Impact of laparoscopic ultrasound during PIPAC directed treatment of unresectable peritoneal metastasis

Introduction

Peritoneal metastasis (PM) is often seen in the late stage of many solid tumors. The prognosis is poor and patients are faced with poor quality of life due to ascites, bowel obstruction and general fatigue. Systemic chemotherapy has a short and limited effect on PM, and pressurized intraperitoneal aerosol chemotherapy (PIPAC) was introduced as a local treatment option a decade ago 1], [2], [3], [4. PIPAC provides significant and measurable local effect on PM with small impact of patients’ quality of life 5], [6], [7], [8. PIPAC, which is normally provided in series of three procedures, is safe, well tolerated and may be repeated until disease progression [9]. However, PIPAC only treats PM and not extraperitoneal metastasis in the liver and/or retroperitoneum. Some patients with limited and stable extraperitoneal metastasis are receiving both systemic chemotherapy and PIPAC (bidirectional treatment), but more often extraperitoneal metastases are considered exclusion criteria to PIPAC [10].

Computed tomography (CT) scan, positron emission tomography-CT (PET-CT) and magnetic resonance imaging (MRI) are used to diagnose PM [11]. However, these imaging modalities have limitations regarding the diagnosis and extent of PM as well as evaluating treatment response 11], [12], [13. In addition, the assessment of small-volume extraperitoneal malignant disease which might exclude the patient from receiving PIPAC, may also be difficult. For the diagnosis of liver metastases, CT has shown a sensitivity of 75 % in patients with gastric cancer as primary tumor and 87 % for patients with liver metastases from colo-rectal cancer, whereas PET-CT showed a sensitivity for detecting liver metastases of 70 % in patients with gastric cancers and 96 % in patients with colo-rectal cancers [14, 15]. The sensitivity of MRI in detection of liver metastasis among patients with colo-rectal cancer is reported as 87 % in a per-patient based analysis, while being 89 % in a per-lesion based analysis [14, 16]. Test accuracy for CT and PET/CT in detecting para-aortic and pelvic lymph node metastases among patients with ovarian cancers has also been studied and shown sensitivities of 47 % and 81 %, respectively [17].

Laparoscopic ultrasound (LUS) combines laparoscopy and ultrasound providing detailed imaging of intraperitoneal structures including liver parenchyma and retroperitoneum in addition to the peritoneum. LUS can be used as a supplement to standard imaging procedures for staging patients with intraabdominal malignant diseases (Figure 1). It is easy and safe to perform, and it may add clinically significant information to the pretherapeutic staging procedures 18], [19], [20], [21.

Figure 1:

Left: the laparoscopic ultrasound (LUS) probe is inserted through the 12 mm trocar, and the camera through the 5 mm trocar. Right: set-up with the ultrasound screen to the left and the laparoscopic screen to the right.

In order to try to ensure that extraperitoneal cancer spread was not missed during both first and additional PIPAC procedures in patients with PM, we introduced LUS as part of the PIPAC procedure in 2016. Since LUS has not been included and evaluated in relation to the PIPAC procedure, we decided to study the potential clinical effect of LUS during the initial and subsequent PIPAC procedures in patients with PM from various primary tumors. The study rationale being that we would be able to detect extra-peritoneal metastasis not seen by conventional imaging, and by this avoid futile PIPACs in patients with already too widespread disseminated disease. Thus, the aim of this present study was to see whether LUS revealed findings otherwise not detected by the standard pretherapeutic evaluation and the potential clinical impact of such findings.

Materials and methods

Retrospective analysis of the findings at LUS performed in patients who were included in a large, prospective phase II trial evaluating the effect of PIPAC directed therapy in patients with PM (PIPAC-OPC2 trial). Details regarding this study have been published previously [6]. In short, patients with PM from abdominal cancers, a maximum of one extraperitoneal metastasis, and in performance status 0–1 were treated with PIPAC. Treatment was planned in series of three PIPACs. Pretherapeutic evaluation of patients was made by a contrast-enhanced CT scan of the chest and abdomen performed within one month prior to PIPAC 1. All patients had a follow-up CT scan two weeks after PIPAC 3, and the findings of this was discussed at the multidisciplinary tumor board conference regarding additional PIPAC treatment. The present study’s only exclusion criteria was non-access during PIPAC 1.

Results

The PIPAC-OPC2 study included 143 patients, from December 2016 to January 2022. Thirty-three of these received electrostatic precipitation PIPAC. Of the 143 patients, nine were excluded due to primary non-access to the abdominal cavity (Figure 2). Demographic data, primary tumor origin and previous treatments regarding the 134 patients included in the final analysis, are listed in Table 1.

Figure 2:

Patient flow from PIPAC 1 to PIPAC 3.

