Abstract
Background: In 2023, collaboration between cardiologists and oncologists was recommended as part of Japan’s Basic Plan to Promote Disease Control Programs for both cancer and cardiovascular diseases. This study explores the extent of this collaboration in Niigata Prefecture.
Methods and Results: Self-administered questionnaires about immune checkpoint inhibitor-associated myocarditis (ICIAM) and anthracycline-related cardiomyopathy (ARCM) were distributed to all cardiologists and leading oncologists in hospitals across the Prefecture, of whom 124 cardiologists and 41 oncologists across 29 hospitals responded. Clinical experience with ICIAM was reported by 31.8% of cardiologists and 24.4% of leading oncologists, significantly lower than experience with ARCM (80.0% of cardiologists, P<0.001, and 58.5% of leading oncologists, P=0.009, respectively). Senior cardiologists reported less experience with ICIAM compared with their young counterparts (18.6% vs. 38.5%, P=0.018). Of the 20 hospitals providing immunotherapy, 12 (60%) reported “no consultation” between the cardiology and oncology departments, and only 5 hospitals (25%) had matching answers for consultation after ICIAM onset between these departments. Conversely, only 4 hospitals (20%) answered “no consultation”, and 12 hospitals (60%) had matching answers, for interdepartmental consultation before or after ARCM onset.
Conclusions: Compared with ARCM, cardiologists and oncologists had less experience, fewer organized measures in place, and increased interdepartmental collaboration vulnerability with ICIAM. Collaboration between cardiologists and oncologists should be promoted in hospitals.
After their launch 10 years ago, immune checkpoint inhibitors (ICIs) have become the fourth pillar of cancer treatment, alongside surgery, radiation, and drug therapy (chemotherapy). ICIs are applicable to the most advanced and recurrent cancers, and the number of patients in Japan using nivolumab is estimated to reach 190,000 by 2024.1 In terms of drug sales in Japan, pembrolizumab and nivolumab are the top two.2
However, ICIs can cause various immune-related adverse events,3 among which ICI-associated myocarditis (ICIAM) occurs in 1–3% of patients treated with ICIs and can be fatal if appropriate treatments such as ICI discontinuation or steroids are not instituted.4,5 Without knowledge of or experience with ICIAM, there is a strong possibility that it will be overlooked or treatment delayed, leading to death from this side effect.6 Therefore, collaboration between oncologists and cardiologists is essential for patients undergoing immunotherapy. The Fourth Basic Plan for Promoting Cancer Control Measures, published in March 2023, encourages collaboration between cancer and cardiovascular care.7
However, the status of this collaboration at the beginning of the fourth phase of the plan in 2023 remains unclear. To date, no survey has been conducted on cardiologists’ knowledge of ICIAM or their treatment experience. Cardiologists may not have been aware of the disadvantages patients face due to the lack of knowledge and collaboration with oncologists. Therefore, we conducted a questionnaire survey among cardiologists and leading oncologists in in community hospitals in Niigata Prefecture to confirm the knowledge and treatment experience of cardiologists regarding ICIAM.
Methods
Participants
Questionnaires were sent to 131 cardiologists and 42 leading oncologists working in community hospitals in Niigata Prefecture in May 2023.
Questionnaires
The key questions and their answer options are detailed below.
Q1. Are you familiar with immune checkpoint inhibitor-associated myocarditis (ICIAM)?
□ I know very little or nothing at all about it.
□ I know the name. (I would not consider it as a differential diagnosis.)
□ I understand the basics. (I could consider it as a differential diagnosis, but I am not confident in diagnosing it.)
□ I know it well. (I can diagnose it.)
Q2. Does your hospital provide treatments involving immune checkpoint inhibitors (ICIs)?
□ Yes.
□ No.
Q3. Have you personally managed or contributed to the care of a patient with ICIAM (including suspected cases), either as the primary physician or as part of a collaborative team?
□ Yes.
□ No.
Q4. At your hospital, is cardiac troponin routinely measured both before and after the administration of ICIs?
□ Yes, there is a protocol in the hospital, and it is carried out systematically.
□ That decision is up to oncologists, and I am unsure if it will be conducted.
□ No.
Q5. (For cardiologists) Have oncologists at your hospital consulted you regarding the screening, diagnosis, or management of ICIAM?
