The main purposes of CART in cancer treatment is to ease the discomfort derived from refractory ascites as a palliative treatment. Thus, the adverse effects related to CART, especially those with subjective symptoms, should be minimized in patients receiving the best supportive care. The current study showed that AEs were observed in 9.4% of 233 procedures. These were mainly mild and tolerable symptoms, as cytokine related-reactions, probably through the reinfusion of excessive amounts of cytokines contained in the ascites. They tended to be caused by the infusion of large quantities of proteins. It is therefore recommended that concentrated ascites be reinfused at a rate of < 100 mL/h, irrespective of prophylactic steroid administration.
AEs related to puncture/harvesting and reinfusion developed at the same frequency as seen in a previous multicenter study . In the overall CART procedure, the most common AEs were fever and fever-related symptoms, such as chills after the reinfusion of concentrated ascites. The frequency of fever in this study, 5.6% (13 events), was comparable to that in previous studies, 5–16.4% [8, 11, 16, 17]. The average increase in body temperature was reported to be 0.1–0.44 °C [1, 9–11, 18]. Although a multi-center study showed that the risk of fever did not differ according to the conditions of reinfusion, such as the amount of reinfused ascites/protein or the speed of reinfusion , our study suggested that the reinfusion of larger amounts of protein may increase the risk of fever; this was similar to the finding of another report that analyzed patients with gynecologic cancer . The multi-center study included cases of transudative ascites due to liver damage, such as liver cirrhosis and hepatic carcinoma. It is therefore hypothesized that fever may occur due to the enriched inflammatory cytokines in concentrated ascites derived from carcinomatous peritonitis. The ascitic concentration of inflammatory cytokines (e.g., IL-6, IL-8 and IL-10) did not have a significant correlation with the changes in body temperature . Additionally, IL-6 in the ascites decreased in the process of filtration and concentration . The exact causes of fever still require investigation.
Puncture/harvesting-related AEs were reported to be less frequent, occurring in 2.5% of procedures in the previous multi-center study, and 0.9% of the procedures in the present study (2 of 233 procedures). The AEs in our study included pulmonary edema, which might be caused by inflation of lungs due to elimination of a large amount of ascites, and hypotension, which might be caused by extravascular defluvium of the blood plasma component. The volume of harvested ascites in these 2 procedures was more than the median in this study, 6,665 mL and 11,535 mL, but improved with transient medical treatment. This could be life-threating, as it could injure vital organs and systems, and the severity might be dependent on the volume of harvested ascites, in addition to the general condition of each patient. Thus, appropriate management of patients, including careful observation and prompt treatment, are required when performing CART, especially when a large volume of ascites is harvested.
In order to avoid AEs, such as cytokine related-reactions, as well as volume overload, the manufacturer’s protocol recommends an ascites reinfusion rate of 100 to 150 mL/h. In most cases, reinfusion was performed after the prophylactic administration of corticosteroids for AEs, because steroids have been shown to be effective for inhibiting body temperature elevation in CART [8, 18]. However, AEs occasionally occurred, even with steroid prophylaxis. The finding in this study, that a reinfusion rate of ≤ 100 mL/h reduced AEs was consistently observed, regardless of the presence of steroid prophylaxis, suggesting the necessity for a stricter guideline regarding the reinfusion rate. CART has recently been applied for more cancer patients, who may have exudative ascites . Although our study was retrospective in nature and performed in a single institute, this information may be helpful for the management of cancer patients.
One of the criticisms of our study was the low recovery rate of total protein and albumin in the processing of ascites (44.9 and 49.0%, respectively). In the modified CART (KM-CART) procedure, the recovery rates of albumin and globulin in 11 cancer patients were reported to be 71.1 ± 9.6% and 57.6 ± 7.1%, respectively, without membrane cleaning , while the protein recovery rate was 40.7 ± 14.0% in 4781 procedures with membrane cleaning , which were comparable to the data in this study. Frequent membrane cleaning therefore reduced the recovery rates of total protein and albumin. In addition, all patients in our study suffered from cancer. A multicenter study revealed that the lowest and middle tertile procedures of the recovery rate (47.3 ± 11.1%, 70.0 ± 6.0%) included a higher proportion of patients with exudative ascites (64.5%, 66.7%) and ascites with higher protein levels (3.6 ± 1.8 g/dL, 2.9 ± 1.4 g/dL), which was in sharp contrast to the highest tertile (89.8 ± 6.7%), included a lower proportion of patients with exudative ascites (32.4%) and demonstrated ascites with lower protein levels (2.2 ± 1.4 g/dL) . The background of ascites in our study was similar to the lowest to middle tertiles rather than the highest tertile. Accordingly, our recovery rate was considered to be reasonable and realistic.
Fever is a transient and mild AE in CART; however, its management is still important and valuable because CART is usually performed as a palliative therapy [1, 11]. Especially in cancer patients, the characteristics and contents of reinfused concentrated ascites vary according to those of the original ascites and modification through the CART procedure. It is therefore difficult to precisely perform a case-control study on CART for advanced cancer patients. Although the progress based on our findings might be limited, the accumulation of these findings will improve the strategy for CART, which is becoming increasingly important for relieving the discomfort associated with refractory ascites in cancer patients.