Correspondence

Global Health & Medicine. 2024; 6(4):268-272.
DOI: 10.35772/ghm.2023.01134

A retrospective single institutional analysis of outpatientchemotherapy in patients with cancer during the COVID-19 pandemic
Yumiko Shimanuki1, Akihiko Shimomura2,*, Chiaki Ogawa3, Masato Komuro1, Hiroyuki Terakado1,
Takahiro Nishimura1, Chikako Shimizu2
1

Department of Pharmacy, National Center for Global Health and Medicine, Tokyo, Japan;
Department of Breast and Medical Oncology, National Center for Global Health and Medicine, Tokyo, Japan;
3
Department of Pharmacy, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
2

Abstract: Providing treatment to patients with cancer, even during the coronavirus disease (COVID-19) pandemic,
is essential. In collaboration with infectious disease specialists, we established guidelines for the management ofpatients with cancer receiving ambulatory treatment during the pandemic on April 8, 2020. This study examined
the practice and management of ambulatory chemotherapy under emergency conditions. Following the guidelines,
our Breast and Medical oncology department developed a chemotherapy strategy for the phases. Additionally,
to distinguish fever during chemotherapy, we developed a flow chart for fever. As part of a fact-finding survey,
the status of outpatient chemotherapy was investigated: (1) whether there was any change in the number ofchemotherapies before and after the declaration of a state of emergency by the Tokyo Metropolitan Government and(2) the frequency and severity of febrile neutropenia (FN) cases. Compared to before the first declaration of the stateof emergency, the number of chemotherapies decreased except after the declaration, but no decrease was observed
during the rest of the period; no difference was observed in the frequency or severity of FN outbreaks or in the useof pegfilgrastim for primary prevention before and after the epidemic. With appropriate treatment guidelines, routine
chemotherapy can be performed in an outpatient setting during an outbreak.
Keywords: COVID-19, coronavirus, cancer, chemotherapy, breast cancer, outpatient

Introduction
It is important to provide medical care without stopping
cancer screening and treatment during an unknown
infectious disease pandemic, such as COVID-19.
However, there were no treatment guidelines at the
beginning of the pandemic, which caused confusion
among healthcare providers. Many information andstates (1-3) from not only Japan but also other countries
were submitted. Regardless of the source of information,
the basic policy was the same: patients who should avoid
treatment interruptions should continue chemotherapy
during the COVID-19 pandemic, while patients withstable disease who could continue treatment without
face-to-face consultations to reduce the frequency ofvisits to the hospital.
We established guidelines for the management ofpatients with cancer receiving ambulatory treatment
during the pandemic in April 2020. This study
examined the practice and management of ambulatory
chemotherapy under emergency conditions.

Activities in our department since the COVID-19
pandemic
Development of treatment guidelines
At the beginning of the COVID-19 pandemic, ouroutpatient treatment center was divided into threephases according to the number of patients requiring
oxygen administration and the number of patientson ventilators. Treatment strategies were establishedfor each phase (Supplemental Table S1, https://www.
globalhealthmedicine.com/site/supplementaldata.
html?ID=88). In Phase 1, the usual medical care wascontinued; in Phase 2, the usual medical care was
reduced to 60%–80%; in Phase 3, the usual medicalcare was discontinued, and the Ambulatory Treatment
Center (ATC) was closed. In addition, the department
established guidelines for chemotherapy (Supplemental
Table S2, https://www.globalhealthmedicine.com/
site/supplementaldata.html?ID=88) according tothese phases. During preoperative and postoperative(268)

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chemotherapy, patients with metastatic breast cancer
continued to receive treatment according to the schedule.
In contrast, patients with relatively stable diseases visitedthe hospital less frequently to prevent infection.

supplementaldata.html?ID=88).

Creation of a flow chart for responding to febrile illness

Evaluation of outpatient chemotherapy performance

Depending on the causative microorganism, FN is ahighly lethal adverse event in cancer chemotherapy(4). Therefore, identifying fever during treatment isimportant. Our department prepared a "Fever Handling
Flow" (Figure 1) for outpatient chemotherapy classified
according to the FN risk of the regimen. Patients
receiving high-risk FN regimens (Supplemental
Table S3, https://www.globalhealthmedicine.com/site/
supplementaldata.html?ID=88) were prescribed an
antibiotic (LVFX: levofloxacin) at initial administration
to manage their FN at home.

