Mechanical thrombectomy for the treatment of large vessel occlusion due to cancer-related cerebral embolism: A systematic review

Abstract

Background

Cancer-related cerebral embolism due to direct tumor embolization results in a rare acute ischemic stroke with large vessel occlusion (LVO). Despite the established status of mechanical thrombectomy (MT) in LVO management, its effectiveness and safety remains inadequately explored in this specific patient group.

Methods

We conducted a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using the Nested Knowledge AutoLit software, encompassing databases like Embase, PubMed, Scopus, and Web of Science, from their inception up to 9 May 2023.

Results

In the review of 35 studies encompassing 37 cases, mean patient age was 52 years, and 30% were female. Cardiac myxoma (29.7%), cardiac papillary fibroelastoma (16.2%), and squamous cell carcinoma of the lung (8.1%) were the most frequent underlying cancers. The left middle cerebral artery was the most commonly affected occlusion site (24.3%). Of the patients, 67.5% underwent MT alone, while 32.5% received MT combined with intravenous thrombolysis. Successful reperfusion (thrombolysis in cerebral infarction (TICI) 2b–3) was achieved in 89.1% of cases, with 59.4% reaching TICI 3. Functional independence was observed in 29.7% of patients.

Conclusion

While limitations exist, this comprehensive study highlights the potential benefits of MT in a patient group historically excluded from major trials, warranting further investigation.

Introduction

Mechanical thrombectomy (MT) for acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a therapeutic option with the best evidence of favorable outcome. ¹ Many conditions increase the likelihood of AIS, and about 10% of patients with AIS are found to have an underlying cancer. ² Whereas the previous percentage was found in hospitalized patients, a 2010 study found AIS in about 15% of patients with underlying cancer upon autopsy. ³

To date, results from studies using intravenous thrombolysis (IVT) for the treatment of patients with cancer-related cerebral embolism (CRCE) due to direct tumor embolism are inconsistent. In one study, IVT in this patient population did not affect hemorrhage risk or mortality when compared to people without underlying cancer. ⁴ Yet, other studies have found the risk of hemorrhage to be greater, thereby supporting the practice of avoiding IVT for the treatment of cancer-related embolic stroke. ⁵ Of note, IVT is occasionally contraindicated in this patient population secondary to the size, location, type, and presence of hemorrhagic metastatic lesions. ⁶

Some studies have suggested that performing MT for patients with LVO in the setting of CRCE should be considered.^6–8 On the other hand, the evidence supporting the use of MT in this patient population is limited due to the exclusion of patients with CRCE from major MT clinical trials. ⁹ To that end, American Heart Association guidelines/American stroke association recommend the use of MT in patients with LVO in the setting of CRCE in carefully selected patients only.^9,10 In this study, we conducted a systematic review to assess the role of MT as a potential treatment of LVO due to CRCE.

Materials and methods

Search strategy

The current systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The literature search was performed on 9 May 2023, using the Nested Knowledge AutoLit software (version 1.46; Nested Knowledge, Saint Paul, MN) and included four major databases: Embase, PubMed, Scopus, and Web of Science. The search strategy employed a combination of Medical Subject Heading (MeSH) terms and keywords (see Appendix). The following search terms were used: “Brain”[Mesh] OR “Cerebrum”[Mesh] OR “cerebral” OR “brain,” combined with “Neoplasms”[Mesh] OR “tumor” OR “cancer,” and further combined with “Thrombectomy”[Mesh] OR “thrombectomy” and (embol*). Detailed information on the full search strategy is available in the supplementary data. Moreover, we conducted a thorough manual search to recover any overlooked articles. All selected articles have an accurate diagnosis of tumor cerebral embolism by histopathological confirmation when retrieving the emboli for examination during endovascular treatment.

