DOI: 10.31038/IMCI.2019215

Abstract

In-111-Octreotide infusion, via intrahepatic catheterization is well established technique in our Institution in hepatocellular carcinoma and neuroendocrine tumors treatment. In order to facilitate repetitive infusions of our patients, a method of implanted ports use, gave a simpler therapeutic way but also improved therapy results. Our aim is to show that radiopharmaceutical fluid flow through implanted port is rich; the absorbed dose in the tumor increased for best therapy results.

Surgically implanted ports have been used in repetitive intra-arterial In-111 radiolabeled Octreotide infusions for 22 patients with hepatocellular carcinoma and similarly 18 patients with neuroendocrine tumors in a continuous base. A percutaneous implantation procedure facilitates safe and less invasive radiopharmaceutical infusions for the treatment. We have focused on the interventional techniques for percutaneous implantation of a vascular access device, consisting of an implantable port, to perform In-111 Octreotide infusions. Hepatic arterial infusion radiotherapy employs a hepatic artery catheter as a conduit to achieve a high concentration of radiolabeled agent to liver tumors. It is performed using less-invasive percutaneous image guided procedures. Various techniques were used to ensure high concentration of radiopharmaceutical in liver tumors, as there are many anatomical hepatic arterial variations and complicated blood flow patterns. These techniques are composed of arterial redistribution by embolization, percutaneous catheter placement, evaluation and management of flow patterns that reflect In-111 Octreotide distribution.

Using fluid flow theory, we describe blood flow alterations that could be performed to obtain selective radiopharmaceutical distribution to the target area and avoid side effects caused by the accumulation of the radiolabeled agent into non tumor areas. By steady, laminar and disturbed flow equations, the rich distribution of our agent in the scintigraphy imaging of the tumor, by the implanted ports technique, can be explained.

The factors affecting hepatic arterial flow in tumor feeding artery were analyzed. The patency rate of the hepatic artery was significantly higher in patients with catheter placement using fixed port method than those undergo fully interventional catheterization. A ratio of 5: 1 to 3: 1 flow increase was calculated through poiseuille flow and Reynolds number for circular pipe.

We consider that in continuous therapy, it is important to use the simplest fixed port method for percutaneous catheter placement instead of interventional catheterization, in order to increase absorbed dose into tumor for best response of radionuclide therapy.

Keywords

Blood flow, Laminar flow, Poiseuille law, Implanted Port, Arterial infusion, In-111-Octreotide Therapy

Blood Flow in Arteries

Blood flow in arteries principally is an unsteady phenomenon. Normal arterial flow is laminar but secondary flows are generated at curves and branches. Arteries may change with the varying hemodynamic conditions. Unusual hemodynamic conditions could create an abnormal biological response. Velocity profile skewing creates pockets, in which the direction of the wall shear stress oscillates.

The study of arterial blood flow will lead to the prediction of individual hemodynamic flows in any patient, the development of diagnostic tools to quantify disease and the design of devices that mimic or alter blood flow.

The blood flow in human arterial system can be considered as a fluid dynamics problem. Simulation of blood flow in the arterial network system will provide a better understanding of the physiology of human body. Simulation studies of blood flow in the diseased condition can diagnose the health problem easily. There are two distinctly different types of blood fluid flow. The first type is known as laminar, the second as turbulent flow.

In laminar flow the fluid particles move along smooth paths in layers with every layer (lamina) sliding smoothly over its neighbor. Laminar flow becomes unstable at high velocities and breaks down into turbulent flow. In turbulent flow the particles follow very irregular and erratic paths, their velocity vectors varying continually both in magnitude and direction [1, 2].

Steady Flow

Steady flow is that one where all conditions, such as velocity and pressure, at any point in a stream remain constant with respect to time. The definition is usually expanded to include flow in which the conditions fluctuate equally on both sides of a constant average value. Arterial flow is pulsatile and each flow may be analyzed in terms of a steady flow together with a number with superimposed sinusoidal components.

Steady flow of Newtonian fluids in rigid vessels is well understood and can serve as a starting point in the study of blood flow in arteries. Blood flow is also relevant as pulsatile flow and can be considered to be the sum of a steady component and a number of oscillatory components which interact neither with each other nor with the steady component [2].

Figure 1. An element of fluid in steady flow at velocity υ takes a time t to traverse a distance s.

Laminar Flow in a Vessel

Flow is laminar when the velocity gradient is smooth and continuous.

Cross section of the vessel shows the laminae moving at different speeds; closest to the edge of the vessel, fluid moves slowly, though near the center moves quickly (2).

Figure 2. Schema of the laminar flow in a cylindrical vessel. The laminae slide over each other, binded by friction from within the fluid.

Poiseuille Flow

Steady laminar flow established in long cylindrical pipes is sometimes referred to as Poiseuille flow. This is a basic type of flow and blood moves in a series of concentric shells such that the velocity profile across the vessel is parabolic. Blood in the center of the vessel is moving most rapidly, though blood in contact with the vessel wall does not move. The velocity of any lamina at radius r from the center of the vessel may be expressed by

υ(r) = υ_max (1-r²/R²) [1]

 Where υ_max is the velocity of the center stream and R the radius of the vessel.

Figure 3. Poiseuille law, viscosity of fluid.

Steady flow discharge Q is sustained in a long rigid tube. The pressure over a length l is P₂-P₁. Poiseuille described how the steady flow of a fluid is influenced by its viscosity, showing that for a pressure difference P2–P1 along a length l of the vessel, the pressure and the flow discharge Q are related to, in the following way

P2–P1 = (8 l v/πr⁴) × Q [2]

Where v is the viscosity and r the radius of the vessel lumen.

Consequently, the fluid resistance increases with the fourth power of decreasing radius of the vessel lumen. So, halving the radius means that a 16-fold increase in pressure is required to maintain the same flow.

According to Poiseuille law the variation of velocity across the lumen of a long cylindrical pipe in steady viscous flow, is smooth and has the form of a paraboloid of rotation. (1–4)

Turbulent Flow

Laminar flow becomes unstable at high velocities and breaks down to turbulent flow. The point at which the transition between the two flow regimes occurs cannot be predicted exactly, but it is largely determined by the Reynolds number, Re, which for a circular pipe is defined as:

Re = υ.D/ν [3]

Where, υ is the average velocity of flow across the pipe, D the diameter of the pipe and v the kinematic viscosity.

Reynolds number (Re) is a dimensionless number that characterizes different flow regimes.

Laminar flow occurs at low Re, as a smooth, constant fluid motion, though turbulent flow because of flow instabilities occurs at high Re.

Turbulent flow may never be described as steady as there are continual fluctuations in both velocity and pressure at every point. 2.25 to 4.45 folds flow increase was calculated through poiseuille flow and Reynolds number, for cylindrical pipe. (4).

