Early Cardio-Oncology Intervention in Thoracic Radiotherapy: Results of the Cardiac Aggressive Risk Mitigation (CARMA) Pilot Study

doi:10.21203/rs.3.rs-3970946/v1

Background

While there is increasing recognition of the morbidity of cardiovascular disease (CVD) in cancer survivors, including accelerated atherosclerosis following thoracic radiotherapy (RT), patients are frequently under-optimized for CV risk.

Methods

In this prospective single-arm pilot study, patients were treated with high-dose thoracic RT and had early consultation with cardio-oncology. The primary endpoint was adherence to cardio-oncology consultation. Secondary endpoints were cardio-oncology CV medication intervention rate and patient-reported intervention perspectives.

Results

Twenty patients were enrolled. The median age was 71 years. Most were female (13/20), had primary lung/mediastinal carcinoma (12/20), and 7/20 had pre-existing atherosclerotic CVD. Cardio-oncology consultation was completed in 19/20 patients and resulted in CV medication optimization changes in 12/19, most commonly to initiate/increase statin therapy. 8/12 patients with a primary cardiologist prior to enrollment had medication changes recommended. Most (12/17) were glad to learn about their heart health during cancer treatment.

Conclusions

To our best knowledge, this is the first study reporting adherence and outcomes of early cardio-oncology intervention and patient reported perspectives. We observed in this high CV risk cohort that early cardio-oncology consultation was feasible, led to CV medication optimization in majority (> 60%) of participants, was viewed positively by patients, and worthy of further study.

Health sciences/Oncology/Cancer/Cancer therapy/Radiotherapy

Health sciences/Cardiology

There is increasing recognition of the morbidity of cardiovascular disease (CVD) in cancer survivors, including CV toxicity from cancer therapies—such as chemotherapy, molecular targeted agents, radiotherapy (RT), and immunotherapy¹. However, patients with cancer are frequently under-optimized for cardiovascular (CV) risk², including less than half of high CV risk patients on statin therapy^3,4. Coronary artery radiation exposure can accelerate the natural history of atherosclerosis⁵ and has been associated with an increased risk of major cardiac events in patients with lung^6–9, esophageal^10,11, and breast^12,13 cancers. While RT associated CV toxicity was historically presumed to have a prolonged latency to clinical manifestation, recent evidence observes a more compressed timeframe following high dose thoracic RT, with 2 year cardiac event rates up to 10–20% and related to baseline CV risk and coronary radiation dose exposure^6,10,11,14. Further, statin therapy has been shown to be protective for stroke risk in patients receiving head and neck or thoracic RT¹⁵ and has been associated with improved survival in a dose-dependent manner following lung cancer chemoradiotherapy^3,16. While consensus cardio-oncology guidelines are now available, they do not incorporate detailed cardiac radiation dose exposure limits in risk assessment or surveillance recommendations, nor reflect the need for more aggressive CV risk mitigation in this patient population^17–19.

Multiple biomarkers are available in clinical practice that help refine baseline CV risk prediction compared to traditional clinical CV risk factors. Coronary artery calcium (CAC) is a marker of atherosclerotic burden and can aid decision-making regarding initiation or intensification of statin therapy in patients at borderline or intermediate atherosclerotic CVD (ASCVD) risk¹. Given that existing primary prevention models do not include cancer treatment(s) or cancer as CV risk factors, they likely underrepresent CV risk in patients with cancer, underscoring the usefulness of CAC and/or other CV risk markers in this setting. Additionally, clonal hematopoiesis of indeterminate potential (CHIP; the clonal expansion of hematopoietic stem cells with somatic mutations²⁰), has recently been identified as a major risk factor ASCVD, doubling the risk of coronary heart disease independent of traditional CV risk factors^21–23. Indeed, CHIP is enriched in patients with solid malignancies, and RT is among the strongest risk factors^22,24, however there is a paucity of data including CHIP as a CV risk factor in cancer studies.

Collectively, the above knowledge gaps underscore the need to better identify high CV risk patients with cancer who may benefit from early intervention with more aggressive CV risk mitigation strategies. To address these critical gaps in CV risk assessment, we launched a prospective single-arm pilot study measuring the feasibility and impact of early cardio-oncology intervention in patients treated with thoracic RT.

