Implementation and evaluation of Pressurized IntraThoracic Aerosol Chemotherapy (PITAC) for the treatment of patients with malignant pleural effusion: study protocol for the Danish phase-I PITAC-OPC5 study

Pressurized IntraThoracic Aerosol Chemotherapy (PITAC)

The first treatment with PITAC for MPE was performed in Germany in 2012. The concept of PITAC is based on experience from Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) [3]. PIPAC is feasible and safe in the treatment of peritoneal metastasis (PM) 12], [13], [14. In addition, PIPAC directed therapy is repeatable with 4–6 week intervals, and the patients may be discharged at postoperative day 0–1 without significant toxicity [13]. The intraperitoneal nebulization of chemotherapy under high pressure increases distribution and penetration of cytotoxic agents to the peritoneum, which may decrease fluid production 15], [16], [17. Theoretically, it should be possible to achieve the same effects in the intrapleural space when using PITAC, but whether this is feasible, safe and able to provide local response is uncertain [18].

To date, data on 21 patients treated with 38 PITACs have been published worldwide, and at Odense PIPAC Center (OPC), five patients have been treated with 11 PITAC procedures (two non-access). The primary indications were MPE and/or pleural metastasis (PLM) due to malignant mesothelioma, gastric cancer, ovarian cancer, rectal cancer, or breast cancer. A recent review by Hansen et al. suggests that PITAC is feasible, but more prospective data are needed to evaluate patient and personnel safety, and potential local effect [3, 15, 19], [20], [21], [22.

Aim

This study aims to evaluate patient and personnel safety during the implementation of PITAC in Denmark.

Recruitment process

Patients with MPE from any primary tumour visible with bedside ultrasound and drained at least one time are eligible for inclusion (Table 1). Patients with MPE who are eligible for PITAC are identified during the multidisciplinary tumour (MDT) conference. Bilateral MPE is acceptable, but the most affected side at the time of inclusion will be treated throughout this study. In case of symptomatic MPE on the contralateral side, the patient may be included as a new patient after the last follow-up.

All personnel will be informed about the procedure both orally and in writing, including occupational health aspects. Only those who volunteer will take part in the PITAC procedure.

Patients will be excluded from the study if (1) requested by the patient, (2) access to the pleural cavity is not possible due to adhesions or other technical aspects, and/or (3) decline in general health resulting in Eastern Cooperative Oncology Group (ECOG) performance status higher than 2. Following events are considered sufficient reasons for discontinuing a subject from the study (1) withdrawal of consent, (2) death, (3) loss to follow up and/or (4) severe AE or surgical complications. The following information will be recorded for patients who have been excluded from the study: Survival, amount and frequency of MPE drainages and illness specific variables (e.g. CT-scan results).

Study intervention and procedures

The patients will be scheduled for clinical assessment in the PITAC outpatient clinic including bedside ultrasound of the pleural cavity and information about the study. Included patients will be scheduled for a maximum of three PITAC procedures and minimum of two PITAC procedures at four-week intervals (Figure 1).

Figure 1:

Study flow chart ^aif visible PLM; ^bif less than 150 mL of MPE present. AEs: adverse events; FEV1: forced expired volume in the first second; MDT: multidisciplinary tumour; MPE: malignant pleural effusion; PITAC: pressurized intrathoracic aerosol chemotherapy; PLF: pleural lavage fluid; PLM: pleural metastasis; SAT: saturation; TRGS: thoracic regression grading score; VAS: visual analogue score.

Patients may have a pleurocentesis up to 14 days before the planned PITAC directed treatment. In case the patients require drainage of MPE between PITACs, this is possible as an outpatient procedure and registered to ensure that the accumulative amount of MPE from the first PITAC directed treatment can be calculated. Patients may receive treatment with systemic chemotherapy or immunotherapy up to 14 days before PITAC treatment, and antihormonal, tyrosine kinase inhibitor (TKI) and/or steroid treatment may be given continuously. The wash out period from PITAC to systemic chemotherapy or immunotherapy is one week.

Preoperative procedure

Baseline blood samples are taken two days before each PITAC. Prophylactic low molecular weight heparin is given before and after the procedure. Oxygen saturation (SAT), forced expired volume in the first second (FEV1), and visual analogue scale (VAS) pain and breathlessness will be measured before each PITAC.