□ No oncologist has ever consulted with or explained anything to me (no consultation).
□ Some oncologists consulted with or informed me before starting immunotherapy (pre-event consultation).
□ Some oncologists consulted with me after a suspected case of ICIAM (post-event consultation).
Q5. (For leading oncologists) Have you consulted with a cardiologist regarding the screening, diagnosis, or management of ICIAM?
□ No (no consultation).
□ Yes, I consulted or informed cardiologists before starting immunotherapy (pre-event consultation).
□ Yes, I consulted with cardiologists after a case suspected of ICIAM arose (post-event consultation).
For comparison, we asked similar questions about anthracycline-related cardiomyopathy (ARCM). Anthracyclines have remained key agents in chemotherapy for over 50 years, and we anticipated that cardiologists would have sufficient knowledge and experience with ARCM.
To increase the response rate, we made follow-up phone calls and offered a gift certificate worth 500 yen (4 dollars) to those who requested it. The responses were collated by the secretariat of Niigata Cancer Center Hospital at the end of May 2023.
Respondent Consent and Protection of Privacy
The request letter clearly stated that the response results and respondent attribute information would be disclosed but that the respondents’ affiliations and affiliated institutions could not be identified. Survey participation was voluntary. Respondents signed their names on their answer sheets to signify consent. This study was approved by the Ethics Committee of the Niigata Cancer Center (No. 1356).
Statistical Analysis
The proportions of responses were statistically compared between cardiologists and leading oncologists, as well as between cardiologists with over 21 years of experience and those with fewer than 21 years, using the Fisher’s exact test for 2×2 tables and the Fisher-Freeman-Halton exact test for 2×4 tables. The relationship between respondents’ years of clinical experience and the proportion of responses was also examined. To compare the clinical experiences of cardiologists and leading oncologists, an age-adjusted analysis using the Mantel-Haenszel method based on 5-year stratified age groups was conducted. The McNemar test was used to evaluate differences in clinical experience with ICIAM and ARCM. To assess the collaboration between the cardiology and oncology departments at each hospital, the majority response to Q5 from individual doctors was used to estimate departmental responses. Respondents were classified into no consultation, post-event consultation, and pre-event consultation groups. A 3×3 table was created to evaluate the degree of agreement using the kappa statistic.8 All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 27.0 (IBM Corp., Armonk, NY, USA). A two-tailed P value <0.05 was considered statistically significant.
Results
Respondent Characteristics
A total of 124 cardiologists and 41 leading oncologists from 29 hospitals (mean number of beds: 357; range: 52–827) responded to the survey (Figure 1). Response rates were 95% for cardiologists and 98% for leading oncologists. The mean years of experience for cardiologists was 19.8 years (range: 2.0–52.0 years), whereas leading oncologists had a mean of 30.6 years of experience (range: 9.0–45.0 years).
Knowledge of ICIAM
In response to Q1, “Are you familiar with ICIAM?”, the response rates for cardiologists were 21.0% for “very little or nothing at all”, 33.9% for “only know the name”, 36.3% for “know the basics”, and 8.9% for “know it well.” For leading oncologists, the rates were 2.4%, 17.1%, 68.3%, and 12.2%, respectively. The proportion of respondents who knew the basics or knew it well was 45.2% for cardiologists and 80.5% for leading oncologists (P<0.001) (Table).
Table.
Questions and Answers
| (A) Responses from all Hospitals |
Cardiologists (n=124) |
Leading oncologists (n=41) |
| n |
% |
n |
% |
| Q1. Are you familiar with ICIAM? |
| A1. Very little or nothing at all |
26 |
21.0 |
 ‡ |
1 |
2.4 |
|
| Only know the name |
42 |
33.9 |
7 |
17.1 |
| Know the basics |
45 |
36.3 |
28 |
68.3 |
| Know it well |
11 |
8.9 |
5 |
12.2 |
| Know it well or the basics |
56 |
45.2‡ |
|
33 |
80.5 |
|
| Q2. Does your hospital provide treatments involving ICIs? |
| A2. Yes |
97 |
78.2* |
|
39 |
95.1 |
|
| No |
27 |
21.8 |
|
2 |
4.9 |
|
| (B) Responses from Hospitals Providing Cancer Treatment |
Cardiologists (n=110) |
Leading oncologists (n=41) |
| n |
% |
n |
% |
| Q3. Have you ever treated a patient with ICIAM? |
| A3. Yes |
35 |
31.8 |
|
10 |
24.4 |
|
| No |
75 |
68.2 |
|
31 |
75.6 |
|
| Q4. Is cardiac troponin routinely measured both before and after the administration of ICIs? |
| A4. Yes |
6 |
5.5 |
† |
11 |
26.8 |
|
| That decision is up to oncologists |
76 |
69.1 |
19 |
46.3 |
| No |
23 |
20.9 |
9 |
22.0 |
| No response |
5 |
4.5 |
2 |
4.9 |
Q5. (For cardiologists) Have oncologists at your hospital consulted you?
