Apatinib successfully administered in malignant tumour patients with severe hypotension: a case series,literature review,and considerations for treatment

Abstract

The most notable side-effect of apatinib, a novel antiangiogenic agent for the treatment of cancer, is hypertension, but there are few published studies regarding the use of apatinib to treat patients with cancer and severe hypotension. Here, the cases of three patients with tumours and severe hypotension are described: case 1, a 73-year-old male patient with lung squamous cell carcinoma who initially received radiotherapy and chemotherapy, and developed pneumonia and severe hypotension after 6 months; case 2, a 56-year-old male patient with nasopharyngeal carcinoma who was treated with chemotherapy and presented with fever and persistent hypotension; and case 3, a 77-year-old male patient with oesophageal cancer who was admitted with deglutition difficulty and severe hypotension. Apatinib was added to the treatment regimen of all three patients for antitumor therapy. Pneumonia, tumour progression, and severe hypotension improved noticeably in all patients within 1 month after receiving apatinib. Apatinib was associated with a positive effect on blood pressure stability, in synergy with other means of therapy, and the patients achieved satisfactory short-term clinical results. The role of apatinib in treating patients with cancer and hypotension merits further investigation.

Keywords

Case series hypotension apatinib chemotherapy radiotherapy vascular endothelial growth factor receptor

Introduction

Hypotension is a common symptom in patients with cancer, with varying causative factors, including dehydration, cancer-related anaemia, and serious adverse effects on the cardiovascular system.¹ Hypotension may also be a symptom of malignant neoplasms.² Paraneoplastic neurological syndromes may affect pathologies of the nervous system, distinct from the neurological sequelae of metastases, and are most frequently associated with solid malignancies, such as lung, breast, and brain cancer. Paraneoplastic neurological syndromes are characterized by subacute features, including impotence and hypotension. Consensus guidelines for the management of these symptoms are lacking.³

Therapeutic strategies against vascular endothelial growth factor (VEGF) and the VEGF receptor (VEGFR) play important roles in carcinogenesis and have been widely studied. Apatinib (YN968D1) is a novel and highly selective VEGFR2 inhibitor that targets the intracellular ATP-binding site of the receptor,^4,5 and has been confirmed in recent clinical trials to have promising therapeutic effects against various tumours.^6–9 Most apatinib-related toxicities are mild (grade 1–2) and well-tolerated; and the most commonly reported treatment-related adverse events are hypertension, proteinuria, and hand-foot syndrome.^10–12 Apatinib is approved by the China National Medical Products Administration for treating gastric cancer and hepatocellular carcinoma, but not lung and nasopharyngeal cancer. However, several previously published studies in China have shown beneficial effects of apatinib in treating patients with advanced lung cancer, oesophageal cancer and nasopharyngeal cancer, following multiline therapy.^13–17

Herein, the cases of three unique patients with cancer and severe hypotension, who were hospitalized between February 2017 and December 2018 at the Oncology Department of People’s Hospital of Nanhai District, Foshan, China, are described. As part of their anti-tumour therapy regimen, the patients were treated with apatinib, which was subsequently found to enhance the therapeutic efficacy by elevating blood pressure. The response was assessed according to the Response Evaluation Criteria in Solid Tumours (RECIST; version 1.1) and the study adhered to CARE guidelines.

Case presentations

In this case series, apatinib was administered to patients at a dose of 500 mg daily, as part of their cancer treatment. The study was conducted in accordance with the Declaration of Helsinki 1975 (as revised in 2000) and was approved by the Research Ethics Committee of People’s Hospital of Nanhai District, Foshan, China (NO.(2018) 1). The study was registered in the Chinese Clinical Trial Registry (ID: ChiCTR-OIC-17013238). Written informed patient consent to treatment and to publish the case data was obtained, and CARE guidelines were followed for publication of the included cases.¹⁸