Blood Flow Energy

Fluid with sufficient kinetic energy is capable of flowing up a pressure gradient. The property of a fluid that determines the direction and speed of flow is its total fluid energy. Fluid energy can take several forms as the following. In real conditions these energy forms may be combined.

a. Pressure energy (P)

Pressure in a fluid may be thought of as the ability to do work, e.g. overcome viscous resistance; so pressure is a form of potential energy.

b. Kinetic energy (K)

Each volume of moving fluid has energy by virtue of its mass and motion, determined as ½ ρ.υ², where ρ is the density and υ the velocity of flow.

c. Gravitational potential energy (G)

Fluid at a higher level than an arbitrary point is also capable of doing work; its weight imparts a potential energy equal to ρ.g.h, where, ρ the density, g the acceleration of gravity and h is the height. This gravitational energy may be transformed into kinetic energy by, e.g., allowing the fluid to flow down.

d. Viscous energy (V)

Flow against a viscous resistance described above may also be seen as a form of energy loss, in which kinetic or potential energy of the fluid is transferred to heat. With laminar flow the magnitude of this loss depends on vessel geometry.

In a single streamline of flow, the principle of conservation of energy holds that the sum of these individual energies, the total fluid Energy E, must remain constant at each point along the path of flow.

It is a difference in blood fluid energy that determines the direction and character of flow.

Mathematically, blood flow is described by Darcy’s law

F = ΔP/R [4]

Where F = blood flow, ΔP = pressure gradient, R = resistance

It is also described approximately by the following Hagen-Poiseuille equation

R = (v.L/r⁴(8/π) [5]

Where ν = blood fluid viscosity, L = length of tube, r = radius of tube

The viscosity of normal blood is about three times as great as the viscosity of water.

It is important to note that resistance to flow changes dramatically, with respect to the radius of the tube as already is referred for fluid flow in Poiseuille law [2–4].

In large arteries blood can be approximated as an homogeneous Newtonian fluid because the vessel size is much greater than the size of particles; particle interactions have a negligible effect on the flow. In smaller vessels, blood behavior is expressed as non-Newtonian [5].

Materials and Method

The treatment of hepatocellular carcinoma via the hepatic artery is based on the existence of arterial hyper vascularization of the tumor. For tumors bigger than 2 cm in diameter, more than 80% of their blood supply is drawn from the hepatic artery. Normal liver parenchyma draws more than 80% of blood from the portal vein. By delivery of radioactive agents into the hepatic artery, which represents almost exclusively the arterial supply to liver tumors, highly selective tumor uptake can be achieved [6].

Figure 4. Human vessels sizes (aorta, artery, arteriole)

The theoretical rationale for hepatic artery infusion is based on the observation that hepatocellular carcinoma and neuroendocrine tumors are hyper vascular tumors and derive the majority of their blood supply from the hepatic artery.

In general the radiopharmaceutical is delivered at the lobar artery level to be distributed to numerous tumors in that lobe.

Figure 5. (Left) an histologic sample of normal (A) and tumor liver cells (B).Cell dimensions and distances between cell surface and nuclei show that DNA lies within the micrometer range of In-111 emissions. (Right) Hepatic artery supplied the tumor is the liver entrance for infusion.

Individually determined patient-specific activities are used. In the case of main hepatic artery injection, radiation is distributed to both lobes of the liver. If the lesions are limited to one lobe, the catheter can be selectively inserted either into the left or right lobar artery supplying the affected lobe, thus sparing the contralateral.

In selected cases, hyper selective, single segment treatments can be considered.

Gentle infusion, by a steady low pressure, should be used to strictly avoid backflow (fig 6).

Figure 6. In order the flow be maintained against viscosity, a force F is applied to the fluid.

Gentle infusion (no excessive pressure) should be used to strictly avoid backflow.

Indium -111- Octreotide

Indium-111 (¹¹¹In) is a radioisotope that was introduced for hepatocellular carcinoma and neuroendocrine tumor cancer cells diagnosis. It is also successfully used for neuroendocrine tumor radio-immunotherapy.

a) Production and Physical Characteristics of In-111

In-111 is produced by cyclotron from Cd-112 collision with protons of energy 2.8 MeV according to the nuclear reaction Cd-112 (p, 2n) In-111. Radioactive In-111 decays by physical half-life time of 2.83 days. The type, energy and emission ratio for In-111 decay, are displayed in Table 1.

Table 1. Indium-111(In¹¹¹) Decay Chart

IT, Internal Transform

Purity of the final product of In-111 is affected by the undesired isotopes In-110m, In-110 and In-114m that are not possible to spare from In-111 due to the similar chemical characteristics of these isotopes with In-111.

Isotopes In-110m and In-110, do not affect dosimetry of radioisotopes labeled with In-111, as these undesired isotopes have minor presence and short half-life time (4.9h and 1.1h, respectively). On the contrary, In-114m that is produced from Cd-114 according to a (p, n) nuclear reaction, has 49.51 days half-life time and decays by internal transition (96.9%) and electron capture (3.2%) with emission of photons at (192, 558 and 725) keV. In-114m affects dosimetry due to its long half-life time [7].

 The Flow Discharge Q depends on the volume V of the fluid that passes in time interval t

That is Q = V/t [6a]

Flow Discharge is also determined by the multiplication of the cross section of the object with mean velocity

Q = S × υ[6b]

Then mean velocity depends on flow discharge and is inversely proportional to the cross section of the tube

υ = Q / S [6c]

Angiographic catheter cross section S_A is smaller than Port catheter cross section S_P, (S_P > S_A) consequently the Port flow Q_P is greater than Angiographic flow Q_A.

Q_P/Q_A = S_P/S_A > 1 [6d]

Assuming that the velocity in angiographic tube is obtained equal to the velocity in port tube v_A = v_P, we consider (by equation 6d) that Port Flow QP > Angiographic Flow QA.

b) In-111 uptake and biokinetic properties

The radiopharmaceutical In-111-DTPA-D-Phe-1 octreotide is a peptide composed of 8 amino acids and is an analogue of the active part of the peptide hormone somatostatin In-111-octreotide. It is used for radio immunotherapy for neuroendocrine tumors of the gastro hepatic system. Octreotide is a somatostatin analogue used for labeling In-111. Somatostatin is a peptide of the gastro enteric system that inhibits the production of the grow hormone.

There is an over expression of the somatostatin receptors at the surface of the neuroendocrine tumor cancer cells. In-111-octreotide is bounded to the somatostatin inhibitors and transferred into the cancer cell. Auger electrons that are emitted from In-111 can damage the DNA of the cancer cell.

In palliative treatment use, the radiopharmaceutical entrance into the tumor cell and its destructive effect to DNA by emission of Auger and internal conversion electrons has been exploited earlier [8, 9].

The Peptide Receptor Radionuclide Therapy (PRRT), a somatostatin-analogue-based targeted therapy, is a field in the palliative treatment of Neuro Endocrine Tumors (NET) with very encouraging data. The treatment modality utilizes radioactive substances that are conjugated with various somatostatin analogues such as octreotide.

Intravenously administrated, these drugs bind to the somatostatin receptor localized on the tumor cells. The ligand–receptor complex is internalized and the attached radiation has the potential to destroy the tumor cells.

The side effects are few and mostly mild, in particularly when treatment protocols consider renal protective agents. Initially used In-111-DTPA-[D-Phe1]-octreotide achieved positive results, whereas stable disease was seen in 42% to 81% of patients and partial remission rates up to 8%. However, because of the limited tissue penetration range of In-111, In-111 coupled peptides are rather ineffective for PRRT and their utilization should be restricted for hepatocellular carcinoma therapeutic purposes.

