Abstract
Background/Aim: Adverse events (AEs) must be managed during cancer therapy. We had previously developed a medication guidance sheet (MGS) to monitor AEs after conditioning therapy with allogeneic hematopoietic stem cell transplantation (HSCT). However, it remains unclear whether this sheet can accurately predict the type, onset, and duration of AEs in clinical practice. In this study, we evaluated the clinical utility of the original MGS in patients receiving total body irradiation (TBI) and cyclophosphamide (CY). Patients and Methods: Fifty-eight patients who underwent TBI/CY were included. The types, onsets, and durations of AEs observed during real monitoring were compared with those listed in the original MGS. Results: A total of 361 subjective AE symptoms were observed, all of which were predictive, as listed in the MGS. However, the durations of several AEs were longer than expected. Thus, the prediction accuracy for all AEs was 67.0%. The accuracy rate was the lowest for anorexia (6.7%), followed by diarrhea (42.6%), and nausea/vomiting (55.6%). Acute graft versus host disease (GVHD) most likely caused the prolongation of AEs. Subsequently, the original MGS was revised to account for the possible occurrence of acute GVHD. Conclusion: When monitoring AEs in patients receiving a TBI/CY conditioning regimen for HSCT, the involvement of acute GVHD-associated AEs should be considered. In this respect, the present modified MGS is particularly useful for rapid and accurate monitoring of AEs.
- Chemotherapy
- medication guidance sheet
- adverse events
- TBI/CY conditioning regimens
- allogeneic hematopoietic cell transplantation
Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for hematologic malignancies, bone marrow failure syndromes, inherited immunodeficiencies, and metabolic diseases (1, 2). Recent advancements in transplantation techniques have greatly improved the clinical outcomes of HSCT, and as a result, many HSCT recipients have become long-term survivors (3). HSCT conditioning varies from high-dose myeloablative conditioning (MAC) to reduced-intensity conditioning depending on the degree of myelosuppression and immunosuppression (4, 5). Among several MAC regimens, a conditioning regimen consisting of 120 mg/kg cyclophosphamide (CY; 60 mg/kg for two days) and 12 gray fractionated (2 gray in each fraction for a total of six fractions over three days) total-body irradiation (TBI) has often been used (6, 7). In addition to the direct toxic action of MAC, the immune-mediated graft-versus-leukemia (GVL) that results from the engraftment of hematopoietic stem cells severely suppresses the leukemia cells (8). However, TBI/CY conditioning causes several serious adverse events (AEs), including anorexia, nausea/vomiting, diarrhea, mucositis, and hemorrhagic cystitis. CY is metabolized by liver enzymes into the active metabolites, phosphoramide mustard and acrolein, the latter of which is highly toxic and induces hemorrhagic cystitis (9, 10) and hepatic injury (11). Moreover, CY frequently induces anorexia, nausea, and vomiting, since the compound at doses used for conditioning is classified as a high emetic risk chemotherapy agent (12). On the other hand, stomatitis and diarrhea, both of which are associated with gastrointestinal mucosal injury, have been reported to frequently occur in patients receiving a conditioning regimen for bone marrow transplant (13, 14). Mucosal injury caused by oxidative stress, followed by the production of inflammatory cytokines, is involved in the etiology of stomatitis and diarrhea associated with irradiation or high-dose CY (15, 16).
In addition to the toxicity associated with TBI/CY, graft versus host disease (GVHD) occurs frequently after hematopoietic stem cell engraftment. Moreover, the day before HSCT, patients begin taking immunosuppressant drugs such as calcineurin inhibitors and methotrexate (MTX). Severe AEs have a negative impact on clinical outcomes, including engraftment, relapse-free survival, and overall survival (14, 17). Therefore, the management of AEs during HSCT is complicated, particularly for patients receiving the MAC regimen.