Case 1

A 73-year-old male patient with no history of chronic illness was diagnosed with lung squamous cell carcinoma with pulmonary metastases (TNM stage: cT3N3M1) in May 2016. The patient was scheduled to receive concurrent chemotherapy and radiotherapy as an inpatient at Sun Yat-Sen University Cancer Centre, Guangzhou, China and was treated with full-dose platinum and paclitaxel doublet chemotherapy comprising two cycles of 135 mg/m² paclitaxel and 75 mg/m² platinum in 250 ml normal saline, administered by intravenous (i.v.) drip every 3 weeks. A 60 Gy dose of external beam radiotherapy was delivered at 2.0 Gy/fraction/day over 40 days on the primary tumour and involved lymph nodes. The patient experienced grade 3 oesophagitis and grade 3 supraclavicular radiodermatitis. After 4 months of therapy, he developed cough, dyspnoea, and anepithymia after catching a cold (Table 1). He experienced cardiorespiratory arrest while travelling to hospital. Family members performed cardiopulmonary resuscitation, and respiration and circulation were completely restored. A series of hospital tests showed pneumonia, metabolic acidosis, tumour progression, and severe hypotension. The infection was promptly treated with antibiotics, initially comprising 1 g piperacillin and sulbactam, i.v., every 8 h for 3 days, then switched to 1 g meropenem, i.v., every 8 h for 7 days due to lack of infection control. His temperature, respiration rate, and oxygen saturation levels returned to normal levels. Other treatment was based on rectifying the acid balance, and vasoactive medicines were administered by continuous i.v. infusion (Table 2) due to a blood pressure following cardiorespiratory arrest of 76/49 mmHg, which was lower than the diagnostic criteria for shock (systolic blood pressure <80 mmHg). However, the patient required continued treatment with varying doses of dopamine or norepinephrine to maintain blood pressure. His heart rate was not substantially elevated at 75–100 beats/min. Apatinib (500 mg, orally, once daily) was then added to the regimen for anti-tumour therapy. Subsequently, there was noticeable improvement in his hypotension (Figure 1); after more than 40 days of vasopressor drug use, 5 of which included concurrent apatinib treatment, the vasopressor drugs could be stopped. Moreover, the patient’s blood pressure eventually increased to 140/90 mmHg with continued apatinib treatment, and antihypertensive drugs (150 mg irbesartan, orally, once daily) were used to maintain his blood pressure within the normal range. Follow-up computed tomography (CT) at 1 month of apatinib administration revealed that the primary lung tumour had not shrunk, but lung metastases were smaller compared with the pre-treatment diagnostic CT scan. The patient obtained stable disease as his best overall tumour response according to RECIST. He eventually succumbed to cerebral haemorrhage 2 months later. No grade 3/4 toxicity was observed during 12 weeks of apatinib treatment (Table 2).

Table 1.

Characteristics of three patients with cancer and hypotension included in the case series.

Patient	Sex	Age, years	Cancer diagnosis	Prior treatment history	Primary symptoms/ associated syndrome	Haemoglobin, g/L
Case 1	Male	73	Lung cancer	Chemotherapy, radiotherapy	Pneumonia, dyspnoea, anepithymia	127
Case 2	Male	56	Nasopharyngeal neoplasms	Chemotherapy	High fever, renal dysfunction, pneumonia	69
Case 3	Male	77	Oesophageal cancer	Chemotherapy, radiotherapy	Vomiting, hyperpyrexia, pneumonia	95

Table 2.

Clinical findings in three patients with cancer and hypotension included in the case series.

Patient	Initial vasopressor dose, mg/h	Vasopressor treatment duration, days	Apatinib dose, mg/day	Apatinib treatment duration, weeks	Apatinib + vasopressor treatment duration, days	Best RECIST response	Grade 3/4 toxicity
Case 1	Dopamine 30/ norepinephrine 0.6	37	500	12	5	Stable disease	None
Case 2	Dopamine 36/ norepinephrine 0.24/ dobutamine 4.8	45	500	1	1	Not evaluated	None
Case 3	Metaraminol 0.8/ dopamine 30	15	500	4	3	Not evaluated	None

RECIST, Response Evaluation Criteria in Solid Tumours.

Figure 1.

Blood pressure course during apatinib treatment in three patients with cancer and hypotension.