Auger electrons with particle ranges (.02–10) μm and Internal Conversion electrons with ranges (200–550) μm that In-111 emits during its transformation procedure are extremely short. In large arteries blood can be approximated as homogeneous Newtonian fluid because the vessel size is much greater than the size of particles; particles’ interactions have a negligible effect on the flow [5, 6, 8, 13].

Implanted Port /Arterial Infusion

Surgically implanted ports have been used in repetitive intra-arterial In-111 radiolabeled Octreotide infusions for 22 patients with hepatocellular carcinoma and similarly 18 patients with neuroendocrine tumors in a continuous base. A percutaneous implantation procedure facilitates safe and less invasive radiopharmaceutical infusions for the treatment. We have focused on the interventional techniques for percutaneous implantation of a vascular access device consisting of an implantable port, to perform In-111-Octreotide infusions.

Hepatic arterial infusion radionuclide therapy employs a hepatic artery catheter as a duct to achieve a high concentration of radiolabeled agent to liver tumors. Various techniques were used to ensure high concentration of radiopharmaceutical in liver tumors as there are many anatomical hepatic arterial variations and complicated blood flow patterns. They are composed of arterial redistribution by embolization, percutaneous catheter placement and evaluation and management of flow patterns reflecting In-111 octreotide distribution.

Using fluid flow theory we describe details of the alteration of blood flow by first pass embolization that can be performed to obtain selective radiopharmaceutical distribution to the target area and to avoid side effects caused by the accumulation of the radiolabeled agent into non tumor areas.

Different hypothetical flow mechanisms lead to different patterns of strain relaxation with time. Representative tissue properties show blood fluid drainage into the local microvasculature to be the dominant flow-related stress/strain relaxation mechanism; due to drainage into the microvasculature is on the order of 5–10 sec. This is the relaxation time of strain in solid tumors under realistic applied pressure magnitudes. The magnitude of the strain relaxation can be as high as approximately 0.4% strain, well within the range of strains measurable by elastography.

A rich distribution of the In-111 radiopharmaceutical that is recorded in the scintigraphy imaging of the tumor, by the implanted ports technique, is explained by steady, laminar and disturbed flow equations [10, 11].

a) Tip-Fixation method

In order to facilitate repetitive infusions of our patients, a method of implanted ports, gave a simpler therapeutic way but also improved therapy results.

Our aim is to show that radiopharmaceutical fluid flow through implanted port is rich and the absorbed dose in the tumor increased for best therapy results.

Implanted ports have been used in repetitive intra-arterial In-111 Octreotide infusions.

The catheter should be placed directly into the artery supplying the tumor. Since the position of the catheter tip cannot be changed after placement, hemodynamic alterations must be taken into consideration.

Patients, with histologically confirmed hepatocellular carcinoma or neuroendocrine tumors lesions located in liver and with normal kidney function, were infused with mean activity of 4500 MBq In-111 – octreotide.

The technique is composed of arterial redistribution, percutaneous catheter placement applying “tip-fixation method, ” evaluation & management of flow patterns that reflect radiopharmaceutical distribution.

The infusion was performed through a port attached to the hepatic artery. The hepatic artery port makes the therapy more comfortable for the patient as in this way the hepatic artery angiography catheterization, at each therapeutic session, is avoided.

Port chamber is made of titanium & silicone membrane (diameter12mm). It is 28 mm long and 13.5 mm wide. Inner diameter of port catheter is 1.2 mm and outer diameter is 2.5mm [12].

Figure 7. Percutaneously implantable catheter-port system.

The “tip-fixation method uses the gastroduodenal artery. Hepatic arterial infusion radiotherapy employs a hepatic artery catheter as a duct to achieve a high concentration of radiolabeled agent to liver tumors.

For the “tip-fixation method, a distal branch of the hepatic artery could also be used to fix the catheter tip. Sometimes, in cases of lower tumor load, a more selective delivery at the segmental artery level is possible.

This is proved to be the best method to give better uptake of the radiopharmaceutical by the tumor. The infusion of the radiopharmaceutical was performed directly to patient liver through the port that was attached to the hepatic artery.

Figure 8. The “tip-fixation method” using the gastroduodenal artery (A) or a distant hepatic artery (B)

To fix the tip of the indwelling catheter, the gastroduodenal artery (GDA) is most commonly used. When using the GDA, an indwelling side-holed catheter is inserted into the GDA. However, if necessary, it is possible to use other arteries.

Scintigraphy

Patient specific dose estimation for the tumor and healthy tissue is very important for radiopharmaceutical therapeutic applications as this is the most accurate way to assign an administered dose to the best therapeutic result. It is also assistance to the physician in order to avoid side effects of the therapy and compare the treatment results to other related therapies as external radiotherapy [13].

Scintigraphy is performed immediately after radiopharmaceutical infusion and at 24h and at 48h post-infusion. Individually determined patient-specific activities are used. Quantitative whole-body scintigraphy imaging one week post therapy is recommended to confirm the distribution of the radiopharmaceutical. This is proved to be the best method to give better uptake of the radiopharmaceutical by the tumor.

Gamma camera is calibrated in order to estimate source organ activity considering count rate, patient’s body diameter and source organ size [14].

Average activity (6.3+-2.3) GBq per session was administered at monthly intervals. Infusion repetition did not exceed the 12th fold.

Results

The patient individualized dosimetry calculations were based on anterior and posterior scintigraphy images that were acquired immediately after radiopharmaceutical infusion, through hepatic arterial port and at 24 and 48 h post-infusion.

The results showed that the tumor absorbed dose ranged from 2.5mGy/MBq to 18.4mGy/MBq depending on the lesion size [13]. The average absorbed dose per session to a tumor for a spherical mass of 10 gr was estimated to be 10.8 mGy/MBq, depending on the histotype of the tumor.

The organ average radiation dose estimation after In-111-DTPA-Phe1-octreotide trans-hepatic infusion was found as follows:

(a) Liver Tumor	10.80	mGy/MBq
(b) Liver organ	0.14	mGy/MBq
(c) Kidneys	0.41	mGy/MBq
(d) Spleen	1.40	mGy/MBq
(e) Pancreas	0.13	mGy/MBq
(f) Bone marrow	0.003	mGy/MBq

Figure 9. Above First pass infusion for selective In-111 Octreotide distribution to the target area. below (A) 1h post infusion via arterial port, (B) 1h post angiography thin catheter infusion.

Figure 10. (Above) Intensity histogram of In111 Octreotide distribution by port infusion (catheter diameter 1.2mm) and (Below) Intensity histogram of In111-Octreotide distribution by angiography (catheter diameter 0.8mm)

Figure 11. Examples of cumulative activity to tumor

Figure 12. Examples of cumulative activity to critical organs.

Discussion

The factors affecting hepatic arterial flow in tumor feeding artery were analyzed. The patency rate of the hepatic artery was significantly higher in patients with catheter placement using fixed port method than those undergo fully interventional catheterization. A ratio of 5: 1 to 3: 1 flow increase was calculated through poiseuille flow and Reynolds number for circular pipe.

The infusion of the radiopharmaceutical was performed directly to patient liver through a port that was attached to the hepatic artery. Percutaneously implantable catheter-port system placement is safe and technically feasible for use in the hepatic artery.