Screening and eligibility criteria

Two independent reviewers conducted the initial screening, assessing the relevance of articles based on their titles and abstracts. Subsequently, full-text articles were assessed to determine their eligibility for inclusion. All studies that met the predetermined population, intervention, comparison and outcomes criteria were included in our analysis. The study population consisted of patients with LVO due to CRCE, and the intervention of interest was endovascular thrombectomy for the treatment of LVO. There were no comparison or control groups in this study. The primary outcome of interest was successful reperfusion, defined as achieving a thrombolysis in cerebral infarction (TICI) score of 2b–3, and the secondary outcomes included hospital discharge and mortality rates. Non-original studies, animal studies, and meeting abstracts were excluded.

Data extraction

Data extraction was performed by two independent authors using a standardized data extraction form. The extracted data encompassed various aspects, including study characteristics, baseline patient characteristics, intervention-specific outcomes, and overall study outcomes. To ensure the accuracy and quality of the extracted data, a senior author conducted a comprehensive review of the extracted information.

Results

Search results and study characteristics

In summary, we conducted four database searches that contained 171 studies including 63 studies in Embase, 86 studies in PubMed, 40 studies in Scopus, and 121 studies in Web of Science. Following the screening and exclusion processes, the literature review included a total of 35 studies, encompassing 37 cases (Figure 1). The mean patient age was 52 years, with gender data missing for two patients. Among the remaining 35 patients, approximately 30% were female (Table 1). The most frequently observed tumors in patients were cardiac myxoma (29.7% in 11 patients), followed by cardiac papillary fibroelastoma (16.2% in six patients), and squamous cell carcinoma of the lung (8.1% in three patients). As for the occlusion site, the left middle cerebral artery (MCA) was the most common, affecting nine patients (24.3%), followed by the right MCA in seven patients (18.9%), and the basilar artery in four patients (10.8%).

Figure 1.

PRISMA 2020 flow diagram. *Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). **If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools. From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Table 1.

Summary of reported cases with their baseline characteristics, interventions used, and outcome data.