(For leading oncologists) Have you consulted with a cardiologist? |
| A5. No consultation |
65 |
59.1 |
|
19 |
46.3 |
|
| Post-event consultation |
20 |
18.2 |
|
15 |
36.6 |
|
| Pre-event consultation |
12 |
10.9 |
|
4 |
9.8 |
|
| No response |
13 |
11.8 |
|
3 |
7.3 |
|
*P<0.05, †P<0.01, ‡P<0.001. ICIs, immune checkpoint inhibitors; ICIAM, ICI-associated myocarditis.
Implementation Rate of Immunotherapy With ICIs at the Hospital
Regarding Q2, “Does your hospital provide treatments involving ICIs?” the response rate for “yes” was 78.2% for cardiologists and 95.1% for leading oncologists (Table). Of 29 hospitals, 20 provided immunotherapy with ICIs and chemotherapy with anthracyclines. In these 20 hospitals, 110 cardiologists and 41 leading oncologists reported the following clinical experience.
Clinical Experience With ICIAM In response to Q3, “Have you ever treated a patient with ICIAM?”, the response rate for “yes” was 31.8% for cardiologists and 24.4% for leading oncologists (Table), which was significantly lower than the clinical experience reported for ARCM (80.0% for cardiologists and 58.5% for leading oncologists (P<0.001, P=0.009, respectively). Figure 2 shows the proportion of years of practice in 5-year age groups and clinical experience with ICIAM of the 110 cardiologists surveyed. The proportion of cardiologists with experience in ICIAM increased over time among cardiologists with fewer than 21 years of clinical experience. However, there was a tendency for cardiologists with 21 years or more of clinical experience to have less experience with ICIAM than those with fewer than 21 years of clinical experience (22.4% vs. 39.3%, P=0.067). In particular, the proportion was significantly lower for senior cardiologists than that of their younger counterparts among the 124 cardiologists across hospitals, including those who did not administer immunotherapy (18.6% vs. 38.5%, P=0.018) (Supplementary Figure). Both cardiologists and leading oncologists with more than 21 years of clinical experience had less experience with ICIAM than with ARCM (Figure 3).
Cardiac Troponin Measurement In response to Q4, “Is cardiac troponin routinely measured both before and after the administration of ICIs?”, the response rates for “yes”, “That decision is up to oncologists” and “no” were 5.5%, 69.1%, and 20.9% for cardiologists, respectively, and 26.8%, 46.3%, and 22.0% for leading oncologists, respectively (Table).
Collaboration Between Cardiologists and Oncologists
In response to Q5 (for cardiologists), “Have oncologists at your hospital consulted you?”, the response rates for “no consultation”, “post-event consultation” and “pre-event consultation” were 59.1%, 18.2%, and 10.9%, respectively. In response to Q5 (for leading oncologists), “Have you consulted with a cardiologist?”, the response rates for “no consultation”, “post-event consultation” and “pre-event consultation” were 46.3%, 36.6%, and 9.8%, respectively (Table). The majority of participants in both groups reported having “no consultation”. The response rates to similar questions about ARCM were 30.9%, 58.2%, and 3.6%, respectively, for cardiologists, and 14.6%, 58.5%, and 22.0%, respectively, for leading oncologists. Thus, most respondents in both groups indicated “post-event consultation” for ARCM.