This is proved to be the best method to give better uptake of the radiopharmaceutical by the tumor. Patient specific dose estimation for the tumor and healthy tissue is very important for radiopharmaceutical therapeutic applications as this is the most accurate way to assign an administered dose to the best therapeutic result [13–15]. It is also assistance to the physician in order to avoid side effects of the therapy and compare the treatment results to other related therapies as external radiotherapy.

In the case of main hepatic artery injection, radiation is distributed to both lobes of the liver. If the lesions are limited to one lobe, the catheter can be selectively inserted either into the left or right lobar artery supplying the affected lobe, thus sparing the contralateral. In selected cases, hyper selective (i.e. single segment) treatments can be considered.

Patient specific dosimetry calculations help the physician to optimize the planning of the treatment, avoid side effects to healthy tissue and assign administered dose to treatment results.

Conclusion

We consider that in continuous therapy, it is important to use the simplest fixed port method for percutaneous catheter placement instead of interventional catheterization, in order to increase absorbed dose into tumor for best response to radionuclide therapy. A percutaneous implantation procedure facilitates safe and less invasive radiopharmaceutical infusions for multiple treatments. Implanted ports have been used in repetitive intra-arterial In-111 Octreotide infusions. The patency rate of the hepatic artery was significantly higher in patients with catheter placement using fixed port method than those undergo fully interventional catheterization. Percutaneously implantable catheter-port system placement is safe and technically feasible for use in the hepatic artery.

Advantages of the use of intra-arterial radionuclide agents are the ability to deliver high doses of radiation to small target volumes, the relatively low toxicity profile, the possibility to treat the whole liver including microscopic disease and the feasibility of combination with other therapy modalities. Disadvantages are mainly due to radioprotection problems.

Percutaneous image-guided catheter placement for hepatic arterial infusion radionuclide therapy is technically safe and provides a viable alternative to traditional methods of hepatic artery access. However, a thorough knowledge of hepatic arterial anatomy, potential of complicated blood flow patterns and management of the infusion devices will ensure a high likelihood of tumor-only delivery of the radionuclide agent.

In summary, we modified the technique of radiologic placement of a catheter and port system for hepatic arterial infusion internal radiotherapy by fixing the catheter tip to the vessel and infusing radionuclide agents from the side hole of the catheter. We conclude that this technique is a safe and not unduly time-consuming method that obviates surgical laparotomy and represents a significant therapeutic advance in the medical oncology field for patients with liver malignancies.

Our intention is to study further, the behavior of the radionuclide fluid as is inserting in arteries and arterioles.

References

1. Evans, DH, McDicken, WN, Skidmore, R., and Woodcock, JP, 1989, Doppler ultrasound: Physics, instrumentation, and clinical applications, John Wiley & Sons
2. Taylor, Kenneth JW, Burns Peter N, Wells Peter NT (1987) Clinical Applications of Doppler Ultrasound, Raven Press 1988
3. Ku David N (1997) Blood flow in arteries, Annual Review of Fluid Mechanics 29: 399–434
4. Sankar DS, Hemalatha K (2007) A non-Newtonian fluid flow model for blood flow through a catheterized artery—Steady flow, Applied Mathematical Modelling 31: 1847–1864.
5. Blessy Th, Sumam KS (2016) Blood Flow in Human Arterial System-A Review, Procedia Technology 24: 339–346.
6. Giammarile F, Bodei L, Chiesa C, Flux G, et al (2011) Therapy, Oncology and Dosimetry Committees, EANM procedure guideline for the treatment of liver cancer and liver metastases with intra-arterial radioactive compounds, EJNMMI 38: 1393–406.
7. Lyra ME Andreou M. Georgantzoglou A et al, (2013) Radionuclides Used in Nuclear Medicine Therapy – From Production to Dosimetry, Current Medical Imaging Reviews. Bentham Science Publishers 9: 51–75.
8. Limouris GS, Chatziioannou A, Kontogeorgakos D. et al., 2008, Selective hepatic arterial infusion of In-111-DTPA-Phe1-octreotide in neuroendocrine liver metastases ejnmmi 35: 1827–1837.
9. Virgolini I, Szilvasi I, Kurtaran et al. (1998) Indium-111-DOTA-Lanreotide: biodistribution safety and radiation absorbed dose in tumor patients. JNM 39: 1928–1936.
10. Arai Y, Takeuchi Y, Inaba Y, Yamaura H, et al. (2007) Percutaneous catheter placement for hepatic arterial infusion chemotherapy, Techniques in vascular and interventional radiology 10: 30–37.
11. Tanaka T, Arai Y, Inaba Y, Matsueda K, et al (2003) Radiologic placement of side-hole catheter with tip fixation for hepatic arterial infusion chemotherapy. Journal of vascular and interventional radiology 14: 63–68.
12. Lyra ME, Limouris GS (2009) In-111 radiolabelled Octreotide therapy -Arterial infusion strategy using implanted ports versus Artery Catheterization- EJNMMI 36: 260–80.
13. Vamvakas I, Lagopati N, Andreou M, et al, (2009) Patient specific computer automated dosimetry calculations during therapy with 111In Octreotide. European J of Radiography 1: 180–183.
14. EANM Guideline (2010) Ellinor Busemann Sokole, Anna Płachcínska, Alan Britten with contribution from the EANM Working Group Maria Lyra Georgosopoulou, Wendy Tindale, Rigobert Klett, Routine quality control recommendations for nuclear medicine instrumentation, EJNMMI 37: 662–671.
15. Maecke H R, Reubi Jean-Claude (2011) Somatostatin Receptors as Targets for Nuclear Medicine Imaging and Radionuclide Treatment JNM 39: 1928–1936.

DOI: 10.31038/IMCI.2019214

Abstract

Introduction: Electrochemotherapy (ECT) is a locally enhanced chemotherapy that combines the administration of chemotherapeutic drugs with well-dosed electric pulses for cell membrane Electroporation (EP). As opposed to thermal ablation, cell death with ECT is primarily induced using electrical energy: electrical pulses disrupt the cellular membrane integrity, resulting in cell death while sparing the extracellular matrix of sensitive structures such as the bile ducts, blood vessels, and bowel wall. This article reports the successful non-thermal ablation treatment of a hepatic recurrence of lung cancer as an individual treatment in order to achieve loco-regional tumor control.

Case Presentation: 50-year-old Caucasian woman was referred for interventional treatment of the largest of the hepatic metastases of lung cancer (6.0 × 4.8 cm), located in the left hepatic lobe and close to the left suprahepatic vein. Due to the size and the immediate proximity to the left suprahepatic vein the patient could neither undergo ablation treatments (RFA or MWA) neither TACE because of tumor size and the high risk of thermal sinks (“heat-sink effect”) potentially resulting in reduction of complete treatment of the target lesion. Due to its ablation mechanism, electrochemotherapy with use of bleomicin was deemed to be the best therapy option for the patient as loco-regional disease control.

Conclusions: Due to its more selective and non-thermal ablation effect , percutaneous ECT is a novel, potentially very effective treatment option in minimally invasive oncologic treatments, especially for hepatic metastases. We showed in this case report that a large hepatic metastatic lesion adjacent to the left suprahepatic vein can be widely ablated by ECT with ablation of a large infiltrating tissue volume.

Keywords

Electrochemotherapy, Reversible Electroporation, Hepatic Metastases.