Case 2

A 56-year-old male patient with a history of dementia and paralysis after cerebral infarction underwent a CT scan at The Third People’s Hospital of Foshan, Guangdong, China, in September 2018, after presenting with a nose bleed. CT images showed nasopharyngeal neoplasms and metastatic malignant tumours in the cervical lymph nodes and right lung. Pathology results from lymph node biopsy revealed a diagnosis of undifferentiated non-keratinized carcinoma. The patient received chemotherapy at People’s Hospital of Nanhai District, comprising one cycle of 70 mg/m² cisplatin and 2.0 g/m² 5-fluorouracil in 250 ml normal saline by i.v. infusion over 4 days. Adverse reactions included third degree leukopenia-neutropenia (leukopenia <0.5 × 10⁹/L) and high fever. Two weeks after initiation of chemotherapy, the patient developed shock, renal dysfunction, and pneumonia (Table 1), and his blood pressure was found to be 64/51 mmHg. Emergency treatment was administered, comprising 1.5 g cefuroxime, i.v., every 12 h for 5 days, followed by 2.5 g piperacillin and sulbactam, i.v., every 8 h for 7 days due to lack of infection control. Emergency treatment also included transfusion, timely treatment and prevention of anaemia, plus insulin and continuous infusion of dextrose for hyperkalaemia due to renal failure. The patient finally recovered to normal temperature and renal function. More than 45 days of vasopressor drugs, including dopamine, norepinephrine and dobutamine, at varying doses according to blood pressure (Table 2), were administered to raise his blood pressure. Attempts to discontinue these medicines were unsuccessful. At that time, the patient started taking 500 mg apatinib, orally, once daily to promote an increase in blood pressure, and the two types of medications (vasopressors and apatinib) overlapped for only 1 day. His blood pressure remained stable and within normal range during 1 week of apatinib treatment after stopping administration of vasoactive agents (Figure 1). However, 34 days later, the patient died from a recurrent pulmonary infection with multiple organ failure after the recovery attempt failed.

Case 3

A 77-year-old male patient who had never smoked presented with abdominal pain in August 2015 and was found to have oesophageal squamous cell carcinoma (stage T4N1M0). During 2015, the patient received four cycles of chemotherapy, comprising 70 mg/m² cisplatin and 135 mg/m² paclitaxel in 250 ml normal saline by i.v. infusion over 3 days; at one point, he refused continued treatment. In February 2017, the patient developed deglutition difficulty and a CT scan indicated tumour progression. He underwent a gastroscopic biopsy and pathology confirmed small cell carcinoma. He was treated at People's Hospital of Nanhai District with one cycle of 200 mg/m² cisplatin and 100 mg/m² etoposide in 250 ml normal saline by i.v. infusion over 3 days, and a 40 Gy dose of external beam radiotherapy that was delivered at 2.0 Gy/fraction/day over 28 days on the primary tumour. He had vomiting and hyperpyrexia, accompanied with pneumonia and severe hypotension (Table 1), with blood pressure of 68/41 mmHg at that time. The patient received i.v. fluids and continuous i.v. infusion of vasopressor drugs to maintain blood pressure (Table 2). Antibiotics (1.0 g meropenem, i.v. every 8 h for 4 days) were used to control infection, however, his blood pressure did not increase significantly. The patient responded quickly to treatment with 500 mg apatinib, orally, once daily (Figure 1). Over the course of nearly 1 week of apatinib treatment, the patient was able to eat a solid diet, indicating relative improvement, and a few days later, he was discharged. The patient received a follow-up assessment after 1 month of apatinib treatment but was then lost to further follow-up.

Discussion

Severe hypotension may occur more widely in patients with late- rather than early-stage cancer, but is underreported and, therefore, not well-recognized. This report describes three patients with malignant tumours who developed severe hypotension. The primary blood pressure of the three patients was 76/49 mmHg, 64/51 mmHg and 68/41 mmHg, respectively, which was below the diagnostic standard for shock (systolic blood pressure <80 mmHg). Thus, these patients were administered vasoactive drugs at varying doses according to blood pressure fluctuation. Vasoactive treatment was difficult to stop in these patients because blood pressure dropped once dosage was reduced. Therefore, treatment with apatinib was selected for these patients to promote the stabilisation of blood pressure. The true hypotension values could not be measured in the patients directly before apatinib administration because of continuous vasoactive medication. In addition, the underlying illness, comorbidities, and other medications may have contributed to the observed hypotension.¹⁹ Therefore, the pathogenesis of patients' hypotension may have been attributed to multiple factors. As described above, the patient in case 1 developed pneumonia and metabolic acidosis, the patient in case 2 developed renal dysfunction and pneumonia, while vomiting, hyperpyrexia and pneumonia were observed in case 3, all of which may cause hypotension. Paraneoplastic neurological syndromes also cause hypotension, however, paraneoplastic neurological syndromes are rarely reported in patients with oesophageal squamous cell carcinoma. We hypothesized that case 3 may have involved a tissue type transition from oesophageal squamous cell carcinoma to oesophageal small cell carcinoma, and that paraneoplastic neurological syndromes might have occurred. There are a few reports of paraneoplastic neurological syndromes in patients with nasopharyngeal carcinoma, combined with paraneoplastic opsoclonus-myoclonus syndrome, paraneoplastic neurological disorder, paraneoplastic dermatomyositis, paraneoplastic leukemoid reaction, and other paraneoplastic diseases.^20–23

