To the best of our knowledge, this is the first report of the survival time and repeat rate of KM-CART procedures in a clinical setting. Regarding the prognosis of patients with malignant ascites, a retrospective review of 76 patients showed that median survival was determined to be 11.1 weeks from time of diagnosis and prolonged survival was found in patients with ovarian cancer [23]. In another study by Garrison et al., it was demonstrated that tumors originating from the female reproductive system had the longest survivals, with a mean survival of 19 weeks, and foregut adenocarcinomas had the poorest survivals, with a mean survival of 10 weeks from the onset of ascites [24]. In this study, of the five major diseases (accounted for 73% of all cases), ovarian cancer had also the longest 50% survival time (49 days), followed by gastric cancer, cholangiocarcinoma, and hepatocellular carcinoma. Pancreatic cancer had the shortest 50% survival time (25 days). Our results of survival time of patients with malignant ascites were shorter compared to those of previous reports because our data were from first KM-CART and data of previous reports were from the onset of ascites. Therefore, prognostic impact of KM-CART is thought to be unclear in this study, and KM-CART mainly provides symptomatic treatment.
Because KM-CART is often performed multiple times to improve the quality of life [17], we examined the repeat rate of this treatment. In this study, about half of the patients underwent repeated KM-CART therapy. Matsusaki et al. have already reported the improvement of treatment results and inspection data, and concluded that KM-CART therapy had the "quality of best supportive care" for patients with malignant ascites [17]. Maeda et al. suggested that higher albumin levels in ascites may lead to multiple treatments [25]. Furthermore, Ito et al. reported that the presence of IL-10 in ascites was related to longer survival after CART, and the immunological environment of cancer-related ascites may reflect the outcome of CART therapy [26]. From the results of this study, we consider the continuity of treatment to be critical. In this study, patients who were treated three or more times with KM-CART procedures had longer survival times than those who are treated once or twice. Thus, if possible, the longer the treatment period, the more benefit to the patient.
Nutritional status is important in enabling terminal stage patients to maintain their quality of life. Ayantunde et al. reported that low levels of serum albumin and total proteins are significant factors affecting survival [27]. In particular, sarcopenia is an established adverse prognostic factor in cancer patients [22]. In this study, pancreatic cancer patients, whose mGPS were in Group B and Group C at the first procedure, had long survival times, with maintenance of QOL. In addition, we found that two ovarian cancer patients, in mGPS Group D before their initial procedures were temporarily assigned to Group B and Group C after treatment. This suggests that a nutritional index, such as mGPS, may be useful as an indicator of the expected treatment effect and the possibility of continuation of treatment.
The outcomes of the 226 KM-CART procedures were almost the same as those in Matsusaki’s report [17]. Although this study does not assess the details of improvements of clinical findings, lower leg edema in many patients in our study improved promptly after KM-CART. Blood osmotic pressure is determined by the number of albumins per unit area, and albumin has the maximum osmotic pressure. It would be extremely important and useful to restore albumin concentrations in order to improve intravascular circulatory failure, by collecting albumin from the ascites fluid and infusing it intravenously. Therefore, KM-CART can be considered to be a very reasonable treatment for refractory ascites [17]. This clinical study suggests that most patients with refractory ascites are malnourished and have hypoalbuminemia, but repeated KM-CART therapy may improve general condition by supplementing albumin recovered from the massive ascites.
This study has several limitations. Firstly, this retrospective study was conducted only in three centers and was based on a small number of cases. A follow-up study is required to determine the survival time after treatment with prognostic surveys from various facilities. Secondly, some patients in this study were also receiving various cancer treatments in addition to KM-CART therapy. Of course, the availability of additional cancer treatment is such that there is a nutritional effect, and it is fully expected that the prognosis will be that much more favorable. It is necessary to consider the post-treatment course of patients with and without such additional treatments.
We conclude that KM-CART can improve rapidly the physical symptoms of patients with malignant ascites. Many malignant diseases with refractory ascites should be treated aggressively with multiple applications of the KM-CART procedure to achieve the good QOL and prognosis.