Advances in the use of ECMO in oncology patient

Abstract Background Over the past decade, ECMO has provided temporary cardiopulmonary support to an increasing number of patients, but the use of extracorporeal membrane oxygenation (ECMO) to provide temporary respiratory and circulatory support to adult patients with malignancy remains controversial. Objectives This paper reviews the specific use of extracorporeal membrane oxygenation (ECMO) in oncology patients. Methods We searched PubMed, CINAHL, Cochrane Library, and Embase databases for studies on the use of ECMO in cancer patients between 1998 and 2022. Twenty‐four retrospective, prospective, and case reports were included. The primary outcome was survival during extracorporeal membrane oxygenation. Results Most studies suggest that ECMO can be used in oncology patients requiring life support during surgery, solid tumor patients with respiratory failure, and hematological tumor patients requiring ECOM as a supportive means of chemotherapy; however, in patients with hematologic oncology undergoing hematopoietic stem cell transplantation, there was no clear benefit after the use of ECMO. Conclusion Current research suggests that ECMO may be considered as a salvage support in specific cancer patients. Future studies should include larger sample sizes than those already conducted, including studies on efficacy, adverse events, and health.


| INTRODUCTION
With the continuous development and advancement of medical technology and drugs, the mortality rate of solid malignancies and hematological malignancies patients is gradually decreasing. 1 Improved efficacy and supportive measures have also changed our attitudes towards patients entering the intensive care unit (ICU). In the meantime, a consensus document highlights the need for full-code ICU management (without limitations of ICU resources) for all critically ill cancer patients if the prognosis of the underlying malignancy is long-term survival. 2 Some patients who survive ICU support have a high quality of life after being discharged from the hospital and can continue their anticancer treatment; their long-term survival depends on the status of the underlying disease and is indistinguishable from oncology patients not admitted to the ICU. 3,4 Nevertheless, mortality remains high in critically ill oncology patients and is associated with complications, such as infection, treatment-related reactions, and disease progression. 5,6 Extracorporeal membrane oxygenation (ECMO) is also used in severe cases of respiratory distress syndrome such as those caused by neocoronavirus and influenza A (H1N1). [5][6][7] ECMO was developed outside of the operating room as an extension of the use of cardiopulmonary bypass (CPB) and was initially used for surgical patients who did not tolerate separation from CPB. CPB provides support to patients undergoing surgery for a few minutes to several hours. In addition to cardiac surgery, it is also used in major vascular surgery, neurosurgery, and transplantation. The use of ECMO in the treatment of patients with respiratory, cardiac, or combined failure can last several days or weeks. The use of ECMO as a potentially lifesaving intervention is becoming increasingly popular and its applications are becoming more diverse. It was initially used in the 1950s to provide support to patients undergoing cardiopulmonary bypass surgery. 8 Depending on the indication, there are two main configurations of ECMO: VV in patients with severe respiratory failure intravenous ECMO (VV) ECMO, and ECMO (VA) for severe heart failure. Venovenous ECMO (VV-ECMO) only provides respiratory support to patients. It is divided into a single cannula approach and a two-cannulation approach, with a single cannula approach flowing through the vena cava or right atrium outflow through circulation and then into the right atrium. The two-cannulation approaches flow from the common femoral vein and through the right internal jugular or femoral vein. 9 Venoarterial ECMO (VA-ECMO) provides both respiratory and hemodynamic support. The VA-ECMO circuit is connected parallel to the heart and lungs, whereas the VV-ECMO circuit is connected in series with the heart and lungs. 10 The Peripheral VA-ECMO cannulation approach is used when blood is drawn from the right atrium or vena cava and returned to the femoral artery, axillary, or carotid artery in the arterial system. 11 As technology grows, its use has expanded. In particular, ECMO for the support of cases of severe respiratory distress syndrome has caused a dramatic rise in the use of ECMO for life support in oncology patients in the last decade. [5][6][7] However, the use of ECMO in patients with malignant tumors remains controversial. First, immunosuppression is listed as a relative risk for ECMO by the Extracorporeal Life Support Organization (ELSO), which manages the ECMO record of operational ELSO centers globally. 12 Most oncology patients are considered immunosuppressed; many suffer from thrombocytopenia or plasma coagulation disorders, and many are receiving chemotherapy or immunomodulatory therapies, all of which may interfere with extracorporeal circulation and are thus considered contraindications for ECMO. 13 Secondly, cancer progression cannot be interfered with or reversed. We can prolong the life cycle of patients with some treatments; however, we have not yet achieved a cure. Finally, the arbitrary use of these resources may place some financial strain on the health care system. 10,14 However, this view has been challenged by retrospective studies showing that ECMO provides an alternative treatment for patients with solid tumors that are unsuitable for conventional surgical resection, thereby improving survival in this group of patients. 15 Furthermore, the most common reason that patients with malignant hematological tumors (such as leukemia, lymphoma, and multiple myeloma) need to be admitted to the ICU is acute respiratory failure. 16 Although patients with hematological tumors have benefited from chemotherapy and hematopoietic stem cell transplantation in recent years, more than 50% of hospitalized patients still require mechanical ventilation. 17,18 In such cases, ECMO may be considered 19 ; ECMO can help patients with tumor lysis syndrome by stabilizing their condition alongside chemotherapy. 20 Therefore, the purpose of this review was to describe how ECMO is used to support different types of oncology patients, evaluate the prognosis of oncology patients who receive ECMO, and identify the types of oncology patients who could benefit from ECMO.