The collaboration between departments of cardiology and oncology across 20 hospitals was categorized into “no consultation”, “post-event consultation” and “pre-event consultation”, as presented in a 3×3 table (Figure 4). Regarding ICIAM, 12 hospitals (60%) affirmed “no consultations” between departments. In 5 hospitals (25%), both departments agreed on “post-event consultation”, but there was no agreement on “pre-event consultation”. These results show differences in collaboration compared with ARCM. For ARCM, only 4 hospitals (20%) reported “no consultation”, whereas 11 hospitals (55%) had consistent responses from both departments for “post-event consultation”. However, only 1 hospital had “pre-event consultations”. There was no statistical agreement between the cardiology and oncology departments for ICIAM (k=0.174, P=0.310) or ARCM (k=0.059, P=0.675).
Discussion
The survey was conducted in May 2023, 2 months after the Cabinet’s decision on the Fourth Basic Plan for Promoting Cancer Control, which advocated for the promotion of onco-cardiology.7 In addition, the Japanese National Plan for Promotion of Measures Against Cerebrovascular and Cardiovascular Disease: Phase 2,9 and onco-cardiology guidelines10 were published at the same time. The aim of this survey was to assess the actual status of specialist and departmental collaboration at the launch of the basic plan to establish a reference point for future evaluations, and identify gaps for improvement in community hospitals. The results from the survey revealed 3 key findings: (1) cardiologists have less knowledge and experience with ICIAM than with ARCM; (2) both cardiologists and leading oncologists have limited clinical experience with ICIAM and (3) collaboration regarding ICIAM has not been established between the departments of cardiology and oncology.
Knowledge and Clinical Experience of ICIAM
Only 45% of cardiologists and 81% of leading oncologists reported knowing an outline or details of ICIAM. Although leading oncologists appeared knowledgeable, less than 25% of respondents had clinical experience with ICIAM, which was significantly lower than their clinical experience with ARCM. This difference may reflect ICIAM as a relatively new disease, providing fewer treatment opportunities than for ARCM, which has over 50 years of accumulated clinical research.11 Moreover, the indications for ICIs remain limited to advanced or recurrent cancers, often with short patient survival times, thereby reducing clinical experience. Moreover, although cardiac troponin testing is essential for the early detection of ICIAM, it may be challenging for community hospitals to perform it systematically due to insurance coverage limitations.
Clinical Experience of ICIAM by Senior Cardiologists and Leading Oncologists
Considering that ICIs are used in various medical departments and that ICIAM is a potentially fatal side effect, effecting robust safety measures in each hospital is pertinent. If ICIAM develops fulminant, pre-event consultation between hospitals and preparations for potential patient transfers to emergency medical centers will be necessary. Oncologists and cardiologists in leadership positions should take charge of these initiatives, but their limited experience with ICIAM treatment poses a challenge. In particular, the lack of ICIAM experience among senior cardiologists may hinder the establishment of hospital-wide measures and impede the fostering of interhospital cooperation necessary to address the emerging risk.
Collaboration Between Cardiologists and Leading Oncologists in Hospitals
In 20 hospitals, 60% of the cardiology or oncology departments reported “no consultation” on ICIAM cases. Current guidelines recommend the creation of a collaborative system for the early detection of ICIAM.10,12 At the time the guidelines were published, interdepartmental collaboration appeared insufficient, highlighting the need for improvements in accordance with the guidelines. Regarding ARCM, 12 hospitals (60%) reported consistent collaboration between cardiology and oncology departments; however, this collaboration occurred primarily after the onset of heart failure. Furthermore, owing to the poor prognosis after the onset of heart failure in ICIAM, more proactive collaboration is required in comparison with ARCM. Therefore, there should be an increase in opportunities to learn about early detection methods and treatments for ICIAM.
Gaps in ICIAM Practice
This survey identified 5 key gaps in cancer therapy, particularly focusing on ICIAM and ARCM as they relate to the management of cancer therapy-related cardiovascular toxicity (CTR-CVT).
(1) Experience Gap: there is a disparity in clinical experience with ICIAM vs. ARCM regarding CTR-CVT among cardiologists and oncologists.
(2) Knowledge Gap: cardiologists and oncologists showed differing levels of knowledge regarding CTR-CVT.
(3) Generational Gap: there is a significant experience gap between junior and senior cardiologists regarding ICIAM.
(4) Interdepartmental Gap: there is insufficient collaboration between cardiologists and oncologists regarding ICIAM management in hospitals.
(5) Interhospital Gap: there are variations in measures for ICIAM and ARCM management across different hospitals.
