Review on treatment of pleural metastasis and malignant pleural effusion with Pressurized IntraThoracic Aerosol Chemotherapy (PITAC)

Introduction

Malignant pleural effusion (MPE) is caused by the spread of malignant cells to the pleural cavity, with increase in fluid production and reduced fluid absorption [1], [2], [3]. It occurs most frequently in malignant mesothelioma, lymphoma or lung, breast, ovarian, and gastrointestinal (GI) cancers, and may itself promote tumor growth and chemotherapy resistance [4], [5], [6], [7]. Presence of MPE is related to a reduced life-expectancy, ranging from three to 12 months depending on primary tumor [2, 5]. Patients present with progressive shortness of breath, weight loss, cough, chest pain, and a reduced quality of life [1, 7, 8]. MPE is found in 15 % of all cancer patients, and accounts for 20 % of the total number of registered patients with pleural effusions in Denmark [8], [9], [10].

Current treatment options include ultrasound-guided pleurocentesis, indwelling pleural catheters (IPC), and chemical pleurodesis [3, 8]. Complications related to these procedures include chest pain, pneumonia or empyema, pneumothorax, catheter related infections, and tract seeding of malignant cells [3, 5, 8, 11]. Hyperthermic intrathoracic chemotherapy (HITHOC) with or without cytoreductive surgery (CRS) has also been used to treat MPE [12, 13]. It can increase tumor cell death, as heat increases the permeability, cytotoxicity, and cytotoxic drug penetration [13]. Still, a systematic review of HITHOC for MPE showed that symptomatic control was achieved in 59–88 % of the patients which was inferior to other forms of surgical pleurodesis [12]. Surgical procedures, such as pleurectomy and pleuro-peritoneal shunting, have been abandoned due to high complication rates and morbidity [3]. In general, the available treatments focus on symptomatic relief, but with suboptimal results, since more than 90 % of the patients require repeated interventions and hospitalization [3, 10, 14].

The lack of effective treatments for recurrent MPE is a significant clinical problem – especially in long term survivors who experience drawbacks of repeated pleurocentesis or complications to IPC and pleurodesis. The ideal treatment of MPE must provide a substantial reduction in the need for fluid evacuation based on a limited number of minimal invasive interventions, but this has not been possible so far.

Materials and methods

A literature search was conducted in PubMed ending October 31^st, 2023. Publications in English that described PITAC directed therapy in humans with MPE and/or pleural metastasis (PLM) were included. No publication status was imposed. The studies were assessed by manual review of the abstracts followed by a full-text review. A backward citation search was done on included studies to ensure inclusion of all relevant studies. Additionally, ClinicalTrials.gov (October 31^st, 2023) was screened for ongoing or completed PITAC trials [22].

To assess feasibility, patient safety, and response to PITAC directed therapy, the following outcomes were reviewed: patient characteristics, indications, prior cancer directed therapy, technical aspects of the PITAC procedure including occupational health, pleural biopsies, pleural cytology, intra- and postoperative complications, patient reported outcomes (PRO), length of stay (LOS), mortality, and number of PITACs.

Results

The literature search yielded 15 potential articles. After review of the abstracts, 12 of these did not describe data on PITAC directed therapy. The remaining three studies were included [23], [24], [25], and a backward citation search led to the inclusion of two additional studies [4, 26]. The included studies were retrospective case series with 10 or less patients. No planned or ongoing PITAC trials were found on ClinicalTrials.gov [22].

A total of 38 PITAC directed therapies were performed in 21 patients with MPE and/or PLM of which 10 patients received two or more PITACs (Table 1).

Discussion

Treatment of MPE (and PLM) is difficult for several reasons, and no ideal treatment strategy is available. The optimal treatment should relieve symptoms, be minimal invasive, have a low risk of complications, a minimum LOS, and (re-)interventions [3]. Based on the experience from PIPAC directed therapy in patients with PM, PITAC has been suggested for use in patients with MPE and/or PLM.

This review identified five minor case series on PITAC directed therapy with a total of 38 PITAC procedures in 21 patients [4, 23], [24], [25], [26]. The studies were retrospective and heterogenous in reporting details related to both patient characteristics, indications, procedures, treatment response, and outcomes. Some studies merged data from both PIPAC and PITAC directed therapy, making it difficult to specifically evaluate the PITAC procedure and related outcomes.

Primary tumors included malignant mesothelioma, gastric- and ovarian cancer, and pseudomyxoma peritoneii. One study performed PITAC solely on PLM, three studies solely on clinically relevant MPE and one study to eliminate microscopic residual disease. It is difficult to evaluate whether PITAC directed therapy could be a treatment option for both PLM and MPE. Repeated PITAC procedures conveyed a positive response in some patients, such as reduced MPE, but the local efficacy of PITAC remains uncertain. No data evaluating the potential clinical and prognostic impact of PITAC induced conversion from malignant to benign pleural cytology were available.

Due to the many limitations of the presented data, it is impossible to estimate whether PITAC may be an alternative to the traditional treatment of MPE. The rate of complications from repeated ultrasound-guided pleurocentesis depends on the number of performed procedures, as the risk accumulates over time due to increased inflammation and loculation [3]. Similar, chemical pleurodesis with talcum causes a severe inflammatory reaction with cough, pain, and fever [3]. Due to the limited PITAC follow up data, similar negative long-term outcomes (e.g., chronic inflammation, loculation, fistulas, etc.) were impossible to evaluate.

Another significant difference between some of the current treatment options and PITAC is the need for general anesthesia. This may entail an increased risk for patients already respiratory affected. Furthermore, the application of a double-lumen endotracheal tube – when or if necessary, requires specialized anesthesiologists.

Despite the focus on occupational health safety issues in relation to PIPAC directed therapy, such data were lacking in the present PITAC studies [28, 29]. The procedure was performed with different setups and in some centers without a dedicated PITAC safety checklist [4, 24, 25]. Such a checklist should be based on the experience from future phase I studies, and should be linked to a standard operating procedure for PITAC – including suggestions for postoperative observation and monitoring [30].

This review is limited by the inclusion of only five small retrospective case series. Data on patient selection, previous treatment, indications, technical aspects of the PITAC procedure, intra- and postoperative complications, response assessments, clinically relevant outcomes, and follow-up are poorly defined and data from serial procedures are lacking. To evaluate the treatment effect of PITAC on either MPE or PLM, future studies may need to assess each entity separately. However, since patients can have MPE and PLM synchronously, treatment response may be investigated by monitoring both fluid reduction, histology, and cytology.

Finally, since patients with MPE and PLM have a poor prognosis, treatment evaluation must include patient reported outcomes to investigate whether an invasive procedure like PITAC is justified in these patients.

When a novel surgical intervention is to be implemented and standardized, the IDEAL framework provides recommendations regarding design, development, and reporting. The implementation should be done in the following stages – idea, development, exploration, assessment, and long-term studies [16]. The included studies suggest that the PITAC procedure is still at the idea stage (phase 1) and possibly moving to the development stage (phase 2a). Some of the presented studies have concluded that PITAC directed therapy is safe, however, well designed and larger prospective phase I trials are needed before any firm safety conclusions can be made, and before moving on to the next level of evidence.

Conclusions

PITAC is on the verge of entering phase 2a of the IDEAL framework, but standard operating procedures, response assessment, safety issues and monitoring strategies are lacking. Prospective data focusing on feasibility, safety, and efficacy are needed, and this will require strict definitions regarding patient selection, PITAC procedure, perioperative patient handling, response evaluation, and outcome assessment.