Author name	Year	Age	Gender	Comorbidities	Primary tumor	Occlusion site	MT only /+IVT	Device/Technique	MT intervention. Hours after onset	Post-TICI	Pre-NIHSS	Post-NIHSS	MRS score	Outcome
Bhatia et al. 18	2010	62	F	n/a	Breast cancer	Left MCA	MT	Merci retriever	n/a	2a	19	-	n/a	Discharged.
Kim et al. 6	2012	22	F	none	Malignant melanoma + mets	Left M1	MT	Force suction thrombectomy	n/a	3	4	1	n/a	n/a
Tejada et al. 19	2014	64	F	Dyslipidemia	Cardiac papillary fibroelastoma	Right MCA M1	MT	Solitaire retriever	4	3	16	3	-	Hemorrhagic stroke transformation. Discharged.
Santos et al. 20	2014	34	M	Smoker	Cardiac papillary fibroelastoma	Left MCA	MT + IVT	Retriever	3.25	2b	13	20/ 14	n/a	Favorable; however, Sequelae of aphasia, with preserved comprehension, and hemiparetic. Discharged.
Baek et al. 21	2014	46	M	n/a	Cardiac myxoma	Left ICA + MCA	MT + IVT	Force suction thrombectomy/Optimo and Microsuction thrombectomy/Penumbra	n/a	2a	n/a	n/a	n/a	Sequelae left eye blindness. Discharged.
Garcia-Ptacek et al. 22	2014	45	-	n/a	Cardiac myxoma	Left M1	MT + IVT	Solitaire retriever, Plymouth, Trevo. Wingspan stent, PHAROS stent	5	0	22/27/19	31	4	Reocclusion due to stent thrombosis. Discharged.
		34	-	n/a	Cardiac myxoma	Left MCA	MT + IVT	Solitaire retriever	6.5	3	26	3	2	Mild aphasia sequelae. Discharged.
Ryu et al. 23	2015	34	M	none	Cardiac myxoma	Right MCA	MT + IVT	Merci retriever with aspiration	n/a	3	9	6/ 1	2	Discharged.
Vega et al. 24	2015	11	M	Reynaud syndrome	Cardiac myxoma	Right M1 + Right Fetal Pcom	MT	Trevo and Penumbra retriever	3.05	3	16	7	1	Discharged.
Itrat et al. 25	2015	62	M	Hypertension, hyperlipidemia, CAD, and tobacco user.	Cardiac papillary fibroelastoma	MCA M1	MT	Solitaire retriever	n/a	3	24	10	3	Discharged.
Stella E Hughes et al. 26	2015	69	M	Hypertension	Lung adenocarcinoma	Right MCA	MT	n/a	6	3	16	n/a	n/a	Discharged. However, died 35 days later due to hospital-acquired pneumonia.
Biraschi et al. 27	2016	75	M	Hypertension, A-Fib	Cardiac papillary fibroelastoma	Left M1	MT	Retriever with aspiration	n/a	3	18	n/a	n/a	Discharged. Right Hemiplegia.
Chung et al. 28	2016	4	M	3-month febrile convulsion	Cardiac myxoma	Left M1	MT + IVT	Solitaire retriever	5	3	16	n/a	1	Discharged.
Zander et al. 29	2016	58	M	Smoker	Pulmonary adenocarcinoma + mets	Left M2	MT	Solitaire retriever	n/a	3	24	10	-	Died. Advanced cancer, palliative care (day 14).
		46	F	n/a	Cardiac myxoma	Right MCA	MT	Solitaire retriever	n/a	3	16	6/2	0	Discharged.
Byon et al. 30	2016	55	M	Hypertension, DM, CAD, and A-Fib	Cardiac high-grade Sarcoma	Right ICA	MT	Penumbra with manual aspiration	2	3	22	n/a	n/a	n/a
Uneda et al. 31	2016	70	M	n/a	Cardiac myxoma	Left ICA	MT + IVT	Penumbra, Trevor retriever	6.3	2b	11	1	2	Sequelae of mild aphasia. Discharged.
Pop et al. 32	2018	56	M	Thrombocytopenia	Pulmonary hilus sarcomatoid carcinoma	Basillar Artery + Left ICA (Same day)	MT	n/a	4.8	2b	n/a	n/a	6	Died due to hemorrhagic transformation of stroke.
Fukami et al. 33	2018	37	M	n/a	Aortic sarcoma	Right ICA	MT + IVT	Trevor retriever	n/a	2b	13	4	2	Discharged with therapy for sarcoma.
Abe et al. 34	2019	79	M	n/a	Cardiac papillary fibroelastoma	Basilar artery	MT	Penumbra catheter (one pass)	2.73	3	40	n/a	-	Died. Worsened chronic heart failure after the onset of the stroke (day 29).
Goddard et al. 35	2019	80	M	HTN, DM, Sleep Apnea, CAD, Vascular dementia, COPD	Large cell high-grade pulmonary endocrine tumor	Basilar artery	MT + IVT	Penumbra catheter	n/a	2c	19	n/a	6	Died (day3). Subsequent stroke and respiratory failure.
Tsurusaki et al. 36	2019	72	M	Prostate Cancer	Lung squamous cell cancer	Left ICA	MT	Solitaire retriever with aspiration, Penumbra catheter and Trevor retriever	1.3	3	13	n/a	n/a	Discharged.
Oyama et al. 37	2020	34	M	Heart failure, A-fib	Lung mucoepidermoid carcinoma + mets	Left ICA	MT + IVT	Penumbra catheter, Solitaire retrieval and aspiration	3.5	2b	17	10	6	Died. Condition worsened and transferred to hospice care. Respiratory failure (day 43).
Yoshikawa et al. 38	2020	66	M	n/a	Lung pleomorphic carcinoma	Right MCA	MT	Trevo retriever	4.5	3	14	n/a	1	Discharged.
Kazuma Tsuto, et al. 39	2020	82	M	DM, Angina, A-fib	Squamous cell carcinoma	Left ICA	MT	n/a	n/a	3	20	n/a	6	Died. Carcinomatous pleurisy, pleural effusion.
Zhou et al. 40	2020	16	F	none	Cardiac myxoma	Right M1	MT	Trevo retriever	n/a	2b	20	1	1	Discharged.
Suguru Araki et al. 41	2020	69	F	n/a	Esophageal carcinoma with mets	Left MCA M1	MT	n/a	n/a	3	25	n/a	0	Discharged.
Moriyama et al. 42	2021	64	M	Paroxysmal A-Fib. History of lacunar infarction.	Lung squamous cell cancer	Right M2	MT	Penumbra and Trevor retriever	4	2b	10	n/a	-	Died. Massive hemoptysis (day 40).
Bhatia et al. 43	2021	42	F	none	Cardiac myxoma	Basilar Artery	MT	Penumbra catheter, Trevor retriever	n/a	3	28	10/8	1	Discharged.
Hyae Lee You et al. 44	2021	9	F	n/a	Papillary thyroid cancer with Mets	Right MCA M1	MT	n/a	n/a	2b	17	n/a	6	Died. Possible embolic or hemorrhagic stroke (day 7).
Dong Kun Lee et al. 45	2021	56	F	none	Rhabdomyosarcmma	Bilateral ICA and right PCA	MT + IVT	Solitaire retriever	n/a	0	17	n/a	6	Died.
Kaoru Nakanishi et al. 46	2021	51	M	n/a	Renal cell carcinoma with mets	Left MCA	MT + IVT	Penumbra and Solitaire retriever	4.3	2b	7	1	n/a	Died due to cancer progression (day 60).
Rebecca A Bedoya et al. 47	2021	43	F	Hypothyroidism, Smoker	Cardiac myxoma	MCA M1	MT	Stent retriever	n/a	3	n/a	n/a	n/a	Mild subarachnoid hemorrhage. Discharged to rehab center.
Aurora Semerano et al. 48	2021	89	F	Hypertension, dyslipidemia, prior pulmonary embolism	Cardiac fibroelastoma	Left MCA M2	MT	Trevo retriever	3.5	3	18	n/a	n/a	n/a
Fujiwara et al. 49	2022	74	M	none	Lung squamous cell cancer	Left M2	MT	Trevor retriever	n/a	2b	22	1	-	Progression of the primary disease. Died on day 27 of the hospital stay.
Fujiwara et al. 50	2023	57	M	none	Thyroid cancer + lung metastasis	Right ICA	MT	Solitaire retriever with aspiration catheter	n/a	3	11	n/a	-	n/a
Ryotaro Nukata et al. 51	2023	80	M	n/a	Metastatic melanoma + mets	Basilar artery	MT	Embotrap III stent retriever with aspiration	n/a	3	33	31	5	Died on day 93 due to tumor progression.