The Cardiac Aggressive Risk Mitigation (CARMA) in thoracic RT trial (NCT05403736) was a prospective single-arm pilot study. Eligible patients were adults with Stage I-III or oligometastatic Stage IV cancer, good performance status (Eastern Cooperative Oncology Group [ECOG] 0–1), treated with high-dose thoracic RT (prescription dose ≥ 30 Gy) with the heart in/near the RT field. Participants were referred to cardio-oncology for early consultation (defined as occurring prior to or during RT), including assessment of all potentially cardiotoxic therapies (e.g., RT, chemotherapy, immunotherapy, molecular targeted agents), to develop a personalized CV risk mitigation plan. Patients with a pre-existing primary cardiologist received a one-time cardio-oncology consultation with direct peer-to-peer communication of trial enrollment, including notice of planned cardio-oncology consultation and subsequent recommendations. This study was approved by the Cedars-Sinai Medical Center (CSMC) Institutional Review Board and all participants signed informed consent.

Radiotherapy was typically delivered at CSMC, although two patients had RT delivered at outside institutions, for which their RT simulation CT scans and RT plans were transferred to CSMC for subsequent analyses. CAC score was manually measured on RT planning CT scans (non-ECG gated, slice thickness 1.25–2.5 mm) using syngo.via (Siemens Healthineers, Malvern, PA) and expressed as a sum score (Agatston method)²⁵. Clonal hematopoiesis (CH) was analyzed using the 75-gene multiplex Archer VariantPlex Myeloid panel with additional variant filtering (Z-AM-Pipeline v1.0). The variant allele fraction was expressed as a percentage (%). 10-year ASCVD risk calculation was performed according the Pooled Cohort Equation (PCE)²⁶.

The primary endpoint was adherence to cardio-oncology consultation. If the number of adherent patients was greater or equal to 18 patients, the intervention was declared as feasible. Secondary endpoints included the rate of CV medication intervention by cardio-oncology and patient-reported intervention perspectives by survey. Data was summarized using descriptive statistics.

Twenty patients were enrolled. The median age was 71 years (interquartile range [IQR], 63-77). Most were female (13/20), white (17/20), or Latin(x) (4/20). Hyperlipidemia (10/20), hypertension (9/20), tobacco use (9/20=former, 1/20=current), and pre-existing ASCVD (7/20) were common (Table 1). Among the 13 patients without ASCVD, the mean ASCVD risk score was 14.8% (±12.7%) and six had CAC >0 (1-99 [n=2]; 100-399 [n=3]; ≥400 [n=1]) on pre-radiotherapy CT scans. Additionally, of the 5 patients with low 10-year ASCVD risk score (<7.5%), the presence of other risk factors such as CAC, LDL, presence of CHIP mutation, and/or mean LAD dose ≥ 5Gy identified two (2/5) patients who may benefit from initiating or intensifying statin therapy (Table 2). Cancers were primary lung/mediastinal (12/20), esophageal (4/20), breast (2/20), or secondary lung metastases (2/20). Several (7/20) received induction systemic therapy (molecularly targeted agent [4/7]; docetaxel, carboplatin, trastuzumab, pertuzumab [2/7]). Most (12/20) received concurrent chemoradiotherapy (carboplatin or cisplatin with pemetrexed [7/12]; carboplatin/paclitaxel [4/12]), while 5/20 received adjuvant immunotherapy. The mean whole heart and LAD radiation dose was 7.0 Gy (± 4.8 Gy) and 3.8 Gy (±3.9 Gy), respectively.

Cardio-oncology consultation was completed before or during RT in 19/20 patients, and the intervention was therefore deemed feasible. Cardio-oncology consultation resulted in CV medication optimization changes in the majority of patients (12/19). The most common recommendations were statin-related (either to start statin [2/8] or increase statin intensity [6/8]). Other changes were to start/stop/change dosage of anti-hypertensives (4/12), start baby aspirin (1/12) or start sacubitril/valsartan (1/12). Of the 12 patients with a primary cardiologist prior to enrollment, 8/12 had medication changes recommended (start [n=1] or increase [n=4] statin, start aspirin [n=1], or anti-hypertensive change [n=4]). At a median follow up of 14 weeks (IQR 11-15), one patient (with prior ASCVD) experienced a non-fatal major cardiac event (non-ST elevation myocardial infarction and acute decompensated heart failure during chemoradiotherapy).