As Oka et al. stated, these gaps indicate the lack of standardization in onco-cardiologic care.13 The indications for ICIs have rapidly expanded from treatment of advanced cancer to prevention of recurrence in early-stage cancers, leaving limited time to establish collaborative measures, as highlighted for ARCM. Additionally, there have been increasing reports of ARCM and CTR-CVT incidence in Japan,14,15 whereas the epidemiology of ICIAM remains unclear. Bridging these gaps is crucial for improving the safety of cancer patients undergoing immunotherapy and for better understanding the effect of ICIAM in Japan. The 2022 ESC Guidelines on cardio-oncology emphasize the importance of communication among healthcare professionals to optimize care for patients with both cancer and cardiovascular disease.12 Improved communication between cardiologists and oncologists can activate multidisciplinary teams and bridge institutional gaps. Furthermore, regional academic societies can facilitate cooperation among hospitals in their regions, and universities and cancer centers are expected to play a central role in these efforts.
Study Limitations
This study was based on the subjective views of respondents and thus may not necessarily represent the actual state of medical care. Additionally, as this study was conducted exclusively in the Niigata Prefecture, the results cannot be extrapolated to other communities with differing medical environments. However, the high number of responses and response rates, along with all responses being signed by physicians, lend reliability to the survey. Therefore, there are valuable insights into the current state of onco-cardiology in this community.
Conclusions
Cardiologists and leading oncologists, especially senior cardiologists, have limited experience in treating ICIAM. Additionally, the collaborative system between cardiology and oncology departments is underdeveloped. Improving communication between these departments is crucial to providing the required care for patients with ICIAM and bridging the gap in onco-cardiology.
Acknowledgments
We thank the cardiologists and oncologists at Gosen Chuo Hospital, Joetsu General Hospital, Kaetsu Hospital, Kashiwazaki General Hospital and Medical Center, Kido Hospital, Kuwana Hospital, Murakami General Hospital, Nagaoka Chuo General Hospital, Nagaoka Red Cross Hospital, Nakajo Chuo Hospital, Niigata Bandai Hospital, Niigata Cancer Center Hospital, Niigata City General Hospital, Niigata Nogeka Hospital, Niigata Medical Center, Niigata Minami Hospital, Niigata Prefectural Central Hospital, Niigata Shirone General Hospital, Niigata University Medical & Dental Hospital, Ojiya General Hospital, Sado General Hospital, Saiseikai Niigata hospital, Saiseikai Niigata Kenoh Kikan Hospital, Shibata Hospital, Shinrakuen Hospital, Tachikawa General Hospital, Uonuma City Koide Hospital, and Uonuma Kikan Hospital. We thank doctors Akihito Momoi, Eiko Sakata, Hisashi Saigawa, Keiichi Tsuchida, Kyoko Shoin, Masato Makino, Masato Moriyama, Qiliang Zhou, Tsunehiro Fujita, Tsuyoshi Yoshida, Yuichi Nakamura, and Yuka Kobayashi in the Onco-Cardiology Association in Niigata (OCAN 2020).
Funding
This study was funded by a Regional Medical Research Grant (GC03720223) from the Medical Association of Niigata City, Japan. The funders of the study had no role in the design and conduct of the study, the collection, management, analysis, and interpretation of the data, the preparation, review, or approval of the manuscript or the decision to submit the manuscript for publication. This was an investigator-initiated study conducted by the Onco-Cardiology Association in Niigata (OCAN 2020), independent of the funding source.
Disclosures
H.T. received lecture fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, and Ono Pharmaceutical. H.T. received research funding from Amgen, AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Janssen Pharmaceutical, MSD, and Ono Pharmaceutical. S.M. received lecture fees from AstraZeneca, Boehringer-Ingelheim Japan, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical. T.I. received lecture fees from AstraZeneca and Ono Pharmaceutical. T.I. is a member of Circulation Reports’ Editorial Team. T.T. received lecture fees from Bristol-Myers Squibb, MSD, and Ono Pharmaceutical. A.K., K.O., N.T., T.K., Y.S. and Y.O. have no conflicts of interest.
IRB Information
This survey was approved by the Ethics Committee of Niigata Cancer Center (No. 1356).
Data Availability
The deidentified participant data will not be shared.
Supplementary Files
Please find supplementary file(s);
https://doi.org/10.1253/circrep.CR-24-0171
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