Clinical pharmacists are responsible for ensuring safe and effective chemotherapy. First, the prescription orders should be reviewed based on the chemotherapy regimens. Second, to relieve patient anxiety, information should be provided about possible AEs in terms of severity, onset timing, duration, as well as countermeasures for prevention or alleviation of AEs. Third, prompt provision for appropriate supportive care must be made (18-24). To quickly and accurately determine potential AEs during cancer chemotherapy, we developed an innovative medication guidance sheet (MGS) for several chemotherapy regimens, including the TBI/CY regimen (18, 25, 26). This sheet was designed to provide visual and quick recognition of the types, their onset, and the duration of AEs. However, it remains unclear whether the sheet correctly predicts the type and timing of AEs. Therefore, we evaluated the usefulness of the MGS for TBI/CY conditioning regimen by monitoring the AEs in patients undergoing the conditioning regimen.
Patients and Methods
Patients. Patients who received a TBI/CY conditioning regimen at the Department of Hematology, Kyushu University Hospital, between April 2013 and September 2021 were included in the present study.
TBI/CY conditioning regimen. CY was administered at a dose of 60 mg/kg IV over 2 h for 2 days, and TBI was 2 Gy fractionated twice daily for 3 days.
GVHD prophylaxis. Calcineurin inhibitors and methotrexate (MTX) were administered for GVHD prophylaxis. From the day before the transplantation, either tacrolimus (0.03 mg/kg i.v. over 24 h) or cyclosporine (3 mg/kg d.i.v. over 3 h twice daily) were administered. MTX was injected by bolus i.v. at 10 mg/m2 on day 1 and 7 mg/m2 on days 3, 6, and 11 after transplantation (day 0).
Preparation of the original MGS. We created the MGS template consisting of two sections: a treatment schedule column and an AE monitoring column during cancer chemotherapy using Microsoft Excel® in Microsoft Windows. The illustrations inserted into the MGS were created by pharmacists at the Department of Pharmacy at Kyushu University Hospital. Data regarding the onset and duration of AEs were obtained from package inserts, manufacturer brochures, and the literature (25-27). Subjective AEs with an incidence rate of 10% or more were listed in the MGS. In addition, the onset timing and duration of AEs were color-coded for quick visual recognition of symptoms requiring attention.
Assessment of AEs using the original MGS. Hematologists, nurses, and pharmacists monitored AEs using the original MGS in patients receiving TBI/CY conditioning for HSCT. The severity of AEs was graded according to the Common Terminology Criteria for Adverse Events, version 5.0 (National Cancer Institute, Bethesda, MD, USA). The categories of AEs and their onset and recovery were compared between the data described in the original MGS and those obtained from the actual monitoring of AEs in patients receiving the TBI/CY conditioning regimen.
Modification of the original MGS based on the present monitoring data. According to reports, when the stem cells are engrafted, acute GVHD appears approximately 15 days after transplantation (22 days after conditioning) (14). The symptoms of acute GVHD include anorexia, nausea/vomiting, stomatitis, and diarrhea, which can last for up to 100 days (14). To account for the possible involvement of acute GVHD in the prolongation of such AEs, the original MGS was revised by setting additional monitoring periods (from days 22 to 36 of conditioning) for anorexia, nausea and vomiting, and diarrhea. Subsequently, the accuracy rates of the AEs were compared between the original and revised MGS.
Data analysis. The incidence rates of AEs associated with the TBI/CY conditioning regimen were calculated in patients who had no preexisting AEs at the time of conditioning therapy. The predictive accuracy of the MGS was evaluated by comparing the AEs and their onset and duration between the data described in the original MGS and those obtained from real monitoring. The accuracy rate was expressed as the ratio of the number of the respective AEs that occurred during the same period as described in the MGS to the total number of the respective AEs. After modification of the original MGS, the rates of prediction accuracy for non-hematological AEs were statistically compared between the original and modified MGS using the chi-square test with Yates correction. Data were analyzed using JMP Pro® 16.2 (SAS Institute, Cary, NC, USA), and a p-value <0.05 was considered statistically significant.