Paraneoplastic neurological syndromes are neuropathies with complex mechanisms. The pathogenesis of paraneoplastic neurological syndromes remains unclear,²⁴ and appears to depend on neural and voluntary actions, encompassing broad symptomatology, including sensorimotor neuropathy, autonomic dysfunction, and vasculitic neuropathy.²⁵ The aetiology of paraneoplastic neurological syndromes varies but is not related to therapeutic side effects, metastases, infections, coagulopathy, or metabolic disturbances.²⁶ There is a broad differential diagnosis of episodic hypotension, including abnormal activation of autonomic reflexes, intermittent vascular obstruction, and abnormal release of vasoactive substances.²⁴ However, all three patients in the present case series displayed progressive, persistent dysfunction, as opposed to intermittent episodes of hypotension. Moreover, the present patients were not taking any medications associated with hypotension, nor were they taking antihypertensives.

It is known that most cancer chemotherapy agents may also cause hypotension during therapy.²⁷ However, in the present three patients, hypotension did not occur during chemotherapy, but occurred at 5 months (Case 1), more than 10 days (Case 2), and 3 days (Case 3), respectively, after chemotherapy had finished. The delay between hypotension and the last chemotherapy treatment made these drugs unlikely causes of the hypotension; patients with malignant tumours can be classified as having ‘definite’ paraneoplastic neurological syndromes when they exhibit a non-classic neurologic syndrome, and resolution of that syndrome with cessation of chemotherapy.²⁸ All three patients in the present case series were treated successfully; the hypotension was resolved by effective fluid infusion, anti-infectious therapy, vasopressor agents, and treatment with apatinib.

There are three possible explanations for the patients’ clinical context: autonomic dysfunction caused by a paraneoplastic neurological syndrome, volume depletion, and infection. Serious infections may worsen haemodynamic changes and heart function. Furthermore, when paraneoplastic hypotension is accompanied by infection and other symptoms that suggest inflammation or organic impairment, treatment options, such as anti-infection therapy, immunomodulation, fluid resuscitation, and positive vasoactive drugs may prevent further damage. However, the persistent hypotension in the present cases cannot be explained by volume depletion or infection because it did not resolve after strict measures for infection control and the maintenance of adequate blood volume. Therefore, the most likely cause of hypotension was a paraneoplastic effect.

The initial management of patients with septic shock should include fluid resuscitation and antimicrobial therapy, and vasopressor support is often required to maintain perfusion pressure.²⁹ As vasodilation is a central feature of septic shock, excessive production of nitric oxide, changes in receptor signalling, and absolute or relative deficiencies of vasoactive hormones, including vasopressin, cortisol, and angiotensin II, play important roles in its pathophysiology.³⁰ Selection of vasopressors based on clinical variables reflecting hypoperfusion could be better individualized.³¹ Increasing the body's fluid and electrolyte intake is the main treatment for low blood pressure. To assist the patient's blood pressure rise, doctors may also prescribe vasopressors. When taking apatinib to elevate blood pressure, the vasopressor may be gradually decreased until discontinuance if the blood pressure is stable at normal values.

