PIPAC : A novel drug delivery system

Dr Aditi Bhatt, Consultant, Surgical Oncology, Fortis Hospitals, Bengaluru, gives an insight about the advantages of pressurised intraperitoneal aerosol chemotherapy (PIPAC), a new method of intraperitoneal drug delivery

‘Peritoneal metastases’ is the term now used for peritoneal cancer spread instead of peritoneal carcinomatosis since it represents a more treatable condition. Cytoreductive surgery (CRS) is an aggressive surgery that involves removal of all the peritoneal tumour combined with hyperthermic intraperitoneal chemotherapy has the potential cure certain patients with peritoneal metastases and prolong the survival significantly in some others.[1] However, only selected patients are candidates for this treatment and recurrence after treatment is common. [2, 3, 4, 5]

New therapeutic strategies are needed to further improve the results of CRS and Hyperthermic intraperitoneal chemotherapy (HIPEC) and to treat patients who are not candidates for the procedure. Patients with peritoneal metastases have a shortened survival as compared to other metastatic sites such as liver metastases. Patients are more prone to develop debilitating symptoms due to ascites and bowel obstruction which are common in these patients.

Pressurised intraperitoneal aerosol chemotherapy (PIPAC)

Pressurised intraperitoneal chemotherapy, is a new method of intraperitoneal drug delivery. Aerosolised chemotherapy is sprayed in to the peritoneal cavity in the setting of a carbon dioxide pneumoperitoneum- what is known as ‘therapeutic capnoperitoneum’. The technique which was developed by Prof Marc Reymond from Germany, has several advantages over other methods of intraperitoneal chemotherapy. [6]

Instead of distributing the chemotherapeutic substance in the form of a liquid solution into the abdomen, the drug is nebulised with carbon dioxide to create an aerosol. Aerosols consist of two phases: a liquid phase (droplets) and a gaseous phase. According to physical laws, if the size of droplets is small, aerosols behave like a gas. Because a gas distributes homogeneously within a closed space, the drug concentration is expected to be equal within the whole abdominal cavity. Parameters, such as composition, temperature, pressure, and humidity, of the gas are well defined. [6]

As a second difference between PIPAC versus intraperitoneal, the aerosol is applied within the pressurised abdominal cavity so that a pressure gradient is artificially generated between the intraperitoneal and the extra-peritoneal space. As a direct consequence, diffusion of liquids and substances through the peritoneum is enhanced. Moreover, the applied intraperitoneal pressure compensates for the interstitial fluid pressure, which impairs drug uptake into solid tumours and contributes to chemotherapy resistance. [7]

Technique of PIPAC

The technique of PIPAC first described by Marc Raymond and collaborators is as follows. A capnoperitoneum of 12mmHg at 37 degrees celsius is created and two balloon trocars are applied.[8] A nebuliser is connected to a high-pressure injector and inserted into the abdomen through a trocar. A pressurised aerosol containing the chemotherapeutic drug is administered. The system is kept in this steady-state for 30 min (application time) and subsequently the aerosol is removed through a closed system. The chemotherapeutic drugs used depend on the primary disease. The procedure is well tolerated and patients are usually discharged the following day. Repeated applications are performed at six to eight week intervals. Before the nebulised chemotherapy is administered, peritoneal biopsies are performed and the peritoneal cancer index (disease extent is evaluated). This provides both a subjective and objective assessment of the response to chemotherapy. [8]

Figure 1: Pressurised intraperitoneal aerosol chemotherapy. A microinjection pump is used to aerosolise the chemotherapy solution that is administered intraperitoneally in the setting of a carbon dioxide pneumoperitoneum maintaining an intra-abdominal pressure of 12mm of Hg for 30 minutes.

Figure 2: Aerosolised chemotherapy being sprayed in the peritoneal cavity

Current clinical evidence

PIPAC is being used in the palliative setting. It is offered to patients who have progressive peritoneal disease on one or more lines of systemic chemotherapy, patients who do not want systemic chemotherapy and those who have chemotherapy refractory ascites. It has been used in patients with colorectal, ovarian, gastric and appendiceal cancers and other rare peritoneal tumours.[9, 10, 11, 12,13, 14,15]

Most of the published reports are case reports, prospective and retrospective case series and a phase II trial. A response rate of 60-70 per cent has been reported. PIPAC has shown good results in two difficult clinical situations- platinum resistant ovarian cancer and gastric cancer with metachronous peritoneal metastases. [9,14]
The use of PIPAC results in disease control, symptom control and an improvement in the quality of life. In some patients >10 applications have been performed resulting in a prolonged disease control. Complete remission has been seen in a small percentage of patients.

In some patients who are not candidates for CRS and HIPEC upfront, PIPAC could be used as neoadjuvant therapy to reduce the tumour burden. Reymond et al reported their institutional experience of 406 patients who had undergone 961 PIPAC procedures. 12 patients were able to undergo a subsequent CRS and HIPEC. [15]

Current Indications

PIPAC is used in for ovarian and colorectal cancer patients with peritoneal metastases who have progressed on two or more lines of systemic chemotherapy; patients with gastric peritoneal metastases who have progressed on one line of chemotherapy and patients who have chemotherapy resistant ascites due to any primary tumour. It can be used for other rare peritoneal tumours where cytoreductive surgery and HIPEC is not feasible.