NIHSS: National Institutes of Health Stroke Scale; mRS: Modified Rankin Scale; TICI: thrombolysis in cerebral infarction; MT: mechanical thrombectomy; IVT: intravenous thrombolysis; MCA: middle cerebral artery.

Treatment outcomes

Among the patient cohort, 25 individuals (67.5%) underwent MT as a standalone treatment, while 12 patients (32.5%) received a combination of MT and IVT. Remarkably, successful reperfusion, defined as achieving a TICI score of 2b–3, was achieved in 33 patients (89.1%), with 22 patients (59.4%) attaining a TICI score of 3. Regrettably, two cases (5.4%) failed to achieve recanalization with a TICI score of 0. Importantly, 11 patients (29.7%) achieved functional independence.

Patient outcomes

Among the patient cohort, 20 patients (54.1%) were discharged from the hospital, with or without complications, and 13 (35.1%) were reported as deceased, including those who passed away during their hospital stay and after discharge. Data on discharge status was missing for four patients (10.8%). Further details can be found in Table 1.

Discussion

This systematic review was conducted to evaluate the use of MT in patients with LVO due to CRCE. The benefit of MT for LVO has been reported in multiple studies to date. ¹¹ However, the use of MT is not well established in patients with LVO in the setting of CRCE as these patients are excluded from major MT clinical trials.^9,12 The current AHA/ASA guidelines direct the use of MT through careful selection of patients with LVO in the setting of CRCE.^9,10

The results from this systematic review regarding the rates of successful reperfusion are in line with results observed from the Italian Registry of Endovascular Treatment in Acute Stroke (IRETAS), 89.1% vs 74%, respectively.^13,14 Yet, other studies have reported significantly lower rates of successful reperfusion with difficulties in retrieving the blood clot using aspiration alone.^15,16

