, YUTAKA TORII, RYOKO ICHIKAWA, AKIKO OWAKI, HIRONORI MIYAMURA, EIJI NISHIO, HIDEZO MATSUDA, NAHO TSUJII-FUJII, AKANE SHIMATO-ISOBE, KOTONE MUKAIJI, KAORI ITO, TAKAHIRO HAYASHI, TAKUMA FUJII, SHIGEKI YAMADA
In Vivo Sep 2024, 38 (5) 2374-2382; DOI: 10.21873/invivo.13704
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