| METHODS
We conducted a comprehensive literature search of PubMed, CINAHL, Cochrane Library, and Embase databases from 1998 to 2022. Databases were electronically searched for relevant publications using combinations of the following medical subject headings (MeSH) and keywords ("Venoarterial Extracorporeal Membrane Oxygenation" or "Venovenous Extracorporeal Membrane Oxygenation") and ("Tumor" or "Cancer" or "Malignancies"). In addition, a hand search of the references in included full texts was performed to identify additional studies for inclusion.
We initially identified 984 publications in the extracorporeal membrane oxygenation and cancer search. All studies were screened for eligibility by reading the title and abstract, and a total of 621 publications were excluded due to the types including review and meta-analysis, basic research, animal research, conference proceedings, and correspondence, leaving 363 publications for evaluation. Three hundred thirty-nine studies were excluded based on the evaluation of both the abstract and full text, as they involved pediatric oncology patients and adult oncology patients who had concurrent COVID-19 infection. At last, we performed a full-text evaluation of 24 papers (Figure 1). Twenty-four studies of ECMO support for oncology patients were included in this review. Ten of the included studies are retrospective, one is prospective, and thirteen are case reports. Further information on these studies is provided in Table 1.

| Respiratory support for patients with malignant tumors
With the growing capacity to inhibit tumor growth, new cancer treatment options have greatly slowed the progression and recurrence of cancer, and promoted remission. However, as life expectancy increases, the risk of acute respiratory failure in cancer patients also increases. Solid tumors and hematological malignancies differ in their pathogenesis, treatment, and patient prognosis. Therefore, it is necessary to discuss these two groups of patients separately. Among these patients, the extubation rate was 35% (17) and the discharge rate was 29% (7). 45 When severely ill cancer patients require invasive ventilator assistance, their prognosis is dismal (20%-30% survival rate). 46,47 However, since 2015, Wu et al. suggest that ECMO should be offered to patients with cancer who are suffering from respiratory failure. Thirteen oncology patients who received ECMO after anticancer treatment were included in this retrospective study. The median follow-up was 11 months, and only four patients survived during this period (partial remission), two of whom died of recurrent cancer. Patients with recurrent or progressive malignancies who have severe granulocytopenia cancer did not benefit from ECMO treatment for acute respiratory failure, according to the authors. 48 Kochanek et al., in 2022, mentioned that cancers associated with severe respiratory failure had a poor prognosis after ECMO treatment. Patients with progressive disease are not recommended to undergo ECMO, and the survival rate for solid body tumors is 30% at 60 days 49 ( Table 2). Compared with the study by Wu et al, relevant physiological parameters (e.g., neutrophil and platelet counts) improved in oncology patients after ECMO use, although patient survival was lower in the study by Gow et al. However, whether this change in parameters is related to patient prognosis requires further investigation. Since 2015, discharge rates for oncology patients have increased in several studies compared with previous studies, which may be related to the increasing number of treatment options for oncology patients and advances in ECMO technology. Meanwhile, researchers have suggested supportive care for solid tumor patients with high functional status (functional status score (PS) <2 or good long-term prognosis).