Clonal hematopoiesis of indeterminate potential (CHIP) was detectable prior to RT in 8/20 patients. By post-RT follow-up, 9/20 had detectable CHIP, including 2/19 with pre-existing DNMT3A (deoxyribonucleic acid methyltransferase 3A) clones who developed additional variants (PPM1D [protein phosphatase Mn²⁺/Mg²⁺-dependent 1D], TP53 [tumor protein 53], NF1 [neurofibromatosis type 1]), and 1/19 with no pre-existing CHIP developed a TET2 (Tet methylcytosine dioxygenase 2) variant.

By study conclusion, among 17 responding participants, most agreed or strongly agreed that they learned new information about their heart health (12/17) and were glad to know this information (12/17). Most participants also reported that this information did not make them feel more anxious (13/17), nor was it overwhelming to focus on their heart health during cancer treatment (14/17).

To our best knowledge, this is the first study reporting adherence and outcomes of early cardio-oncology intervention and patient reported perspectives of cardio-oncology intervention. We observed in this high CV risk cohort that early cardio-oncology consultation was feasible, led to CV medication optimization in majority (> 60%) of participants—including two-thirds of those with a primary cardiologist, and was viewed positively by patients. The most common intervention was initiating/intensifying statin therapy, for which this recommendation in several participants was based on CAC and/or consideration of potentially cardiotoxic RT/chemotherapy/systemic therapy treatment(s), underscoring the importance of cardio-oncology assessment of the totality of CV risks. Even among low ASCVD risk patients, 40% (2/5) harbored CAC with LDL > 130 mg/dL (including one of two patients with detectable CHIP) for which statins were started/increased (Table 2), highlighting the need for comprehensive CV risk assessment.

Furthermore, our study demonstrated how readily available CV risk markers, such as the presence of CAC on RT planning CTs and/or LAD radiation dose exposure, can capture additional at-risk patients for CV events. Baseline CAC on RT planning CT scans has been associated with increased risk of major cardiac events in patients with breast^27,28 and lung cancer^9,29–31, yet CAC assessment prior to initiation of cancer treatment is not routinely performed. Similarly, evidence suggests that cardiac substructure radiation dose exposure, particularly to the left coronary arteries, is a better predictor of MACE compared to whole heart dose (i.e., mean heart dose) and warrants inclusion into the global CV risk assessment of patients receiving cardiotoxic cancer therapies^6,10–13 We further characterized the prevalence of CHIP at baseline and after completion of RT. CHIP is novel CV risk factor that may help identify patients who may benefit from intensified CV risk mitigation approaches. Indeed, we observed a high baseline prevalence of CHIP (8/20, 40%) as well as the development of new variants in 3/20 patients following completion of RT. This is consistent with the observation that radiation exposure is one of the strongest risk factors for CHIP, preferentially selecting for mutations in DNA response genes³². Specific CHIP variants, including RT-induced clones, may better predict for CV risk, metabolic perturbations, and/or response to anti-inflammatory CVD therapies, highlighting the need for further investigation of the utility of CHIP monitoring in patients with cancer, particularly those treated with RT^33–35.

Statins are the cornerstone for ASCVD risk mitigation due to their pleiotropic lipid-lowering, anti-inflammatory, and anti-fibrotic properties. A recent study suggested that not only being on a statin, but statin dose intensity was independently associated with improved survival following definitive chemoradiotherapy for NSCLC¹⁶. A similar study in patients with locally advanced NSCLC observed that high heart radiation dose was associated with mortality in statin naïve patients, but not in patients on statin therapy, suggesting a potential cardioprotective effect in these high risk patients³. Notably, there was no difference in cardiac event rates in the above studies, which may be explained in part by the observation that patients with lung cancer are typically under optimized for CV risk and that patients on statin therapy in retrospective cohorts often represent the highest CV risk strata. This is consistent with the current findings that even among patients on statin therapy and/or with a baseline cardiologist, initiation and/or intensification of statin therapy was frequently warranted. Further, ASCVD risk estimation based solely on traditional risk models, such as the PCE, may under capture at risk populations that would benefit from primary prevention statin use. As such, there is a need for improved CV risk estimation models in patients with cancer treated with cardiotoxic cancer therapies (such as thoracic RT), that incorporate the diagnosis of cancer, cardiotoxic cancer treatment(s), and enhanced biomarkers, such as CAC, CHIP, and potentially others. The ongoing CARTIER study (NCT03711110) is a much awaited randomized, open-label clinical trial studying the impact of intensive CV monitoring and treatment vs usual care in patients ≥ 65 years old with colon, breast, or hematologic cancers. Together, these studies and the current study, highlight the existing knowledge gaps in identifying patients with cancer who may benefit most from earlier and/or intensified CV risk intervention strategies.

