A 91-year-old male presented to the cardiology clinic for 1 week of fatigue, chest tightness and shortness of breath. His self-measured oxygen saturation was around 90% and pulse rate was around 50 bpm using a finger pulse oximetric device. The patient denied chest pain, hemoptysis, productive cough, abdominal bloating, edema or oliguria. He had no swelling or palpable cords in the legs. Heart auscultation found no abnormal heart rhythm or pathological murmurs except for reduced heart rate. He had a history of hypertension for more than 10 years with the highest systolic blood pressure over 160mmHg and took candesartan 8mg in the morning and 4mg at night, which had his blood pressure well controlled around 120-130/60-80mmHg. Besides, he was diagnosed with lung adenocarcinoma (stage T3N3M1, MET Y1003S mutation) 2 months ago (2020-11-18) and accepted targeted therapy alone because of intolerance of surgery and chemotherapy. He had taken crizotinib orally 250mg twice a day for more than 1 month till then and non-specific discomfort emerged since the therapy initiation.
Key laboratory test results were demonstrated as follows: CK-MB 7 ng/mL↑ (reference range, 0.3 to 4), troponin I 0.01ng/mL (reference range, ＜0.20), D-dimer 3.09mg/L↑ (reference range,＜0.55), NT-proBNP 53.0pg/mL (reference range, 5 to 263). Electrocardiogram (ECG) on presentation showed sinus bradycardia (HR 57bpm) and first degree atrioventricular block (PR interval 280ms). Out of caution, the patient was admitted into our department for further evaluation. Vital signs were measured as follows: T 36.3℃, HR 51 bpm, R 18 breaths/min, BP 138/65 mmHg. No dynamic change was found after repeat myocardial enzyme and D-dimer tests (CK-MB 5.8↑ng/mL, troponin I 0.01ng /mL, D-dimer 2.58↑mg/L). The ECG showed persistent bradycardia (HR 51bpm) and first degree atrioventricular block (PR interval 288ms) (figure 1A). The arterial blood gas analysis indicated hypoxemia with partial pressure of oxygen at 8.67↓kPa, partial pressure of carbon dioxide at 6.07↑kPa, oxygen saturation at 91.4↓% when breathing ambient air. Other routine laboratory test results were normal. Accordingly, supportive therapies including oxygen inhalation, ECG telemetry monitoring, and 24-hour urine volume recording were initiated in the first place and diagnostic examinations were performed to clarify the patient's etiology.
Given the history, clinical manifestations and current examinations of the patient, a comprehensive evaluation for circulatory and respiratory disorders was conducted to identify the causes of his bradycardia and hypoxemia.
A computed tomography (CT) scan of the chest was notable for a rounded mass in the right upper lobe with the largest cross-section at 26*11 mm and multiple enlarged lymph nodes in the mediastinum and both hilum (figure 2B), which regressed remarkably in comparison with previous CT images acquired at diagnosis. And no sign of pneumonia, atelectasis or emphysema was observed. Thus, common etiology of hypoxemia such as pneumonia, neoplasm progression or chronic obstructive pulmonary disease was ruled out.
A transthoracic echocardiography showed normal systolic function with left ventricular ejection fraction of 64%.There were no ventricular hypertrophy or dialation other than an enlarged left atrial with diameter of 41 mm.The diastolic function was evaluated by the Doppler echocardiography and tissue Doppler imaging (TDI), which revealed that the ratio of peak Doppler velocities of early (E) to late diastolic flow (A) was 0.5, the ratio of mitral velocity to early diastolic velocity of the mitral annulus E/E’ on the side of the ventricular septum and left ventricular lateral wall were 15.2 and 7.8, respectively, both indicating diastolic dysfunction.
The ECG telemetry displayed persistent bradycardia, so an ambulatory ECG monitoring was ordered to rule out severe arrhythmia. The result confirmed the diagnosis of bradycardia with an average heart rate at 54bpm, ranging from 41bpm to 78bpm (total heart beats 68040 in 21 hours) and persistent first degree atrioventricular block (average PR interval 292ms). The arrhythmia was recently formed based on an ECG obtained 2 months earlier when he was hospitalized in the respiratory department for lung cancer (figure 1B).
In absense of chest pain, myocardial enzyme elevation and ST variation in ECG, there was no indication for urgent coronary angiography. Howerver, the patient had high risks for coronary heart disease. His fasting blood glucose and glycosylated hemoglobin was 6.17↑mmol/L and 6.9↑% respectively. Besides, arterial plaques in carotid and femoral arteries were detected by vascular ultrasound regardless of normal lipidemia. Accordingly, a coronary computed tomography angiography was performed, which showed mild multivessel stenosis and a local myocardial bridge in the middle-to-distal segement of the left anterior descending branch. The patient was then diagnosed with chronic coronary syndrome for atherosclerosis and myocardial bridge.