Introduction

Electrochemotherapy (ECT) is a locally enhanced chemotherapy that combines the administration of chemotherapeutic drugs with well-dosed electric pulses for cell membrane electroporation (EP) [1].

Tissue electroporation is a novel approach to introduce molecules and genes into the cells of specific areas of the body. It employs the ability of certain electrical fields to reversibly permeabilize the cell membrane in a process known as reversible electroporation [2].

The exposure of biological membranes to a sufficiently high external electric field can lead to a rapid and large increase in electric conductivity and permeability, called membrane EP. While applying an electric field on cell membranes, their surface tension will be destabilized and nonpermanent molecules can diffuse into the cytosol. According to the theory of aqueous pore formation, pores are able to form spontaneously, when the bilayer is exposed to an electrical field (>50 V) [2,3].

Mass transfer can now occur through these channels (pores), which in reversible electroporation persist for a period of a few seconds. Typically, in reversible electroporation, the permeabilization pulses are delivered on a time scale of microseconds, and the pores reseal on a time scale of seconds. Macromolecules in the extracellular space can enter the cells by diffusion during the time the pores are open [4].

When electric pulses are applied to cells, 2 different phenomena are observed: reversible EP and irreversible electroporation (IRE), both used in clinical practice. Reversible EP will increase cell membrane permeability and open an access route for molecules that are too big to cross the cell membrane (DNA, RNA) or facilitates cell enter by hydrophilic molecules (bleomycin [BLM], cisplatin) [5–7]. These molecules once crossed the cell membrane exert their effect in the resealing and intact cells. In contrast, IRE (>600 V/cm) is used as non-thermal form of soft tissue ablation in clinical routine [8]. The IRE of cell membranes leads to a disturbance of the cell homeostasis and thus ultimately to apoptosis in the treated tissue [9–11].

Electrochemotherapy is a promising method to locally treat tumors regardless of its histological type with minimal adverse side effects and a high response rate [12,13].

The efficacy of ECT treatment is well demonstrated for cutaneous and subcutaneous melanomas, and the technique can be applied in a variety of malignant lesions [14,15]. The range of applications can be divided into 3 groups: (1) treatment of cutaneous and subcutaneous metastases located in head or neck, melanoma, non-melanoma skin cancer, or breast cancer metastases to the skin [14, 16–19]; (2) treatment of non-cutaneous metastases located in bone, liver, or Soft Tissue Sarcoma (STS) [20–22]; and (3) clinical trials for the treatment of primary tumors, such as ovary or colon cancer [23,24].

Its applications were described by Neumann et al nearly 3 decades ago when electrical fields were used to temporarily create pores in cell membrane to facilitate gene transfer into mouse lyoma cells [25]. The use of electroporation to increase the permeability of the cell membrane in tissue was introduced by Okino and Mohri in 1987 [26] and by Mir et al in 1991 [27], who described that combining an impermeant anticancer drug with reversibly permeabilizing electrical pulses greatly enhanced the effectiveness of the treatment compared with either therapy alone.

The liver is an organ of particular current research interests in ECT. Besides established ablation modalities like microwave ablation [28] or RFA [29] and IRE [30] there is need for a controlled non-thermal ablation modality that enhances the efficacy of chemotherapeutic agents. The benefit of non-thermal ablation, like IRE, is the ability to treat lesions without thermonecrosis. This enables the ability to ablate near-sensitive structures like vessels and nerves, as no heat will be produced which spread around the treated area. An already established loco-regional method is TACE. During TACE, embolizing agents and chemotherapeutics will be administrated via catheter to obtain tissue-specific necrosis. As both therapy concepts are based on loco-regional application of cytostatic in hepatocellular parenchyma, a similar response rate of ECT by liver lesions can be possible. Similar to TACE, ECT allows for a controlled loco-regional additional chemotherapy without marked systemic side effects. As the chemotherapeutics applied during ECT are membrane impermeant, even better results might be possible [1].

First trials of ECT by hepatic tumors were conducted in animal models. Electrochemotherapy was shown to be effective to reduce the volume of hepatic metastases of colorectal cancer in the rats [31].

Electrochemotherapy of solid organs has been evaluated in phase I and II trials in humans [21, 32]. A significant reduction of viable tumor tissue in ECT-treated metastases was observed. Infarct-like necrosis occurred presumably caused by the cytotoxic and vascular-disrupting effect on tumor cells and small tumor blood vessels [32,33].

Histopathological analysis of colorectal liver metastases after ECT treatment revealed necrotic and fibrotic changes of tumor and normal tissue in the treated area, whereas 3 months later, regeneration was observable. The analysis also revealed that after ECT treatment, most vessels (>5 mm) and biliary structures were preserved [34].

In a small clinical trial, patients received an open approach of ECT for the treatment of unresectable colorectal liver metastases. The obtained response rates 4 weeks after ECT were 55% as complete response and 45% stable disease [35].

A recent study by Gasljevic et al. [34] Demonstrated regressive changes in the whole ECT-treated area of the liver. It confirmed that ECT could be proposed for the therapy of metastases near major blood vessels in the liver to provide a safe approach with good antitumor efficacy.

The successful establishment of ECT as hepatic lesion treatment can offer an additional minimally invasive treatment in the case of malignant lesions with decreased systemic side effects.

This article reports the successful non-thermal ablation treatment of a hepatic recurrence of lung cancer as an individual treatment in order to achieve loco-regional tumor control.

Case Presentation

 A 50-year-old Caucasian woman was referred for treatment of one of the liver metastases of lung cancer. After initial diagnosis of lung cancer with multiple bone metastases and a single hepatic lesion in 2013, a systemic chemiotherapy was performed with subsequent radiotherapy with the initial result of partial tumor remission. The hepatic lesion was treated with microwave ablation and was obtained a great loco-regional tumor control.

Under systemic chemotherapy (denosumab and navelbine), after a partial remission and subsequent disease stability, in 2018 a systemic progression was observed with appearance of peritoneal carcinomatosis, multiple lymphadenopathy, brain metastases and numerical and dimensional increase of bone and hepatic metastases.

The largest of the hepatic lesions was located in the left hepatic lobe and close to the left suprahepatic vein. The tumor size was 6.0 × 4.8 cm in axial section at the abdominal CT scan (Figure 1).

Figure 1. Contrast-enhanced axial CT scan demonstrating the large hepatic metastases (6.0 × 4.8 cm ) located in the left hepatic lobe and close to the left suprahepatic vein prior to ECT procedure. CT indicates computed tomography; ECT indicates electrochemotherapy.

The patient’s case was discussed at the multidisciplinary tumor board for therapy options: due to the size and the immediate proximity to the left suprahepatic vein the patient could neither second ablation treatments (RFA or MWA) nor TACE because of tumor size and the high risk of thermal sinks (“heat-sink effect”) potentially resulting in reduction of complete treatment of the target lesion. Electrochemotherapy with use of bleomicin was deemed to be the best therapy option for the patient as loco-regional disease control.