We e v a l u a t e d t h e n u m b e r o f c h e m o t h e r a p i e sadministered at the ATC of the Department of Breastand Medical Oncology at the National Center for Global
Health and Medicine, Tokyo, Japan. We evaluated for
30 days before and after the first (April 7, 2020), second(January 8, 2021), third (April 25, 2021), and fourth(July 12, 2021) declarations of emergency in Tokyo.
The first period (Period 1; P1) is from March 8, 2020,
to May 6, 2020. The second period (Period 2; P2) isfrom December 9, 2020, to February 6, 2021. The third
period (Period 3; P3) is from March 26, 2021, to May 24,
2021, and the fourth period (Period 4; P4) is from June
12, 2021, to August 10, 2021. We evaluated the typeof cancer, stage of disease, number of chemotherapies,
regimens, and changes in treatment strategy (changes in
regimen and discontinuation) related to the pandemic,presence of fever, and COVID-19. The exclusion
criteria were as follows: i) patients who did not receive
chemotherapy within 60 days before the emergency
declaration, ii) Patients who participated in a clinical
trial. All information was retrieved from electronic
medical records.

Creation of COVID-19 vaccination procedures inpatients with cancer
Patients with cancer are at a high risk of severe disease
when they contract COVID-19 (5), and patients withcancer under treatment were identified as priority
candidates for COVID-19 vaccination (6). Various
guidelines (2,7-9) reported that COVID-19 vaccination
should be considered prospectively, so to differentiate
between vaccine- and treatment-induced fever, ourdepartment developed a procedure for COVID-19
vaccination in patients with cancer (Supplemental
Table S4, https://www.globalhealthmedicine.com/site/

Research on outpatient chemotherapy during the
COVID-19 pandemic

Research regarding whether the frequency of FN
occurrence changed before and after the COVID-19

37.5℃ or higher

Patients prescribedlevofloxacin

Patients not prescribedlevofloxacin

Started taking
levofloxacin

Fever does not resolve
48 h after taking
levofloxacin

Contact Hospital

Figure 1. Flow chart for handling fevers established by our department.
Figure 1(269)

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pandemic in patients on high-risk FN regimens

cyclophosphamide was comparable to that reported in aprevious study (9%) (10).