Apatinib is a novel and highly selective tyrosine kinase inhibitor of VEGFR2 and is available in mainland China.³² Apatinib restrains angiogenesis and subsequently controls tumorigenesis in various solid tumours by inhibiting several signal transduction pathways, thus, it can be applied to a variety of solid tumours,³³ and may improve progression-free and median overall survival of patients without severe adverse reactions. The disease control rates with apatinib have been reported as 74.2% and 61.9% as salvage treatment for patients with advanced non-small-cell lung cancer and oesophageal squamous cell carcinoma, respectively.^34,35 In another study,⁶ the incidence of hypertension after treatment with apatinib was found to be 35.2%. The appearance of side-effects, such as hypertension, hand-foot syndrome, and proteinuria may be feasible biomarkers for treatment effectiveness.³⁶ Endothelin-1, nitric oxide, oxidative stress, the renin-angiotensin-aldosterone system, and rarefaction may be important mediators of the side-effects and hypertension associated with VEGF anti-cancer treatment.^37,38 The patient with cerebral haemorrhage described in Case 1 died, and the analysis of cause of death revealed that, although hypotension was corrected during treatment with apatinib, the patient's blood pressure became high enough to have easily induced cerebral haemorrhage. It was not ruled out that the patient’s clinical condition was complicated by cerebrovascular malformation or aneurysm causing rupture and bleeding, however, an autopsy was not performed on this patient, so the cause of death could not be further investigated. Blood pressure management should be strengthened for patients with high blood pressure. For some patients being treated with apatinib in whom blood pressure is too high, the dose of apatinib may be adjusted to reduce the hypertension side-effects, and antihypertensive drugs may be administered to control blood pressure.

Although the significance of the present case series is limited by the small number and heterogeneity of the cases, it does suggest a solution to the problem of patients with malignant tumours and hypotension. In our opinion, causation in hypotensive patients should be assessed. It should be noted that patients with advanced malignant tumours are more vulnerable to hypotension and should receive timely attention, particularly those with serious acute infections. Patients with serious complications may become hypotensive, particularly if they are hypovolemic, malnourished, and have a paraneoplastic neurological syndrome, and they must receive screening or surveillance recommendations. Patients with chronic or life-threatening low blood pressure should use i.v. vasopressors for symptom management. However, this treatment was linked to a decreased ability to perform daily activities while the patients were lying in a hospital bed. Apatinib, an oral small-molecule tyrosine kinase inhibitor, may reverse the hypotensive effect and control the growth of various solid tumours by controlling tumour angiogenesis.

Overall, three unique patients with severe hypotension that immediately resolved after the initiation of apatinib therapy are described, suggesting that the use of apatinib may stabilize blood pressure. Moreover, the clinical symptoms of all cases improved and, for the patient in Case 1, tumour assessment after baseline was evaluated as stable disease.

In conclusion, three patients with advanced malignancies who developed hypotension, with the potential causal role of a combination of many factors, are described. The patients were treated with apatinib while exhibiting hypotension, and achieved satisfactory short-term clinical results. Individuals at risk of low blood pressure due to paraneoplastic neurological disease and metastatic cancer may be prescribed anti-VEGFR2 medications, such apatinib, to raise blood pressure. The present research suggests that the hypertension adverse consequence of apatinib may benefit both symptomatic and asymptomatic patients who have no history of hypertension. This is because it helps address hypotension while apatinib also reduces tumour angiogenesis. Meaning that in patients with no history of high blood pressure, low blood pressure and tumour-related concerns may be addressed by apatinib. Asymptomatic individuals experiencing bed-bound hypotension may find it challenging to return to their normal daily activities. While apatinib may improve short-term survival, its potential impact on long-term survival remains to be seen. Following discovery of this clinical phenomenon, the present authors plan to conduct further experiments in vivo, and recruit more patients with cancer complicated with hypotension to verify the efficacy of apatinib. Apatinib may not only provide a new method to improve anticancer activity, but also increase blood pressure in patients with malignancy. Further research on the management of this hypotensive situation is urgently required.

Footnotes

Acknowledgment

The authors thank the patients who agreed to provide them with the data used in these cases. We would also like to thank Editage () for English language editing.

Author contributions

HMC, MHH and XFL prepared the manuscript. YYL and WGG were involved in data analysis and interpretation. All authors revised the manuscript, and read and approved the final manuscript.

Data availability statement

All data generated or analysed during this study are included in this published article.

Declaration of conflicting interests

The authors declare that there are no conflicts of interest.

Funding

This work was supported by the Funds of Medical Scientific Technological Department-funded Research Projects of Foshan City, Guangdong Province, China under contract No. (2017AB000362), and Medical Science and Technology Innovation Platform Construction Project belonging to the sub-item of Foshan Science and Technology Innovation Project under contract Nos. (FSOAA-KJ218-1301-0036 and FSOAA-KJ218-1301-0037).

ORCID iD

Haiming Chen

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