The concept of ECT is based on the aforementioned properties of reversible EP combined with therapeutic efficacy of chemotherapeutic agents. Due to the increased permeability of the cell membrane, chemotherapeutic agents can pass into cells and induce cell death mitosis in the targeted tissue. Electrodes located around or inside the tumor will deliver defined electric pulses which enables diffusion of otherwise membrane nonpermeant anticancer drug into the target cells [1]. This – in contrast to thermal ablation techniques like Radiofrequency Ablation (RFA) or Microwave Ablation (MWA) – potentially allows tumor cell ablation without concomitant destruction of connective tissue, blood vessels and nerves.

Due to this potentially selective cell ablation technique, ECT was offered as a therapy option because it provided the opportunity of tumor mass reduction and decrease of tumor burden with reduced risk of impairment of surrounding blood vessels. The procedure with risks and benefits was discussed with the patient and informed consent was obtained.

 The patient was put under general anesthesia and neuromuscular blocking to prevent arrhythmia. The procedure was performed using a commercially available RE system. Due to the large tumor volume a total of five needles were placed into the target area (Figure 2). The percutaneous placement of the electrodes was guided by ultrasound using a multifrequency probe (1 to 5MHz). As recommended by the manufacturer and recorded by the RE generator the following parameters were used: number of electrodes: five; type of electrodes: monopolar; distance of electrodes: 0.5m (minimum), 1.5cm (maximum); impulses per electrode: 80; voltage: 500V (minimum), 3000V (maximum); maximum deliverable current: 50A. An intravenous administration of an anticancer drug (BLM) was done so it could evenly distribute over the vascular system and extracellular space of the tissue. After that, electrodes located around or inside generated the electric pulses for a time of 8 minutes with consequent diffusion of otherwise membrane nonpermeant anticancer drug into the target cells. After a short time, a few seconds to several minutes after exposure to the electric field, the membrane permeability would return to its initial state and the specific chemotherapeutics would cause multiple DNA breaks (BLM) in the abnormal tumor cells. A stepwise ablation procedure with replacement of two electrodes at the level of the caudal portion of the lesion was performed.

Figure 2. Percutaneous placement of five electrode needles for hepatic lesion treatment.

During the electrochemotherapy the patient did not have any cardiovascular events, in particular no supraventricular tachycardia and no atrial fibrillation. Complications, especially post-interventional bleeding, were not observed.

Follow-up imaging, after one week, showed good response to the treatment of the hepatic lesion in absence of remaining viable tumor tissue. Contrast-enhanced CT scan at 3 and 6 months after electrochemotherapy procedure showed a complete necrosis of the tumor and reduction of tumor volume (Figure 3).

Figure 3. Follow-up imaging post-ECT procedure: contrast-enhanced axial CT scan (a) at one week demonstrating no residual or recurrent tumor; (b) at 3 and (c) 6 months showing a complete necrosis of the tumor and reduction of tumor volume. CT indicates computed tomography; ECT indicates electro chemotherapy.

Discussion

The majority of patients who are diagnosed with liver malignancies are not eligible for resection or transplantation due to inadequate functional liver function, multifocal or advanced disease, prohibitive tumor location or the presence of medical co-morbidities. In some highly selective scenarios resection appears to remain superior in terms of disease recurrence rates and overall and disease-free survival. For curative intentions in term of local tumor control there are reports of equivalent results following local-regional ablation treatments when compared to resection in selected patients [36–38].

Image-guided tumor ablation techniques have significantly broadened the treatment possibilities for primary and secondary hepatic malignancies. A tumor resection leads to immediate absence of tumor tissue, in contrast (thermo)ablative procedures will induce necrotic damages whereas chemoablative procedures induce cell apoptosis [1].

 Monopolar RFA is an established technique for the treatment of tumors that are limited in number (3 or less) and size (3 cm or less) and are located 1 cm or more from critical structures and vessels. MWA appears to have the potential to improve the rate of complete ablation achieved with RFA in tumors that are larger than 3 cm or when multiple and seems to have the potential to overcome the limitations of RFA in the treatment of tumors in perivascular locations [39].

 A new ablation technique, Reversible Electroporation (RE) with use of chemiotherapy (as BLM), is recently added to the treatment armamentarium. As opposed to thermal ablation, cell death with ECT is primarily induced using electrical energy: electrical pulses disrupt the cellular membrane integrity, resulting in cell death while sparing the extracellular matrix of sensitive structures such as the bile ducts, blood vessels, and bowel wall. The preservation of these structures makes electrochemotherapy attractive for liver metastases that are unsuitable for resection and thermal ablation owing to their anatomical location. In contrast to chemoembolization techniques, ECT relies on membrane non-permeant chemotherapeutics, which need EP for cell uptake. Improvements need to be done to achieve homogeneous EP in the treated area, as well as steady concentrations of cytostatic drug in big lesions [1].

The establishment and expansion of ECT in deep-seated tumors (eg, liver, bone metastases) will open up new opportunities for minimally invasive treatment of metastases and carcinomas. Even if only few experiences have been published for colorectal liver metastases treated by ECT, considering the proven safety and the promising results, this treatment option deserves further attention. ECT can induce tumor volume shrinkage, suggesting an implementation in clinical routine as neoadjuvant treatment to enhance future tumor resection. In most cases, it is used in treatment of advanced neoplastic lesions in which radical surgical treatment is not possible (eg, due to lesion location, size, and/or number) [1].

Even though percutaneous ablation techniques are used as possibly curative therapies, palliative tumor ablation can be useful to achieve loco-regional control of tumor growth, pain relief or pain control, especially in patients with unresectable tumor manifestations [40]. Indeed, electrochemotherapy is usually applied in palliative settings for patients with unresectable tumors, resulting in amelioration of quality of life.

Electrochemotherapy allows treating tumor nodules in the proximity of important structures like vessels and nerves and the safety profile of ECT is favorable. Due to heat dissipation to adjacent structures there is an inherent risk of thermal damage of adjacent organs, blood vessels and nerves. Thus, lesions close to adjacent structures with high risk of unintended heat destruction still pose a challenge for percutaneous thermal ablation techniques [41]. In particular, ECT – in contrast to thermal ablation – would allow tumor cell ablation without concomitant destruction of connective tissue, blood vessels and nerves, which means ablation of tumor cells in those areas where thermal ablation was not possible before. In the proximity of larger blood vessels thermal ablation techniques are also hindered by the heat-sink effect. Due to its cooling effect blood flow is an important determinant as much as a limiting factor of thermal ablation techniques [42,43]. ECT seems to be unaffected by the blood flow and conversely does not potentially affect the macro vascularization of the ablation zone.

Most of the observed adverse events are local and transient, including moderate local pain, erythema, edema, and muscle contractions during ECT. No serious adverse events or deaths related to ECT have been reported. Limitations of ECT are the need for interventional individual electric pulse generating systems, individual electrode needles, and complex preinterventional planning. As the success of difficult interventions in deep-seated tumors will rely on accurate needle placement, robotic navigated systems as well as image guidance improve successful ECT treatment and minimize reintervention [1].

Conclusion

Percutaneous ECT of solid organs is a novel, potentially very effective treatment option in minimally invasive oncologic treatments, especially for hepatic metastases.

Due to its more selective and non-thermal ablation effect ECT widens the field of minimally invasive treatable lesions. We showed in this case report that a large hepatic metastatic lesion adjacent to the left suprahepatic vein can be widely ablated by ECT with ablation of a large infiltrating tissue volume.