Elevation of D-dimer arouse concern about pulmonary embolism. The hypoxemia and history of malignancy were both highly suggestive of pulmonary embolism. Albeit lacking evidence of venous thrombosis in lower extremity ,the patient was confirmed of thrombus in the lower lobe of the left lung by the computed tomography pulmonary angiography (CTPA) . Furthermore, the simplified Pulmonary Embolism Severity Index (sPESI) was 2 points in the patient, which evaluates blood pressure, heart rate, oxygen saturation, age, and a history of cancer,lung disease or heart disease. A score of sPESI＞0 is associated with notable elevation of in-hospital or 30-day mortality as ESC guidlines illustrated(4).
Taken together, the patient was now notable for partial remission of the lung adenocarcinoma, chronic coronary syndrome, new onset bradycardia and subsegmental pulmonary embolism. Given the close association between crizotinib application and aforementioned manifestations on the timeline, the potential impact of crizotinib,a widely used tyrosine kinase inhibitor (TKI) targeting ALK, ROS1 and MET/ HGFR, raised our concern. In light of this, a multidisciplinary team including respirologists, oncologists, radiologists and cardiologists was brought together.
Targeted therapy was a more appropriate option for an elderly advanced lung cancer patient than surgery, chemotherapy or radiotherapy from an oncologist perspective. Although, common driver mutation genes such as EGFR, ALK, ROS1 and MET Exon14 was failed to be detected via the conventional PCR method and the next generation gene sequencing technology, a very rare MET Y1003S mutation was eventually identified by the high-throughput sequencing. The patient was thus endowed with a treatment opportunity and opted targeted therapy of crizotinib.
As radiologists point of view, CT scan of tumor at baseline and after less than 2 months of crizotinib treatment demonstrated rapid reduction in tumor volume, meeting RECIST partial response criteria (-30%), which indicated remarkable anticancer efficacy of crizotinib (figure 2A, B).
From respirologists interpretations, it’s difficult to determenate whether the PE was a new onset due to absence of a previous CTPA image for the patient. While no complain of chest tightness or breath shortness at the first place may suggest for a new onset. Once thrombosis in the pulmonary artery is identified, risk stratification is necessary to determine the appropriate treatment strategy. The patient was classified into the intermediate risk category of PE with a positive sPESI score and stable hemodynamics. So anticoagulation alone with no need for mechanical intervention was recommended.
From the perspective of cardiologists, the patient posessed multiple risk factors, including age, hypertension, diabetes and chronic coronary artery syndrome, which increased his susceptibility to antitumor-related CV complications and undesired CV complications hampered his targeted therapy course, leaving him at the crossroads of oncology and cardiology. Optimization of CV risk factors is imperative during whole course of cancer treatment to achieve best possible outcomes.
The paradox is that the most beneficial oncological therapy for the adenoma caused grave cardiological complications. A consensus was reached in a multidisciplinary approach. First of all, anticoagulation is an important strategy in patients with submassive subsegmental pulmonary embolism. Thus, subcutaneous, weight-adjusted low molecular weight heparin once a day in hospital under the monitoring of coagulation indices and conversion to the oral anticoagulant agent rivaroxaban at discharge was recommended. Secondly, given the non-severity of his CV complications and symptom alleviation after oxygen inhalation, there was no indication for drug withdrawal then. A preservation of standard dose of 250 mg each time twice a day was recommended. Taking a step back, the dose could be reduced to 250 mg once a day or 250 mg twice every other day till the maximum tolerable dose, if the negative dromotropic and thrombogenesis effect persisted. Thirdly, it was imperative to stick on cardiovascular protective medications and have regular cardiovascular examinations. Statins and candesartan were prescribed for the patient to modify risk factors. What’s more, other selective MET inhibitor such as capmatinib or savolitinib could be a cardiac-safe alternatives, though no evidence for their antitumor efficacy in NSCLC patients with MET Y1003S mutation.
The patient was regularly followed up in the outpatient clinic after discharge. No significant change was observed in terms of tumor progress between the chest CT image in March 2021 and January 2021, with the largest cross-section of the mass in right upper lobe at 26*11 mm (figure 2B,2C). Considering his high CVD risks and stable progress of tumor, the dosage of crizotinib was halved to 250 mg twice every other day to optimize the balance between oncological benefit and CV hazards. The sustained remission of tumor was confirmed by another chest CT image two months after the dose reduction (figure 2D). And the patient had an amelioration of subjective symptoms, characterized by a relief of chest tightness and an elevation of pulse rates around 65 bpm. Therefore, it came to the conclusion that the dose adjustment alleviated adverse CV reactions and maintained the antitumor efficacy simultaneously. It was the joint efforts of oncologists and cardiologists that brought optimal clinical outcome for the patient, setting the way forward for the cardio-oncology towards multidisciplinary consultation and individualized medicine.