There are several limitations to this study. The sample size was small and eligibility criteria permissive for many cancer types, though our cohort was largely comprised of patients with lung/mediastinal and esophageal cancers. There was a wide variance of baseline CV risk factors, though overall this was a high CV risk population with 35% having known ASCVD. The inclusion of patients both with and without an established primary cardiologist introduced heterogeneity in potential for intervention, though the observation that these patients were intervened upon at high frequency was notable, and worthy of further study. Lastly, follow up duration was short given pilot nature of the trial, and sample size insufficient to detect changes in clinical CV outcomes, though one serious event was observed during the trial period.

In conclusion, we observed that early cardio-oncology intervention in high CV risk patients treated with thoracic RT is feasible, resulted in CV medication optimization changes in the majority of patients, and was viewed positively by patients. As oncologic outcomes continue to improve, it will become increasingly important to improve CV assessment and mitigation approaches, including integration with novel CV risk markers (e.g., CHIP), additive effects of cardiotoxic therapies, and optimal surveillance schedules.

Funding: Dr. Atkins reports funding from the Garber Award for Cancer Research.

Disclosures: KA reports honoraria from OncLive. MK reports receiving personal fees from Theragenics, Alessa, GTMedical, and Springer, outside the submitted work. EV reports consulting with Bayer, Eli Lilly, AstraZeneca, Janssen, Pfizer, Sanofi, Thermo Fisher, Illumina, Caris, Tempus, PierianDx; employment by LungLifeAI. RM reports consulting with AstraZeneca, ViewRay, Novartis, Sio Capital Mgmt, Varian Medical Systems; advisory board with ViewRay, AstraZeneca; grant funding from AstraZeneca, ViewRay. The remaining authors have nothing to disclose.

Corresponding author: Dr. Katelyn Atkins; Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048; tel: 310-423-9248, fax: 310-659-3332, email: [email protected]

Tweet: Good CARMA! Early prospective Cardio-Oncology intervention in thoracic RT results in CV med changes in >60% (commonly: start statin or intensity), identifies CV risk pts for intensified surveillance, and importantly – was positively viewed by patients. #CardioOnc @_katelynatkins @Dr_RayMak @SamZhangMD

Acknowledgements: None

Author contributions:

KMA, APN, and RHM conceptualized the research idea. KMA and APN were responsible for over-seeing the project, clinical trial, data collection, data analysis. FP, JOG assisted with clinical trial management and data collection. SCZ, JOG, CE, KDS, FP, WZ were responsible for data collection and analysis. KMA, APM, RHM, SCZ devised the data analysis plan and developed the initial manuscript. EV, CE, MK, BH, AM assisted with management and coordination of the project and helped review the manuscript. All authors performed a critical review and approval of the final manuscript for interpretation of the data, intellectual input, and to confirm accuracy.

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Table 1. CARMA Patient Clinical Characteristics.
Characteristic	n (%) or median (IQR)
Age	71 (63-77)
Sex: female, male	13 (65%), 7 (25%)
ECOG: 0, 1	14 (70%), 6 (30%)
Ethnicity: Hispanic/Latin(x), Non-Hispanic/Latin(x)	16 (80%), 4 (20%)
Race: Asian, Black or AA, White	2 (10%), 1 (5%), 17 (85%)
Hypertension	9 (45%)
Hyperlipidemia	10 (50%)
Diabetes mellitus	1 (5%)
Smoking: never, current, former	10 (50%), 1 (5%), 9 (45%)
Smoking: Pack-years	30 (15-39)
CAD, HF, MI, CABG	5 (25%), 1 (5%), 3 (15%), 2 (10%)
Stroke, valvular heart disease, arrhythmia	1 (5%), 2 (10%), 2 (10%)
COPD, CKD	2 (10%), 3 (15%)
PVD, PE, family history early onset CVD	0 (0%)
Any ASCVD	7 (35%)
Systolic / diastolic blood pressure	128 (116-138) / 71 (63-83)
Total cholesterol (mg/dL), LDL-C (mg/dL)	159 (143-109), 86 (59-102)
HgbA1c (%)	5.4 (5.3-5.8)
On statin	13 (65%)
On anti-platelet	5 (25%)
On oral anti-hyperglycemic	2 (10%)
On anti-HTN; #anti-HTN agents: 1, 2, 3	10 (50%); 4 (40%), 3 (30%), 3 (30%)
Cancer type: NSCLC, thymus, esophagus, breast, lung metastasis	11 (55%), 1 (5%), 4 (20%), 2 (10%), 2 (10%)
Cancer Stage: I-II, III, IV	8 (40%),6 (30%),6 (30%)
Surgery Induction systemic therapy (prior to RT) Concurrent chemotherapy (during RT) Adjuvant systemic therapy (after RT)	4 (20%) 7 (35%) 12 (60%) 7 (35%)
RT modality: photon, proton, SBRT	19 (95%), 1 (5%), 3 (15%)
RT: mean whole heart, LAD dose (Gy) (±SD)	7.0 (± 4.8), 3.8 (±3.9)