References

1. Probst U, Fuhrmann I, Beyer L et al (2018) Electrochemotherapy as a New Modality in Interventional Oncology: A Review. Technol Cancer Res Treat 17:1533033818785329.
2. Weaver J, Chizmadzhev Y (1996) Theory of electroporation: a review. Bioelectrochem Bioenerg 41: 135–160.
3. Pliquett U, Langer R, Weaver J (1995) Changes in the passive electrical properties of human stratum corneum due to electroporation. Biochim Biophys Acta 1239: 111–121.
4. Yair Granot and Boris Rubinsky (2008) Mass Transfer Model for Drug Delivery in Tissue Cells with Reversible Electroporation. Int J Heat Mass Transf 51: 5610–5616.
5. Belehradek M, Domenge C, Luboinski B, et al. (1993) Electrochemotherapy, a new antitumor treatment. First clinical phase I–II trial. Cancer 72: 3694–3700.
6. Calvet C, Andre F, Mir L. (2014) Dual therapeutic benefit of electroporation-mediated DNA vaccination in vivo. Oncoimmunology 3: 28540.
7. Ivanov MA, Lamrihi B, Szyf M, et al. (2003) Enhanced antitumor activity of a combination of MBD2-antisense electrotransfer gene therapy and bleomycin electrochemotherapy. J Gene Med 5: 893–899.
8. Onik G, Mikus P, Rubinsky B (2007) Irreversible electroporation: implications for prostate ablation. Technol Cancer Res Treat 6: 295–300.
9. Miller L, Leor J, Rubinsky B (2005) Cancer cells ablation with irreversible electroporation. Technol Cancer Res Treat 4: 699–705.
10. Wiggermann P, Bruenn K, Baeumler W (2017) Irreversible electroporation (IRE): a minimally invasive therapeutic option in prostate cancer [in German]. Radiologe 57: 637–640.
11. Niessen C, Thumann S, Beyer L, et al. (2017) Percutaneous irreversible electroporation: long-term survival analysis of 71 patients with inoperable malignant hepatic tumors. Sci Rep 7: 43687.
12. Jaroszeski MJ, Gilbert R, Nicolau C, et al. (1999) In vivo gene delivery by electroporation. Advanced Drug Delivery Reviews 35: 131–137.
13. Dev SB, Rabussay DP, Widera G, et al. (2000) Medical Applications of Electroporation. IEEE Transactions on Plasma Science 28: 206–223.
14. Marty M, Sersa G, Garbay J, et al. (2006) Electrochemotherapy—an easy, highly effective and safe treatment of cutaneous and subcutaneous metastases: results of ESOPE (European Standard Operating Procedures of Electrochemotherapy) study. EJC Suppl 4: 3–13.
15. Mali B, Jarm T, Snoj M, et al. (2013) Antitumor effectiveness of electrochemotherapy: a systematic review and metaanalysis. Eur J Surg Oncol 39: 4–16.
16. Quaglino P, Mortera C, Osella-Abate S, et al. (2008) Electrochemotherapy with intravenous bleomycin in the local treatment of skin melanoma metastases. Ann Surg Oncol 15: 2215–2222.
17. Eggermont A (1996) Treatment of melanoma in-transit metastases confined to the limb. Cancer Surv 26: 335–349.
18. Sersa G, Cufer T, Cemazar M, et al. (2000) Electrochemotherapy with bleomycin in the treatment of hypernephroma metastasis: case report and literature review. Tumori 86: 163–165.
19. Campana L, Mocellin S, Basso M, et al ( 2009) Bleomycin-based electrochemotherapy: clinical outcome from a single institution’s experience with 52 patients. Ann Surg Oncol 16: 191–199.
20. Fini M, Salamanna F, Parrilli A, et al. (2013) Electrochemotherapy is effective in the treatment of rat bone metastases. Clin Exp Metas 30: 1033–1045.
21. Edhemovic I, Gadzijev E, Brecelj E, et al. (2011) Electrochemotherapy: a new technological approach in treatment of metastases in the liver. Technol Cancer Res Treat 10: 475–485.
22. Linnert M, Iversen H, Gehl J (2012) Multiple brain metastases—current management and perspectives for treatment with electrochemotherapy. Radiol Oncol 46: 271–278.
23. Perrone A, Cima S, Pozzati F, et al. (2015) Palliative electrochemotherapy in elderly patients with vulvar cancer: a phase II trial. J Surg Oncol 112: 529–532.
24. Pellegrino A, Damiani G, Mangioni C, et al. (2016) Outcomes of bleomycin-based electrochemotherapy in patients with repeated loco-regional recurrences of vulvar cancer. Acta Oncol 55: 619–624.
25. Neumann E, Schaefer-Ridder M, Wang Y, et al. (1982) Gene transfer into mouse lyoma cells by electroporation in high electric fields. EMBO J 1:841–845
26. Okino M, Mohri H (1987) Effects of a high-voltage electrical impulse and an anticancer drug on in vivo growing tumors. Jpn J Cancer Res 78: 1319–1321
27. Mir LM, Orlowski S, Belehradek J Jr, et al. (1991) Electrochemotherapy potentiation of antitumour effect of bleomycin by local electric pulses. Eur J Cancer 27: 68–72.
28. Simon C, Dupuy D, Mayo-Smith W (2005) Microwave ablation: principles and applications. Radiographics 25: 69–83.
29. Gazelle G, Goldberg S, Solbiati L, et al. (2000) Tumor ablation with radio-frequency energy. Radiology 217: 633–646.
30. Rubinsky B, Onik G, Mikus P (2007) Irreversible electroporation: a new ablation modality—clinical implications. Technol Cancer Res Treat 6: 37–48.
31. Chazal M, Benchimol D, Baque P, et al. (1998) Treatment of hepatic metastases of colorectal cancer by electrochemotherapy: an experimental study in the rat. Surgery 124: 536–540.
32. Edhemovic I, Brecelj E, Gasljevic G, et al. (2014) Intraoperative electrochemotherapy of colorectal liver metastases. J Surg Oncol 110: 320–327
33. Sersa G, Jarm T, Kotnik T, et al. (2008) Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma. Br J Cancer 98: 388–398.
34. Gasljevic G, Edhemovic I, Cemazar M, et al. (2017) Histopathological findings in colorectal liver metastases after electrochemotherapy. PLos One 12: 0180709.
35. Coletti L, Battaglia V, De Simone P, et al. (2017) Safety and feasibility of electrochemotherapy in patients with unresectable colorectal liver metastases: a pilot study. Int J Surg 44: 26–32.
36. American Association for the Study of Liver Diseases – Practice Guidelines.
37. Diaz-Nieto R, Fenwick S, Malik H, et al. (2017) Defining the Optimal Use of Ablation for Metastatic Colorectal Cancer to the Liver Without High-Level Evidence. Curr Treat Options Oncol 18: 8.
38. Alice Gillams, Nahum Goldberg, Muneeb Ahmed, et al. (2015) Thermal ablation of colorectal liver metastases: a position paper by an international panel of ablation experts, the interventional oncology sans frontières meeting 2013. Eur Radiol 25: 3438–3454.
39. Riccardo Lencioni, Thierry de Baere, Robert C. Martin, et al. (2015) Image-Guided Ablation of Malignant Liver Tumors: Recommendations for Clinical Validation of Novel Thermal and Non-Thermal Technologies – A Western Perspective Liver Cancer. 4: 208–214.
40. Mylona S, Karagiannis G, Patsoura S, et al. (2012) Palliative treatment of rectal carcinoma recurrence using radiofrequency ablation. Cardiovasc Intervent Radiol 35: 875–882.
41. Christoph Niessen, Ernst-Michael Jung, Andreas G Schreyer, et al. (2013) Palliative treatment of presacral recurrence of endometrial cancer using irreversible electroporation: a case report. Journal of Medical Case Reports 7:128
42. Patterson EJ, Scudamore CH, Owen DA, et al. (1998) Radiofrequency ablation of porcine liver in vivo: effects of blood flow and treatment time on lesion size. Ann Surg 227: 559–565.
43. Charpentier KP (2012) Irreversible electroporation for the ablation of liver tumors: are we there yet? Arch Surg – Chicago 147: 1053–1061.