| Respiratory support for patients with hematological malignancies
Poor prognosis for patients with hematological malignancies who present with severe respiratory failure. 50 The results of ECMO support in patients with hematological malignancies are inconsistent. Among 72 adult patients with malignancies studied by Gow et al., 21 had hematological malignancies, and four underwent HSCT. Accordingly, 32% of patients with hematological tumors survived hospital discharge, supporting the general view that ECMO is not indicated for these patients. 45 However, Wohlfarth et al. provided a different view, arguing that ECMO can be used for specific patients with hematologic malignancies in respiratory failure, and is associated with long-term disease-free survival. During a 36-month follow-up period, 7 patients survived, including one in complete remission, one in partial remission, and one in F I G U R E 1 Flowchart of study selection.  The procedure was completed successfully with the hemodynamic conditions provided by ECMO, and the patient was discharged on the third day after the operation Meltzer et al. 36 Case report Report on the use of VA-ECMO to provide cardiopulmonary support for chemotherapy in patients with lymphoma The patient achieved complete radiographic remission after receiving chemotherapy with ECMO support but unfortunately passed away due to infection 1 year later Allain et al. 37 Case report A report on chemotherapy with ECMO support in patients with primary cardiac lymphomas(PCLs) following the onset of cardiogenic shock The patient had successful chemotherapy and recovered Chung et al. 38 Case report Report on a patient with metastatic choriocarcinoma who was admitted to the intensive care unit due to hemodynamic instability. The patient received chemotherapy after VA-ECMO Case report A patient with a large mass in the mediastinum was described, and the mass was causing compression of the airway. The patient received treatment with antineoplastic therapy and was supported with cardiopulmonary assistance on ECMO The patient was successfully discharged after receiving antitumor treatment with cardiopulmonary support on ECMO, and the tumor shrank T A B L E 1 (Continued) hematological malignancies than for those who were immunocompetent; however, there was no significant difference in the complications that occurred between the two groups. This study suggests that patients who require emergency support require further consideration 51 ( In 2013, a B-cell acute leukocyte patient treated with hematopoietic stem cell transplant underwent ECMO support and showed a complete absence of respiratory failure and other symptoms. It is clear from this case that ECMO may be successful in treating such patients, although its prognosis has not yet been addressed. 26 However, this was not the case in the 2014 study by Koinuma et al., in which a patient with leukemia who had received hematopoietic stem cell transplantation and ECMO respiratory support for 11 days died shortly after extubation. 56 According to a retrospective study conducted in 2017, 19% (n = 7) of patients received ECMO for respiratory failure after ASCT. Only one patient who started ECMO within 240 days died, whereas six patients who started ECMO after 240 days survived. 57 A retrospective study in 2018 analyzed 25 patients, 11 of whom had undergone HSCT. Overall, 68% of these patients died, 20% (5) survived until discharge, and all patients who underwent HSCT were died. Therefore, the use of ECMO to support ARDS in patients receiving ASCT needs to be considered with caution. 29 In the retrospective studies described above, it appears that except in a few cases, patients treated with ECMO support with ASCT complicated by respiratory failure had a higher mortality rate. However, in a 2017 study, the authors mentioned that 240 days after ASCT, patients had a better prognosis with ECMO than those within 240 days, which was related to the low immune status of patients who had just finished ASCT treatment.

| Adjunctive perioperative support for patients with solid tumors
Extracorporeal lung support (ECLS) is gaining acceptance for thoracic surgery. It has been increasingly used in oncological thoracic surgery since its initial use in lung transplantations. Classification can be based on the patient's treatment needs and can be divided into surgery without a history of extensive resection on the contralateral side or patients with severely impaired lung function and procedures requiring both ventilatory and hemodynamic instability support. ECMO has been used as a means of support to assist patients with breathing since 1998 when it successfully supported adult men with severe acute mediastinal tumors causing airway compressions. 44,58 In 2021, Huang et al. similarly described a case in which a patient underwent mediastinal tumor resection with ECMO support. 59 Lang et al. retrospectively analyzed nine patients with thoracic malignancies between 2001 and 2011. All nine patients underwent complex tracheobronchial resection with ECMO support, and eight patients (89%) achieved R0 resection. 60 In 2009, Smith et al. similarly described two patients who underwent successful resection of bronchial tumors with ECMO support. 42 Spaggiari et al. retrospectively analyzed six cases in which ECMO was assisted by tracheal sleeve pneumonectomy (TPS) to improve ventilation, and patients with lung cancer received complete surgical treatment. The follow-up period was 8.4 months and all patients survived. 15 The use of ECMO is not only limited to bronchial or lung malignancies but can also be used to help patients with esophageal cancer. This is based on an isolated case but may prove significant. Approximately 12 years ago, the patient underwent left pneumonectomy, followed by chemotherapy and radiotherapy for non-small-cell lung cancer. Although lung cancer was prominent, esophageal cancer could not be ruled out. According to the oncologist, surgical resection is recommended for radical esophageal cancer. In the case of a patient who had only one lung, and with the postoperative complications of esophageal cancer already high, the use of ECMO to support the surgery was proposed. Patients with multiple or more complex comorbidities may benefit from ECMO during major thoracic surgery. 61 Similarly, Audrey et al. described a patient with esophageal adenoid cystic carcinoma that invaded the trachea. The patient underwent tumor resection and tracheal repair while on ECMO. 62 Pheochromocytoma crises are rare, but with sudden onset and nonspecific symptoms, nearly a quarter of the patients die. Salvage ECMO is used in most severe cases, effectively helping patients overcome circulatory failure. According to a French study by Rinieri et al.'s from 2015, 36 patients were divided into three separate groups. The 30-day mortality rate in the group receiving full ECMO support was only 7%, which was statistically significant compared with the other two groups. ECMO can also be used to support conventional lung ventilation, according to the authors. 63 Six patients underwent pneumonectomy using both high-and low-flow modes. Redwan et al. reported that VV-ECMO could provide lung support in different settings. 64 In 2017, a French multicenter cohort study included 34 patients with pheochromocytoma (the largest series of patients with pheochromocytoma), of which 41% (14) used ECMO for decortication. The overall ICU mortality rate was 24% (8 out of 34 patients). Ninety days after the patient was admitted, the overall mortality rate was 27% (9 out of 34 patients), and there was no significant difference between patients using ECMO and those not using it. Because heart failure during a pheochromocytoma crisis may be reversible, ECMO can  66 In conclusion, by providing surgical resection, ECMO offers a glimmer of hope to patients who would otherwise be inoperable.