Ethics and consent. All study protocols were approved by the Medical Ethics Review Committees of the Kyushu University Graduate School and Faculty of Medicine (approval no. 22151-00) and Doshisha Women’s College of Liberal Arts (approval no. 2022-19).
Results
Baseline clinical characteristics of patients. Fifty-eight patients were included in this study. Table I presents the baseline clinical characteristics of the patients. The median age of the patients was 40 years (range=17-57 years). The majority of the patients (57 of 58) exhibited a good performance status (0-1). The most common disease was acute myeloid leukemia (AML). The period (median day) from the end of the previous chemotherapy was 57.9 days (range=6-92 days).
Patient characteristics.
Notably, most patients (N=56, 96.6%) exhibited nonhematological AEs before treatment with radiation chemotherapy. Moreover, fifty-three patients (91.4%) had preexisting myelosuppression.
Incidence of AEs. As shown in Table II, 361 subjective symptoms of AEs occurred in 58 patients after treatment with TBI/CY for HSCT. The most common AEs were nausea/vomiting, diarrhea, and fever (93.1% each), followed by stomatitis and pharyngeal pain (91.4% each), anal pain (81.0%), and anorexia (77.6%). Hemorrhagic cystitis occurred in only one patient (1.7%) with grade 1 symptoms. Grade 3/4 AEs were observed in 187 of the 361 cases (51.8%), with the highest incidence of stomatitis and pharyngeal pain (63.8% each), followed by anorexia (60.3%), diarrhea (55.2%), fever (41.4%), anal pain (20.7%), and nausea/vomiting (17.2%).
Accuracy of the medication guidance sheet (MGS) for predicting the incidence of various grades of non-hematological adverse events (AEs) in patients who received total body irradiation-cyclophosphamide (TBI/CY) conditioning regimens in allogeneic hematopoietic stem cell transplantation (HSCT).
Evaluation of the original MGS for prediction of AE items and their onsets and durations. Notably, no unpredictable AEs appeared in the present study, and the AEs observed during the monitoring of patients receiving TBI/CY followed by HSCT were predictable from the original MGS. With 242 out of 361 subjective symptoms occurring during the same period as those described in the original MGS, there was a 67.0% accuracy in the prediction rate. However, the prediction accuracy rate for diarrhea and nausea/vomiting was lower (42.6% and 55.6%, respectively), while the rate was extremely low for anorexia (6.7%). This inconsistency was mostly due to the differences in duration of the AEs rather than the onset timing (Table III). The AEs observed in real monitoring appeared to have a longer duration than expected, particularly in cases of anorexia, nausea/vomiting, and diarrhea.
Comparison of onset days, recovery days, and durations of adverse events (AEs) among data obtained from the present AE monitoring in patients receiving total body irradiation-cyclophosphamide conditioning regimens in allogeneic hematopoietic stem cell transplantation and those indicated in the original and revised medication guidance sheet (MGS).
Modification of the original MGS based on the present monitoring data. Gastrointestinal complications associated with acute GVHD, including anorexia, nausea/vomiting, diarrhea, and stomatitis, appeared 15 days after transplantation (22 days after conditioning) and lasted up to 100 days (14). In view of the possible involvement of acute GVHD in gastrointestinal AEs, the follow-up periods for anorexia, diarrhea, and nausea/vomiting were extended in the revised MGS: 1-36 days for anorexia, 3-36 days for diarrhea, and 1-36 days for nausea/vomiting. The modified MGS is shown in Figure 1.
Modified version of medication guidance sheet (MGS) for total body irradiation-cyclophosphamide (TBI/CY) conditioning regimens for allogeneic hematopoietic stem cell transplantation (HSCT). The original MGS was revised from the aspect of the onset timing and duration of adverse events (AEs) after implementation of actual monitoring of AEs in patients receiving TBI/CY followed by HSCT. The upper part represents drug names, including supportive care medicines, immunosuppressants and chemotherapeutic agents, and treatment schedule, while the lower part presents the predicted AEs and their onset timing and duration. A brief explanation for each AE is also described. The check box was newly added to identify pre-existing AEs associated with previous therapy.