PITAC

The procedure will be performed in an operating room (OR) with a modern direct flow ventilation system that complies with ISO norm class 5. The chemotherapy is evacuated through a closed air waste system at the end of the procedure. The operating personnel will wear protective barrier garments, double layered gloves and glasses throughout the entire procedure.

Prior to general anaesthesia a bedside ultrasound is performed in the OR to ensure the presence of MPE. General anaesthesia and prophylactic antibiotics are administered and the patient is intubated in the supine position and flipped into the prone position. In the prone position ultrasonography is repeated to ensure optimal access to the pleural cavity, and the first entry point is marked with a pen before surgical dressing is applied. Under video-assisted thoracoscopy two trocars (5 and 12 mm) are placed and exclusion of the ipsilateral lung is confirmed when relevant. MPE is removed (and submitted for cytology) and measured and the extent of visible PLM is assessed macroscopically using the PLM-score (Figure 2). If no or only small amounts of MPE are present, pleural lavage is performed and PLF is submitted for cytology. The PLM-score is a modification of the known PCI-score. The parietal pleura is divided into four quadrants and assessed on a scale from 0-3 depending on the size of visible tumour lesions (Figure 2). Quadrant biopsies are taken from visible PLM on the parietal pleura for histological assessment.

Figure 2:

Macroscopic evaluation of visible pleural metastasis (PLM) (PLM-score).

The CE-certified nebulizer is inserted pointing away from lung tissue. A safety checklist is followed to ensure maximum safety for both patients and personnel.

PITAC is performed at an intrapleural pressure of 12 mmHg using normothermic carbon dioxide (CO₂). The injector is controlled from outside the OR and the settings will be a maximum of 300 pound-force per square inch (Psi) with a flow-rate of 0.5–1.8 mL/s as defined for the used nebulizer. Diffusion time is 30 min. The injector and patient observation monitors are visible through a window.

The chemotherapy filled air in the pleural cavity is removed through a closed air waste system. Sufficient re-ventilation of the ipsilateral lung is ensured when relevant/possible. The two trocar access points are closed with suture in both the fascia and skin. Chest tubes are not used routinely. Local anaesthetics are applied at the trocar sites.

Histology

Quadrant parietal pleural biopsies will be collected, if possible. The biopsies will be fixed in formalin and embedded in paraffin followed by step-section at three levels, and stained with haematoxylin and eosin (H&E), followed by a section immunostained for epithelial cell adhesion molecule (Ep-CAM (or Hector Battifora and MEsothelioma 1, HBME1, in case of malignant mesothelioma)), and a final series of three step sections stained with H&E [24, 25]. Additional immunostains will be used at the discretion of the pathologist. Histological response to treatment will be assessed in each biopsy according to the proposed TRGS, a modification of the Peritoneal Regression Grading Score (PRGS) [23, 26, 27]. TRGS-1 equals complete histological response, and is defined as the absence of residual cancer and harbours only regressive histological features. TRGS-2 is defined as a biopsy where regressive changes are predominant over cancer cells (major response). TRGS-3 is a biopsy where cancer cells are predominant but regressive changes are present (minor response), and TRGS-4 is a biopsy with cancer but without histological features of regression (no response).

Cytology

A maximum of 250 mL MPE or PLF pr. PITAC procedure will be collected and analysed. Pleural lavage is performed in cases with no or less than 200 mL of MPE present in the pleural space. The fluid will be centrifuged, and smears of the sediment analysed by conventional cytology (Papanicolaou and May-Giemsa Grünwald staining). Leftovers of the sediment will be embedded in paraffin wax of which one section will be stained with H&E. If necessary, further sections will as part of the standard routine be cut for immunocytochemical analyses for markers such as calretinin, thyroid transcription factor 1 (TTF1), carcinoembryonic antigen (CEA), cytokeratin (CK) 7, CK20, synaptophysin, cluster of differentiation (CD) 56 or P40. The cytological specimens will be categorized as one of the following: Malignant cells, cells suspicious of malignancy, atypical cells, no malignant cells, or ”inconclusive” (for technical reasons).