| ECMO as a bridge to chemotherapy
In general, chemotherapy is not routinely recommended for patients with ECMO because of possible complications such as neutropenia or thrombocytopenia. However, according to ELSO regulations, chemotherapy for ECMO is not an absolute contraindication. 67 Some patients who are sensitive to chemotherapy can achieve tumor reduction and have a better prognosis. A 40-year-old woman was diagnosed with a ventricular large B-cell lymphoma. She successfully transitioned to chemotherapy with cardiopulmonary support from VA-ECMO to achieve a reduction in tumor load and survived for up to 1 year. 68 In 2015, Allain et al. described a 65-year-old man newly diagnosed with primary cardiac lymphoma who was successfully treated with chemotherapy and supported by ECMO. Cardiogenic shock occurred during the course of treatment, and circulatory support was required from the ECMO. Emergency chemotherapy with cyclophosphamide, vincristine, and solu-medrol was administered on day 8 of ECMO support, and complete recovery was achieved 6 months later. 69 A young woman with choriocarcinoma recently presented with refractory circulatory failure following a pulmonary embolism. Chemotherapy was administered with extracorporeal membrane oxygenation support, and the prognosis was good. The authors noted that ECMO helps patients with pulmonary embolism to transition to surgical embolization and chemotherapy. 70 A 21-year-old male with primary B-cell lymphoma invading the trachea developed refractory dyspnea, requiring chemotherapy in conjunction with ECMO support. After completing four cycles of chemotherapy, the patient was asymptomatic. He was discharged with a Karnofsky score of 100. 71 Positive efficacy of ECMO in chemotherapy-sensitive oncology patients was observed in these cases. Therefore, ECMO should not be ruled out in the first instance as salvage therapy for cancer patients with stable disease who are eligible to receive full-code ICU care immediately. Comprehensive and rigorous study designs, such as prospective studies, are required to determine the statistical significance and to help inform our conclusions in case reports.

| CONCLUSION
In summary, as mentioned in the consensus, cancer is only a relative contraindication to ECMO and not an absolute contraindication. ECMO is applied as a support for cancer patients during surgeries, solid tumor patients with respiratory failure, or blood cancer patients in severe condition during chemotherapy. However, according to current studies, there is still a large proportion of oncology patients who do not benefit from ECMO. Thus, further thought should be given on how to assess oncology patients regarding their eligibility for ECMO. Such evaluations can be completed through multidisciplinary treatment efforts (e.g., in collaboration with oncologists and surgeons) and should make use of full codes and individualized treatment for patients admitted to the ICU requiring ECMO. This topic needs to be evaluated more comprehensively in rigorously designed and highly powered clinical studies. Future studies should enroll larger sample sizes than those that have been conducted to date and include research on efficacy, adverse events, and health economics.

ACKNO WLE DGE MENTS
For their understanding and recognition of our work, we thank all patients who participated in this study.

FUNDING INFORMATION Sichuan Province Key Clinical Specialty Construction
Project.