Comparison of the rate of prediction accuracy in the onset and duration of AEs between the original and revised MGS. To determine whether the modified MGS effectively predicted AEs, the prediction accuracy rates were compared between the original and modified MGS. As shown in Figure 2, the rates of accuracy in predicting anorexia, nausea/vomiting, and diarrhea significantly improved from 6.7% to 100% (p<0.001) for anorexia, 42.6% to 94.4% for diarrhea (p<0.001), and 55.6% to 100% (p<0.001) for nausea and vomiting. Consequently, the accuracy rate for the prediction of total AEs significantly (p<0.001) increased from 67.0% (242 of 361 events in the original MGS) to 91.4% (330 of 361 events in the revised version). In addition, grade 3/4 AEs were similarly highly predictable in the modified MGS (57.2% in the original version versus 90.4% in the revised version, p<0.001).
Comparison of the rates of prediction accuracy of adverse events (AEs) that occurred in patients receiving total body irradiation-cyclophosphamide (TBI/CY) conditioning followed by allogeneic hematopoietic stem cell transplantation (HSCT) between the original medication guidance sheet (MGS) and the revised MGS. The prediction accuracy represents the rate of coincidence of the onset and duration of any AE appeared during the monitoring period with those shown in the MGS. *p<0.01, **p<0.001 by chi-square test with Yates’s correction.
Discussion
In the present study, a large number of patients (96.6%) had pre-existing but mild (grades 1/2) non-hematologic AEs such as anorexia (17.2%), diarrhea (6.9%), stomatitis (5.1%), elevated serum creatinine (29.3%), alanine aminotransferase (29.3%), and aspartate aminotransferase (20.6%) levels before the start of TBI/CY therapy. Myelosuppression was observed in most (91.4%) patients before radiation chemotherapy. This was because the patients had a history of chemotherapy or radiotherapy before HSCT, including remission-induction chemotherapy, maintenance therapy, and consolidation therapy. Therefore, care must be taken when monitoring AEs before chemotherapy initiation in patients receiving TBI/CY conditioning therapy.
In the present monitoring of AEs using the original MGS, a total of 361 subjective symptoms were observed, of which the most common AEs (incidence rate >90%) were nausea/vomiting, diarrhea, fever, stomatitis, and pharyngeal pain, whereas hemorrhagic cystitis; a representative side effect of CY, occurred only in one patient (1.7%) with grade 1 symptoms. In the present study, all the patients underwent mesna hydration with forced diuresis (28). Almalag et al. (29) observed a retrospective chart review of 718 patients and found that the mesna-treated group showed hemorrhagic cystitis less frequently than the untreated group (0.4% versus 3.5%, p<0.004). Taken together, these results suggest that in the present study, hemorrhagic cystitis might have been effectively prevented by mesna hydration.
Notably, the AEs observed in the present study were predicted using the original MGS. Among the 361 events of AEs, 242 occurred during the period predicted by the MGS, indicating a prediction accuracy rate of 67.0%. These values were comparable to those previously reported for rituximab/ESHAP (60.6%) (25), idarubicin/cytarabine (68.2%) (30), rituximab/CHOP (70.8%) (26) and high-dose cytarabine regimens (69.1%) (31).
The accuracy rate of prediction was high (>85%) for pharyngeal pain, stomatitis, and anal pain. In contrast, the rate was the lowest (6.7%) for anorexia, and the recovery day for this condition occurred significantly later during the actual monitoring (day 36) than it had been predicted by the original MGS (day 15). Additionally, recovery from diarrhea was also slightly longer in the actual monitoring than in the MGS (day 32.5 against day 31). The original MGS was prepared by predicting the onset and duration of AEs limited to the TBI/CY conditioning. Therefore, the delay in recovery from anorexia and diarrhea is likely attributable to other factors that influence the incidence and duration of AEs.