Data represent n (%), median (interquartile rage [IQR]), or mean (± standard deviation) where indicated. Abbreviations: ECOG (Eastern Oncology Cooperative Group), AA (African American), CAD (coronary artery disease), HF (heart failure), MI (myocardial infarction), CABG (coronary artery bypass graft), COPD (chronic obstructive pulmonary disease), CKD (chronic kidney disease), PVD (peripheral vascular disease), ASCVD (atherosclerotic cardiovascular disease), PE (pulmonary embolus), CVD (cardiovascular disease), LDL (low-density lipoprotein), RT (radiotherapy), SBRT (stereotactic body RT), LAD (left anterior descending) coronary artery.

Table 2. Cumulative cardiovascular risk and cardio-oncology medication intervention recommendations in patients treated with thoracic radiotherapy

Total Cohort (n=20)

Pre-Existing ASCVD (n=7)

No prior ASCVD (n=13)¹

10yr risk >20%

(n=5)

10yr risk ≥ 7.5% to <20% (n=1)

10yr risk <7.5% (n=5)

Statin at baseline

13

7

4

1

LDL<70 mg/dL

LDL 70-130 mg/dL

LDL>130 mg/dL

5

10

3

4

NA

1

3

1

NA

3

2

CAC 0

CAC 1-99

CAC 100-399

CAC >400

8

3

6

1

NA

5

2

NA

2

1

NA

3

2

0

Clonal Hematopoiesis

At baseline

By end-RT/follow-up

8

9

4

5

2

0

1

Cardiac radiation exposure

Mean heart ≥5 Gy

Mean LAD ≥5 Gy

13

6

3

0

1

0

2

Cardio-oncology impact

Any CV med change

Statin therapy-related

Start statin

Increase statin intensity

12

2

6

NA

2

3

NA

3

NA

2

1

¹n=2 with incomplete data to calculate ASCVD. ²To calculate ASCVD, age 79 was imputed for one patient age 89 years, LDL=70 mg/dL was imputed for one patient with LDL <70 mg/dL. Abbreviations: ASCVD=atherosclerotic cardiovascular disease; yr=year; RT=radiotherapy, LDL=low density lipoprotein, CAC=coronary artery calcification; CV=cardiovascular; NA=not applicable.

Yes there is potential Competing Interest. EV reports consulting with Bayer, Eli Lilly, AstraZeneca, Janssen, Pfizer, Sanofi, Thermo Fisher, Illumina, Caris, Tempus, PierianDx; employment by LungLifeAI, outside the submitted work. MK reported receiving personal fees from Theragenics, Alessa, GTMedical, and Springer, outside the submitted work. RM reports consulting with AstraZeneca, ViewRay, Novartis, Sio Capital Mgmt, Varian Medical Systems; advisory board with ViewRay, AstraZeneca; grant funding from AstraZeneca, ViewRay, outside the submitted work. KA reports honoraria from OncLive, outside the submitted work. The remaining authors have nothing to disclose.

IIT202107AtkinsCARMAProtocolv304JAN2023trackedka.doc
Study protocol

Early Cardio-Oncology Intervention in Thoracic Radiotherapy: Results of the Cardiac Aggressive Risk Mitigation (CARMA) Pilot Study

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