Similarly, the findings of the current study showed that the 90-day all-cause mortality rate was around 35%. A third of the deaths were directly related to the cancer progression. This is in line with data from Letteri et al., which stated that 90-day all-cause mortality was around 33%. However, these results contradict those from the Selection Criteria in Endovascular Thrombectomy and Thrombolytic Therapy (SECRET) registry, which reported worse outcomes in the active cancer group when compared to the no cancer group, with the understanding that about one-third of the cancer patients who underwent MT achieved functional independence. ¹⁷ Their reported percent of patients regaining functional independence is consistent with the results from the present study, in which independence was achieved by 30% of the patients treated with MT.

Of note, cardiac myxoma was the most common type of cancer associated with LVO in CRCE in this study, accounting for about one-third of the cases. Other studies reported that different cancers account for the majority of cases, such as lung and gastrointestinal cancers.^13,17

Despite the exclusion of patients with LVO due to CRCE from being treated with MT, data from this study together with that from multiple registries, including IRETAS and SECRET, support the use of MT to treat LVO in patients with CRCE. We found that MT is technically successful in this patient population, and clinical outcomes are similarly favorable, with about 30% of patients achieving functional independence. Further research should be conducted in this patient population given their unique characteristics and historical exclusion from major trials.

This study has limitations. First, we did not have access to individual patient data, which limited the analyses we were able to perform. Due to the scarcity of literature regarding this topic, the present study may be underpowered. Additionally, we were not able to stratify outcomes based on tumor location, LVO location, or other variables. Finally, publication bias may have occurred due to scenarios with unsuccessful outcomes or when recanalization and retrieval of the emboli was not achieved, leading to poor evidence of negative end-results and possible overestimation of the safety and efficacy of MT. Despite these limitations, to our knowledge, the present systematic review represents the largest and most comprehensive study regarding MT in patients with CRCE.

Conclusion

MT is a reasonable treatment option for LVO due to CRCE, with a reperfusion rate comparable to non-cancer patients and a reasonable degree of functional independence achieved in this historically MT-excluded patient population. Future studies should be conducted in this patient population to determine if they benefit from adjunct therapy.

Appendix

Key words

We searched the PubMed database using the following keywords (“Brain”[Mesh] OR “Cerebrum”[Mesh] OR “cerebral” OR “brain”) AND (“Neoplasms”[Mesh] OR “tumor” OR “cancer”) AND (“Thrombectomy”[Mesh] OR “thrombectomy”) AND (embol*). We also searched the Web of Science using Search Strategy (v0.1) # Database: All Databases # Entitlements: - WOS: 1900 to 2023 - BCI: 1969 to 2023 - CCC: 1998 to 2023 - DRCI: 1993 to 2023 - DIIDW: 1993 to 2023 - KJD: 1980 to 2023 - MEDLINE: 1950 to 2023 - PPRN: 1991 to 2023 - SCIELO: 2002 to 2023 - ZOOREC: 1993 to 2023 # Searches: 1: (Brain OR Cerebrum OR cerebral OR brain) AND (Neoplasms OR tumor OR cancer) AND (Thrombectomy) AND (embol*) (Topic) and Preprint Citation Index (Exclude – Database) Date Run: Tue May 09 2023 14:26:13 GMT-0500 (Central Daylight Time) Results: 123.

In addition, the Embase search was done using the following criteria: <1974 to 2023 May 08 >1 (Brain or Cerebrum or cerebral or brain).ab,ti. 1841993 2 (Neoplasms or tumor or cancer).ab,ti. 4116215 3 (Thrombectomy or thrombectomy).ab,ti. 27174 4 embol*.ab,ti. 224893 5 1 and 2 and 3 and 4 71. Finally, the Scopus database was searched using the following keywords: (TITLE-ABS-KEY ((Brain OR Cerebrum OR cerebral OR brain) AND (Neoplasms OR tumor OR cancer) AND (Thrombectomy OR thrombectomy) AND (embol*))