To our knowledge, this is the first report of successful application of chemotherapy as a pressurized aerosol within the abdomen of human patients. It has been predicted that innovative concepts overcoming pharmacologic limitations of IPC could improve, perhaps dramatically, its efficacy.5 A superior dose–response ratio after PIPAC could be expected from preclinical data. In the human patient, plasma concentration-time profile analysis now confirms such superior ratio between dose, systemic, and local drug concentration: PIPAC required only 1/10 of the doxorubicin dose to achieve higher tumor concentrations (0.03–4.1 μmol/g) as reported for HIPEC (0.02 μmol/g).15 In contrast, systemic availability of doxorubicin after PIPAC and HIPEC were equal as indicated by the approximately ten times lower maximal plasma concentration after PIPAC.
We and others have reported that increasing intraperitoneal pressure enhanced particularly the uptake of drugs into the tumor, resulting in a higher local disposition.9,10,15,16 After PIPAC, doxorubicin was not only detected in significant concentrations in PC nodules, but nuclear staining was demonstrated throughout the peritoneum, up to deeply into the retroperitoneal fatty tissue. Another explanation for superior local disposition could be the high drug concentration in the aerosol. Although used in only 1/10 of the total dose, doxorubicin concentration in the aerosol (52 μM) is three times higher as in the intraperitoneal fluid usually used in HIPEC (18 μM) without impairing tolerability, which was reported after applying higher concentrations of IPC.15,17
Tumor response was observed in all three cases after PIPAC, as a consequence of the well-documented antitumor activity of doxorubicin and cisplatin and the superior local disposition. However, we were surprised by the extent of macroscopic and microscopic response in these multidrug-resistant tumors. We documented a complete remission of PC in two patients, which was indeed unexpected.
At this stage, it would be clearly premature to claim that combined PIPAC with cisplatin and doxorubicin improves survival in advanced PC. However, in our three patients with multiresistant tumors, low performance index, and very limited life expectancy, we observe a mean survival of more than 288 days. Remarkably, 567 days after her first PIPAC patient 3 is still alive.
In sharp contrast to HIPEC, PIPAC was very well tolerated and the only severe adverse effect observed was a bowel perforation after CRS (Table 1). Otherwise, postoperative courses were uneventful, with early hospital discharge.
PIPAC might create synergies with SC. Liver and renal tests showed neither acute nor cumulative toxicity after PIPAC, which appears reasonable bearing in mind the 90 % dose reduction compared with conventional SC.19 Moreover, PIPAC permits repeated cycles of IPC and therefore might allow effective regimen combining SC and PIPAC. Importantly, repeated laparoscopy enables objective staging, assessment of therapeutic response, and adaptation of further therapy accordingly, which was barely possible until now. Finally, considering that all three patients were in poor physical condition with a low performance index, PIPAC might allow therapy in polymorbid patients—when SC is contraindicated.
We observed tumor regression even in platin-resistant tumors, after application of cisplatin and doxorubicin. This is not surprising since drug effect is usually dose-dependent. PIPAC might become an alternative therapy for platin-resistant tumors, in particular in women with ovarian cancer where tumor progression is diagnosed after first-line therapy with carboplatin–Taxol. Repeated intraoperative analysis of the environmental air showed that PIPAC is safe for staff and meets the requirements of the German working safety regulations.12