In HSCT, the remaining malignant cells are diminished by the engrafted stem cells via the GVL effect. However, the major complication of HSCT is GVHD, in which several organ systems of the recipient, including the gastrointestinal tract, liver, and skin, are injured by donor-derived cells (32). A mismatch in human leukocyte antigens (HLA) between the donor and host cells is the main cause of acute GVHD. Acute GVHD occurs within 100 days following transplantation, whereas chronic GVHD occurs thereafter.
In a study of 740 patients who had acute GVHD after allogeneic transplantation, Martin et al. (33) reported that 396 patients (54%) exhibited gastrointestinal complications. Diarrhea, vomiting, and anorexia are representative acute GVHD symptoms (32). Morphological observations indicated luminal dilatation with thickening of the small-bowel wall.
Taken together, these results suggest that acute GVHD contributes to the prolongation of anorexia, nausea, vomiting, and diarrhea in patients receiving TBI/CY followed by HSCT. Therefore, the original MGS was revised to account for the incidence of acute gastrointestinal GVHD and included additional monitoring periods for anorexia, nausea/vomiting, and diarrhea. Consequently, the prediction accuracy rates were significantly elevated for anorexia (6.7% to 100%), diarrhea (42.6% to 94.4%), and nausea/vomiting (55.6% to 100%). The overall prediction accuracy increased significantly from 67.0% to 91.4%.
A major concern for patients undergoing HSCT is long-term toxicity, which leads to late morbidity and mortality (34). Moreover, patients’ subjective symptoms negatively affected their quality of life, resulting in a general fear of chemotherapy (35). Thus, the management of subjective AE symptoms is of pivotal importance in cancer therapy.
In this regard, the present revised MGS is useful for the accurate monitoring of AEs in patients receiving a TBI/CY conditioning regimen followed by HSCT. In addition, the revised MGS is presented in the form of a clinical path, making it visually comprehensible not only to cancer patients and healthcare professionals, but also to pharmacy students (18, 24). Therefore, regardless of the duration of practical experience, the revised MGS is expected to enable the identification of AEs in a reliable and timely manner.
Study limitations. This study included a small number of patients from a single institution, and the data were analyzed retrospectively. Moreover, the present study lacks information on the hematological data and the diagnosis of acute GVHD. A larger multicenter prospective study is required to confirm the accuracy of the revised MGS.
Conclusion
AEs were monitored using the original MGS in patients receiving the TBI/CY conditioning regimen followed by HSCT. Although the AEs observed during monitoring were all predicted from the MGS, large differences existed in the duration of gastrointestinal AEs such as anorexia, nausea/vomiting, and diarrhea between the real monitoring and the original MGS. Subsequently, the MGS was revised in consideration of an involvement of acute gastrointestinal GVHD. As a result, the prediction accuracy of the revised MGS was greatly improved to the degree of precision that enables exact monitoring of AEs in the clinical practice.
Acknowledgements
The Authors are grateful to Professor Ryozo Oishi, Professor Emeritus at Kyushu University (Fukuoka, Japan); Professor Yoshinori Itoh, Professor Emeritus at Gifu University (Gifu, Japan); and Dr. Hiroaki Ikesue at the Department of Pharmacy, Kobe City Medical Center General Hospital (Kobe, Japan).
Footnotes
Authors’ Contributions
Mayako Uchida: Conceptualization, methodology, data collection, formal analysis, and writing - original draft preparation. Shigeru Ishida, Erika Mochizuki, Nana Ozawa, Hiroko Yonemitsu, Hideki Ochiai and Hanae Nakamura: Data collection. Takehiro Kawashiri, Koji Kato, Nobuaki Egashira: Writing - review and editing. Koichi Akashi, Ichiro Ieiri: Writing - review and editing, supervision.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
Funding
This research was supported by a research grant of Doshisha Women’s College of Liberal Arts.
- Received May 30, 2023.
- Revision received June 23, 2023.
- Accepted June 28, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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