Side effects

PIPAC is generally a well-tolerated procedure and most of the patients are discharged the next day. The toxicity of chemotherapy is low due to 1/10 the dose of systemic chemotherapy used for the procedure. [16] A transient chemical peritonitis following the procedure leads to a rise in the C-reactive protein. There may be a transient alteration in the hepatic and renal functions. [16].
Some complications that can arise are trocar site hernias, bowel access lesions, subcutaneous toxic emphysema, small bowel obstruction, port site metastasis, therapy resistant ascites. At least some of these, like bowel access lesions, subcutaneous toxic emphysema and trocar site hernias can be avoided by the use of proper surgical technique.

Advantages and limitations

PIPAC has pharmacokinetic benefits like increased tumour drug penetration using 1/10 the dose used in HIPEC with limited systemic absorption. [17] There is more homogenous drug distribution over the peritoneal surfaces.[9] PIPAC has limitations as well. The current protocol does not allow it to be performed with CRS. Reported toxicity is more when is it performed immediately after CRS. [17] The technical feasibility and the efficacy of PIPAC are largely dependent on the degree of entero-enteral and entero-parietal adhesions. Reported rates of non-access are 5-17 per cent. Moreover, only exposed peritoneal surfaces that can be reached by the aerosol can be treated with PIPAC. At present, there is no method of stratifying patients according to adhesions, however, it may be difficult or impossible to perform PIPAC in patients who have had CRS and or HIPEC before.[16]

The advantages, disadvantages and contra-indications are summarised below

Advantages

• High tumour drug concentration using 1/10 of systemic dose
• Easy to perform-no learning curve
• Limited major morbidity
• Possibility of multiple applications
• Can be combined with systemic chemotherapy
• Evaluation of response to therapy possible
• No risk of port site metastases
• Minimal adhesion formation
• Subsequent CRS and HIPEC is possible

Disadvantages

• Cannot be combined with CRS
• Prior adhesions limit its application and efficacy
• Certain areas like the lesser sac remain untreated
• Contra-indications
• Laparoscopic non-access
• Malignant bowel obstruction
• Debilitating ascites with malnutrition

Future role

The current use of PIPAC is only in the palliative setting. Following the favourable reports of preclinical and clinical studies, several trials are currently underway to further evaluate the role of PIPAC. These trials are mainly phase II trials evaluating the safety and efficacy of the procedure (NCT02735928, NCT0185425, NCT02320448). A dose escalation trial (NCT02475772) is also currently underway for platinum resistant ovarian cancer.

The PIPAC EstoK 01 is a Phase II trial designed to evaluate the effect of PIPAC with oxaliplatin combined with systemic chemotherapy in patients with gastric PM that are not candidates for CRS and HIPEC.

Electrostatic PIPAC

Electrostatic PIPAC (ePIPAC), is based on the hypothesis that electrostatic charging the aerosol particles may further enhance the pharmacologic properties of PIPAC. [108]

In an in vivo porcine model ePIPAC allowed a more efficient drug uptake as a result of which a lowering of the drug dose and a shorter application time was possible. The tumour drug concentration with ePIPAC was ten times the concentration obtained with PIPAC.

Summary

PIPAC overcomes certain limitations of other methods of intraperitoneal chemotherapy. PIPAC is used in the palliative setting and has shown good response rates in patients who are progressive on chemotherapy with minimal side effects. It can currently be used for these patients to control the disease and/or symptoms and thus improve the quality of life. The results of clinical trials will further define its role in other situations.

References

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Goéré D1, Souadka A, Faron M, Cloutier AS, Viana B, Honoré C, Dumont F, Elias D. Extent of colorectal peritoneal carcinomatosis: attempt to define a threshold above which HIPEC does not offer survival benefit: a comparative study. Ann Surg Oncol. 2015 Sep;22(9):2958-64. doi: 10.1245/s10434-015-4387-5. Epub 2015 Jan 29

Glehen O, Gilly FN, Arvieux C, Cotte E, Boutitie F, Mansvelt B, Bereder JM, Lorimier G, Quenet F, Elias D. Peritoneal carcinomatosis from gastric cancer: a multi-institutional study of 159 patients treated by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy. Ann Surg Oncol 2010; 17: 2370-2377 [PMID: 20336386 DOI: 10.1245/s10434-010-1039-7]

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Konigsrainer I, Horvath P, Struller F, Forkl V, Konigsrainer A and Beckert S: Risk factors for recurrence following complete cytoreductive surgery and HIPEC in colorectal cancer-derived peritoneal surface malignancies. Langenbecks Arch Surg 398(5): 745-749, 2013.

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Solass W, Kerb R, Mürdter T, et al. Intraperitoneal Chemotherapy of Peritoneal Carcinomatosis Using Pressurized Aerosol as an Alternative to Liquid Solution: First Evidence for Efficacy. Annals of Surgical Oncology. 2014;21(2):553-559. doi:10.1245/s10434-013-3213-1.

Tempfer CB, Celik I, Solass W, Buerkle B, Pabst U, Zieren J, et al. Activity of pressurized intraperitoneal aerosol chemotherapy (PIPAC) with cisplatin and doxorubicin in women with recurrent, platinum-resistant ovarian cancer: preliminary clinical experience. Gynecol Oncol 2014;132(2):307–11

Tempfer CB, Solass W, Buerkle B, Reymond MA. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) with cisplatin and doxorubicin in a woman with pseudomyxoma peritonei: a case report. Gynecol Oncol Rep 2014;10:32–5.

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Kakchekeeva T, Demtröder C, Herath NI, et al. In Vivo Feasibility of Electrostatic Precipitation as an Adjunct to Pressurized Intraperitoneal Aerosol Chemotherapy (ePIPAC). Annals of Surgical Oncology. 2016;23(Suppl 5):592-598. doi:10.1245/s10434-016-5108-4.