During PIPAC 1, LUS was performed in 112 of 134 (84 %) PIPAC procedures and LUS was complete in 83 of the procedures (75 %) (Table 2). The median time spent on LUS during PIPAC 1 was 5 min (range 1–14).

During PIPAC 2 and 3, LUS was performed in 59 of 104 (57 %) and 42 of 78 (54 %) procedures, respectively. LUS was complete in 39 (66 %) and 24 (57 %) of these, and the median time spent on LUS was 4 min (range 1–10).

In one procedure (0.5 %), the LUS probe caused injury of the splenic capsule, which was managed conservatively. The PIPAC treatment continued after 15 min of hemostasis, and the postoperative recovery was uneventful. No other intraoperative complications related to the LUS procedure were seen.

Discussion

No previous study has investigated the potential clinical impact of LUS in patients with PM scheduled for PIPAC. Our data showed that LUS could be safely performed during PIPAC, and that LUS detected additional liver lesions and/or retroperitoneal lymph nodes in 22 patients throughout PIPAC 1–3. However, only in one patient did these findings change the overall treatment strategy due to detection of multiple liver metastases prior to PIPAC 1.

LUS also found liver metastases in one patient during PIPAC 3, but these were already detected at laparoscopy. Thus, the supplement of LUS was not considered to change the overall treatment strategy.

LUS detected previously unseen pathological lymph nodes in retroperitoneum in 16 patients (12 %) throughout PIPAC 1–3. LUS gave rise to suspicion of liver metastases in four patients (3 %). None of the findings initiated further examinations or changed the overall treatment strategy because these findings were not considered relevant to alter treatment strategy according to the PIPAC-OPC2 protocol. However, if these findings would have changed the treatment strategy, the clinical impact of LUS would have been higher.

Similar results about LUS suspected liver metastases were observed in a randomized study on patients with colo-rectal cancer. This study found four patients where LUS suspected liver metastases, but it turned out to be benign liver lesions (14). None of the surgeons were blinded, and performance bias might had occurred. Thus, the study concluded that LUS during laparoscopic surgery for primary colorectal cancer could not be recommended.

In patients with gastric, pancreatic, and colo-rectal cancer scheduled for curative surgery, the addition of LUS changed the therapeutic strategy in 2 % [20, 22, 23]. This is in agreement with the present study, and because of this limited clinical impact, LUS is not considered as a routine part of pretherapeutic evaluations of patients with presumed curable cancers in the stomach, pancreas, or colon. Interestingly, previous studies of smaller study populations found that diagnostic laparoscopy in combination with LUS changed treatment strategy in up to 38 % of the patients [24, 25]. It is noteworthy that both studies are more than 20 years old, and that the technology regarding preoperative imaging like CT has improved since then. That might be one explanation why the clinical impact of LUS was reported that high. A recent systematic review about intraoperative ultrasound and LUS in patients with colorectal cancer also found that LUS detected 13 % additional liver metastases compared to contrast-enhanced CT [18]. This systematic review included few studies on LUS, and no meta-analysis was performed. Another systematic review included more studies regarding LUS, and found that LUS detected between 3 and 13 % additional patients with liver metastases compared to preoperative contrast enhanced CT [20].

One might speculate if the potential impact of LUS would be higher in patients with PM because extraperitoneal malignant disease is probably more likely in these patients compared to patients considered not to have PM. Thus, in a study on the localization of metastases in patients with colorectal cancer, 34 % of the patients with PM also had synchronous liver metastases [26]. Despite this high incidence of liver metastases in patients with PM, LUS had limited clinical impact in our study, which is probably because extraperitoneal metastatic disease had already been identified by CT, MRI, or PET/CT scan and the patient would therefore not be scheduled for PIPAC.

LUS was incomplete in about one third of the cases. This was mainly due to intraabdominal adhesions where access to all parts of the liver or retroperitoneum was not possible. There were no sign of any systematic selection bias towards more aggressive disease in these patients. Thus, the potential inclusion of these patients would not have altered the outcome of the study.

Routine LUS during PIPAC was not fully implemented until March 2018, which is an obvious limitation related to the retrospective study design.

This study only registered the number of patients with “positive” findings at LUS i.e., additional extraperitoneal metastatic disease, which would be a contraindication to PIPAC. Thus, our study did not correlate the findings at LUS with the findings at 14 days follow up CT after PIPAC 3. The sensitivity of LUS can therefore not be calculated, but this was not the aim of the study.

The present study showed that limited time was spent on LUS, and this might be another explanation why LUS had a limited clinical impact. A similar time consumption for LUS was observed during a study on robotic-assisted surgery for primary colorectal cancer [27], and no liver metastasis was detected by LUS in this study either.

Conclusions

Laparoscopic ultrasound may be safely performed, but it has limited clinical impact and cannot be recommended as a routine procedure in patients scheduled for PIPAC.