The differentiation of fever during treatment is important.
The target period was February 1, 2019, to January 31,2020 (Period 5; P5) before the pandemic and February
1, 2020, to January 31, 2021 (Period 6; P6) after the
pandemic. In patients with breast cancer on preoperativeand postoperative chemotherapy who received a highrisk FN regimen (Supplemental Table S3, https://www.
globalhealthmedicine.com/site/supplementaldata.
html?ID=88), we retrospectively investigated whether
there were changes in the number of FN cases, response
to FN (use of prophylactic antimicrobial or pegfilgrastim[Peg-G-CSF] primary prevention for FN), frequency andseverity of FN, and number of patients with COVID-19.
These studies were performed in line with theprinciples of the Declaration of Helsinki. Approval was
granted by the Institutional Review Board of the National
Center for Global Health and Medicine, Tokyo (Date:
March 20, 2020; No. NCGM-G-003481-01).
Evaluation of outpatient chemotherapy performance
The number of eligible patients was 131, 133, 150, and
157 in P1 to P4, respectively (Table 1). The number ofchemotherapy sessions was 303, 319, 376, and 409 in
P1 to P4, respectively, decreasing after the declaration(112 times) compared with before the declaration of
emergency status (191 times) in P1. The number ofpatients for whom treatment was (or could have been)changed was 27, two, three, and eight in P1 to P4,
respectively. Fever was observed in eight, nine, six, and20 patients (including 10 with adverse reactions to the
COVID-19 vaccine) from P1 to P4. None, one, one, andtwo patients with COVID-19 infection in P1 to P4 andone patient in P3 had moderate or severe COVID-19
symptoms and received hormone therapy.
After the COVID-19 pandemic, the frequency of FN
changed in patients on high-risk FN regimens
A total of 93 patients (64 in period 5 and 29 in period 6)
were included in the study. The total number of regimens
administered was 317 (P5: 226, P6: 91), the numberof FN cases (including suspected FN) was 32 (10%,P5: 26 [12%], P6: six [6.6%]), and the number of FN
cases requiring hospitalization was four (1.3%, P5: four
[1.3%], P6: none [0%]). The number of chemotherapy
regimens using Peg-G-CSF for primary prevention waseight (2.5%, P5: eight [2.5%], P6: none [0%]), and there
was no significant difference between the periods. The
number of FN (or suspected FN) cases was one patient
whose regimen was pertuzumab plus trastuzumab plus
docetaxel in P5 and one patient who received docetaxel
plus cyclophosphamide in P6. All other patients'
regimens were doxorubicin plus cyclophosphamide. The
number of patients with FN treated with doxorubicin andDiscussion
According to the declarations, the number ofchemotherapy sessions was affected in P1 but not in P2
to P4. This is consistent with the results of a previous
study (11) and may be due to the pandemic, whichcaused a shortage of personal protective equipment(PPE) which are essential for healthcare providers whenadministering chemotherapy. In P2, with the first reason
for this being P1, the number may have decreased owing
to the lack of treatment guidelines, both institutional andprofessional. The fact that the number of chemotherapy
treatments recovered after the treatment guidelines
were established suggests that familiarity with the basic
policy and the establishment of treatment guidelines
at individual facilities may help healthcare providers
provide medical care to patients without confusion
during a pandemic. Second, PPE, such as masks andgowns, were in short supply, and the environment for
medical care needed to be more conducive in P1. Third,
after the first declaration, people were more cautious
about the unknown virus, and patients might haverestricted themselves from going out for hospital visits.
Of the patients who had COVID-19 during the study,
only one had moderate or severe symptoms and wasundergoing hormonal therapy for breast cancer. Thispatient did not meet any of these criteria that is reported
in previous studies (12). It is also important to proceedwith cancer treatment without unnecessary fear because
COVID-19 does not necessarily cause severe diseaseeven if the patient is immunosuppressed while receiving
cytotoxic anticancer drugs.
This study found no differences in the frequency
or severity of FN occurrence, preventive use of
antimicrobials, or Peg-G-CSF in high-risk FN regimens
by period. The frequency of FN with doxorubicinplus cyclophosphamide was similar to that reported
previously. This suggests that FN treatment can becontinued during the COVID-19 pandemic without
special measures. Peg-G-CSF acts on neutrophil
progenitor cells to promote neutrophil differentiation.
Because lymphocyte counts have been reported todecrease during COVID-19 infection (13), Peg-GCSF is unlikely to be useful for active use other thanin identifying fever, even in light of its mechanism ofaction.
Our study had two limitations. First, because it
was conducted at a single institution or department, it
was limited to the target population and needed moregenerality. Second, the proportion of patients with
COVID-19 among eligible patients during the study
period was small. The number of positive COVID-19
cases in the country increased after the sixth wave
(January 1, 2022). However, this period was outside the(270)Global Health & Medicine. 2024; 6(4):268-272.

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Table 1. Chemotherapy-related outpatient treatment implementation status(A)
Characteristics
Age, median [interquartile range], years
Type of Cancer
Breast cancer
Gynecologic cancer
OthersStages of disease
NAC or adjuvant
Palliative
Number of chemotherapeutic regimens
NAC or Adjuvant
Palliative
Number of chemotherapeutic times
Percentage of chemotherapeutic times※
Before the declaration
NAC or Adjuvant
Palliative
After the declaration
NAC or Adjuvant
PalliativeP1 (n = 131)

P2 (n = 133)

P3 (n = 150)

P4 (n = 157)

58 [28–88]

57 [29–89]

55 [29–89]

56 [29–89]

122 (93%)
7 (5.3%)2 (1.5%)129 (97%)
4 (3.0%)0 (0%)