Chemotherapy

Depending on the primary tumour and previous/bidirectional systemic chemotherapy, the following regimes will be applied: Patients with MPE from non-colorectal or -appendix cancer will be treated with cisplatin (10.5 mg/m² body surface in 150 mL saline) and doxorubicin (2.1 mg/m² body surface in 50 mL saline). Patients with MPE from colorectal or appendiceal cancer will receive oxaliplatin (92 mg/m² body surface in 150 mL dextrose).

Cisplatin, oxaliplatin and doxorubicin are standard, commercially available cytostatic drugs in oncologic treatment with alkylating and topoisomerase inhibitor effect, respectively. The most common side effects of administering Cisplatin and oxaliplatin intravenously are: Fever, nausea, diarrhoea, kidney failure, pancytopenia and ototoxicity. With regard to doxorubicin, it is furthermore: Debilitation, shivers, infections, skin eruptions, electrocardiogram changes, thrombophlebitis and deep venous thrombosis. Based on the literature and experience gained from more than 1000 PIPAC procedures at OPC, PIPAC (i.e. local treatment) with cisplatin, oxaliplatin and doxorubicin is well tolerated with only a minimal of nausea, vomiting and transient abdominal pain. The experience with PITAC directed therapy is limited, but the above mentioned systemic adverse events from cisplatin, oxaliplatin and doxorubicin are not expected with PITAC directed treatment. The use of cisplatin 10.5 mg/m², oxaliplatin 92 mg/m² and doxorubicin 2.1 mg/m² are based on dose finding studies, stating that the above-mentioned dosages are safe for intraperitoneal use [28, 29].

Postoperative procedure

The patient is monitored for a minimum of one day. A chest X-ray is performed if the patient shows signs of respiratory distress to consider the indication for a chest tube. SAT, FEV1, and reactions/complications will be registered before discharge of the patient.

Thirty days after each PITAC directed therapy the patient will attend an outpatient appointment for bedside ultrasound and registration of postoperative reactions/complications. The 30 day follow-up must be collected prior to the next PITAC directed treatment.

The last follow-up including a CT scheduled three months after the last PITAC. Furthermore, patients will be evaluated in the outpatient clinic including bedside ultrasound, SAT and FEV1.

Occupational health safety aspects

Summarized, there are three barriers between personnel and the chemotherapy: The closed intrathoracic cavity, the modern OR ventilation with a direct air-flow system, and the OR walls. Possible air-leakage is controlled by allowing a maximum of CO₂ flow of 0.1–0.2 L/min corresponding to the intraperitoneal body resorption of CO₂. The intrapleural air saturated with chemotherapy is evacuated through a series of filters into a closed ventilation system. Special chemotherapy waste bins are available for all single-use equipment and the trocar sites, removal and disposal of dressings and syringes are performed by the surgeon alone.

From previous PIPAC knowledge, is has been demonstrated that the procedure is safe in terms of the personnel safety and fulfils the European Community working space law. It is theorized that these data can be directly transferred to the PITAC procedure [12, 14]. Danish Technological Institute will analyse the toxicological workspace for traces of platinum to validate the occupational health safety during PITAC.

In the present study, blood samples from the surgeons will be analysed for traces of platinum immediately after the first procedure and again after the 10th procedure. The surgeons also perform weekly PIPAC procedures. Previous tests for platinum in the surgeońs blood after PIPAC were negative, why we expect only negative results [12].

Study design

This is a non-randomized, non-blinded, prospective, single-center phase-I study designed to treat patients with MPE from any primary tumour with PITAC.

Sample size

There are no data to support the estimated number of patients needed for this phase-I study. The non-access rate, based on previous experience, is estimated to 20 %. This study will include consecutive MPE patients until 20 patients have completed at least two PITAC procedures. Interim analyses will be performed in order to monitor patient safety.

Ethical declarations

The study will be conducted in compliance with the protocol, principles of good clinical practice (ICH-GCP), Regulation (EU) No 536/2014, and in accordance with the ethical principles put forward in the second Declaration of Helsinki. The study is GCP monitored and has been approved by the Danish Medicines Agency and Ethical Committee (EU CT number 2023-503297-20-00). Oral and written consent from patients is mandatory and collected before any study-related procedures are performed.

Statistics

Demographic data will be presented with range and median where appropriate.

Hypothesis

Based on OPC´s experience with PIPAC and preliminary data from previously performed PITAC procedures, we expect that this study will show that PITAC is both feasible and safe for patients and the involved health care personnel.