145 (97%)
5 (3.0%)0 (0%)

152 (97%)
5 (3.0%)0 (0%)

43 (33%)88 (67%)137
48 (35%)89 (65%)303
62%
191 times (39%)
72 (15%)119 (24%)112 times (23%)
50 (10%)62 (13%)35 (26%)
98 (74%)140
39 (28%)101 (72%)319
58%
157 times (28%)
49 (9%)108 (20%)162 times (29%)
60 (11%)102 (18%)48 (32%)102 (68%)164
57 (35%)107 (65%)376
61%
194 times (32%)
69 (11%)125 (20%)
182 times (30%)
64 (10%)118 (19%)56 (36%)101 (64%)167
59 (35%)108 (65%)409
61%
192 times (28%)
83 (12%)109 (16%)217 times (32%)
94 (14%)123 (18%)(B)
Characteristics

P1 (n = 131)

P2 ( n = 133)

Number of patients who changed (or may havechanged) treatment※

27 (21%)2 (1.5%)

Change of regimens
Extention of interval
Skip of therapy
Postponement of treatment initiation
Prescription by telephone
OthersNumber of patients with fever
Number of patients with COVID-19

NAC or Adjuvant
Palliative
9 (6.9%)18 (14%)0 (0%)
3 (2.3%)2 (1.5%)4 (3.1%)1 (0.76%)
4 (3.1%)3 (2.3%)6 (4.6%)3 (2.3%)2 (1.5%)3 (2.3%)1 (0.76%)
8 (6.1%)0 (0%)

NAC or Adjuvant
Palliative
0 (0%)
2 (1.5%)0 (0%)
0 (0%)
0 (0%)
2 (1.5%)0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
9 (6.8%)1 (0.75%)(C)
Characteristics
Number of patients who changed (or may havechanged) treatment※
Change of regimens
Extension of interval
Skip of therapy
Postponement of treatment initiation
Prescription by telephone
OthersNumber of patients with fever
Number of patients with COVID-19

P3 (n = 150)

P4 ( n = 157)

3 (2.0%)8 (5.1%)

NAC or Adjuvant
Palliative
0 (0%)
3 (2.0%)0 (0%)
0 (0%)
0 (0%)
2 (1.3%)0 (0%)
1 (0.67%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
6 (4.0%)1 (0.67%)

NAC or Adjuvant
Palliative
1 (0.64%)
7 (4.5%)0 (0%)
0 (0%)
0 (0%)
1 (0.64%)0 (0%)
6 (3.8%)0 (0%)
0 (0%)
0 (0%)
0 (0%)
1 (0.64%)0 (0%)
20 (13%)
1 (1.3%)In the case of oral medications, we counted the number of prescriptions as the number of chemotherapies. The percentage of chemotherapeutic times
was calculated based on the total number of patients and the number of chemotherapeutic times. ※The total does not add up because of overlapping
element. Abbreviation: NAC, Neoadjuvant chemotherapy. COVID-19, Coronavirus disease 2019.

study's coverage period.
The COVID-19 pandemic has allowed healthcare
providers to consider the actions that should be takenin the event of a pandemic. With limited information
available, hospital guidelines were developed, and theirimplementation did not result in any serious problems.

When a similar situation arises in the future, developing
guidelines and triages within the information available atthe time can help healthcare providers and patients makeappropriate decisions. As the pandemic progresses, it isimportant to continue providing cancer treatment whileconsidering the risks and benefits for individual patients.

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Acknowledgements

7.

We thank Masayo Kawamura, Department of Breastand Medical Oncology, National Center for Global
Health and Medicine, for her assistance with theseprocedures.
8.

Funding: None.
Conflict of Interest: The authors have no conflicts ofinterest to disclose.

9.

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---Received December 20, 2023; Revised July 9, 2024; Accepted
July 29, 2024.
Released online in J-STAGE as advance publication August 3,
2024.
*Address correspondence to:
Akihiko Shimomura, Department of Breast and Medical
Oncology, National Center for Global Health and Medicine,
1-21- 1 14 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
E-mail: akshimomura@hosp.ncgm.go.jp(272)