DOI: 10.31038/IMCI.2019213

Abstract

Objective: While the use of intraoperative laser angiography (SPY) is increasing in mastectomy patients, its impact in the operating room to change the type of reconstruction performed has not been well described. The purpose of this study is to investigate whether SPY angiography influences post-mastectomy reconstruction decisions and outcomes.

Materials and Methods: A retrospective analysis of mastectomy patients with reconstruction at a single institution was performed from 2015–2017. All patients underwent intraoperative SPY after mastectomy but prior to reconstruction. SPY results were defined as ‘good’, ‘questionable’, ‘bad’, or ‘had skin excised’. Complications within 60 days of surgery were compared between those whose SPY results did not change the type of reconstruction done versus those who did. Preoperative and intraoperative variables were entered into multivariable logistic regression models if significant at the univariate level. A p-value <0.05 was considered significant.

Results: 267 mastectomies were identified, 42 underwent a change in the type of planned reconstruction due to intraoperative SPY results. Of the 42 breasts that underwent a change in reconstruction, 6 had a ‘good’ SPY result, 10 ‘questionable’, 25 ‘bad’, and 2 ‘had areas excised’ (p<0.01). After multivariable analysis, predictors of skin necrosis included patients with ‘questionable’ SPY results (p<0.01,OR:8.1,95%CI:2.06 – 32.2) and smokers (p<0.01,OR:5.7,95%CI:1.5 – 21.2). Predictors of any complication included a change in reconstruction (p<0.05,OR:4.5,95%CI:1.4–14.9) and ‘questionable’ SPY result (p<0.01,OR:4.4,95%CI:1.6–14.9).

Conclusion: SPY angiography results strongly influence intraoperative surgical decisions regarding the type of reconstruction performed. Patients most at risk for flap necrosis and complication post-mastectomy are those with questionable SPY results.

Background

In recent years, intraoperative laser (SPY) angiography has been shown to be effective in identifying areas of ischemic tissue and predicting skin or nipple areolar necrosis during mastectomies [1–5]. One of the most significant complications following a skin or nipple sparing mastectomy with reconstruction is flap necrosis [6,7]. Consequently, SPY angiography has been found to be a useful adjunct to clinical assessment in identifying and potentially preventing complications such as skin necrosis [2].

While studies have demonstrated the ability of SPY angiography to predict mastectomy flap necrosis, none have investigated the impact of SPY angiography on intraoperative decision making, such as changing the type of reconstruction performed. In order to identify the independent predictive value of SPY angiography for postoperative complications, prior studies have not allowed SPY results to impact intraoperative reconstruction decisions [1]. Other studies have described the usefulness of SPY in identifying areas of flap ischemia intraoperatively so that compromised skin could be excised, resulting in decreased complication rates compared to those who did not use SPY [4]. To date, there are no studies describing whether SPY angiography affects surgical decision making regarding the type of breast reconstruction performed. Nor are there studies evaluating whether SPY angiography results can predict other complications, such as seroma or infection. These complications can result from skin necrosis, but independent predictive values have not been evaluated.

Our study aims to describe the impact of SPY angiography on intraoperative decision making regarding type of breast reconstruction. Additionally, we aim to investigate the utility of SPY in predicting other postoperative complications.

Materials and Methods

Patients

After receiving institutional review board approval, a retrospective analysis was performed of a single institution breast care center from 2015–2017. Adult female patients age 18 or older who underwent Nipple Sparing Mastectomy (NSM) or Skin Sparing Mastectomy (SSM), with or without sentinel lymph node biopsy (SLNB) and/or Axillary Lymph Node Dissection (ALND) were identified. The study included patients with a diagnosis of breast cancer and patients undergoing prophylactic surgery. All mastectomies were performed by one of three breast surgical oncologists at our institution. All patients underwent immediate reconstruction with Tissue Expander (TE) or fixed volume implant during the same procedure by one of three plastic surgeons, and all had intraoperative indocyanine green (ICG, standard dose of 2.5mg/ml with 4ml) SPY angiography using the SPY Elite System to evaluate skin perfusion prior to reconstruction.

Variables

Preoperative patient variables including age, smoking status (defined as current smoker at the time of surgery), diabetes, obesity (BMI >/= 30kg/m²), breast weight, and exposures (history of chest wall radiation or chemotherapy) along with intraoperative variables including type of surgery (NSM vs SSM) and ALND were compared. SPY results were defined as described by the plastic surgeon in their operative report as ‘good,’ ‘questionable,’ ‘bad ’or‘ areas excised.’ Documentation of planned reconstruction was noted in the preoperative clinic note and the performed reconstruction was identified in the final operative report. A change in intraoperative reconstruction was either placement of an expander rather than implant, minimal expansion of an expander, or no reconstruction at all. Complications assessed included necrosis (full or partial flap or Nipple-Aerola Complex (NAC) necrosis, dehiscence, or those requiring reoperation), infection (abscess, cellulitis or sepsis), seroma (requiring aspiration or surgical intervention), or explantation of implant within 60 days of surgery. These outcomes were compared between those who had SPY results that changed the type of reconstruction performed and those who did not.

Statistics

Univariate analyses were performed using chi-square tests, Fisher’s exact test, independent sample t-tests, and F-tests in ANOVA for categorical and quantitative variable analysis, respectively. A change in reconstruction was used as the predictor variable with each outcome of interest being the dependent variable tested for significant univariate association. Patient demographics and intraoperative variables were tested for univariate association with our predictor variable to identify possible confounders. These variables were adjusted for in multivariable logistic regression models when the respective univariate p-value was less than 0.1. Covariates in the final multivariable logistic model were considered statistically significant if the p-value was less than 0.05. All statistical analysis was done using SAS version 9.3 (Cary, NC).

Results

Of the 267 mastectomies identified, 42 breasts from 25 patients (15.7%) underwent a change in the type of reconstruction intraoperatively due to SPY results. Of the 42 changes in reconstruction type, 6 breasts had ‘good’ SPY results, 10 had ‘questionable’ SPY results, 25 had ‘bad’ SPY results, and 2 breasts ‘had areas excised’ (p<0.0001) (Table 1). Of the patients who underwent a change in reconstruction, 39 of 42 breasts (92.8%) had a TE placed instead of implant or a TE placed with lower volume, while 3 breasts (7.1%) did not undergo any reconstruction based on intraoperative assessment.

Table 1. SPY results and frequency of intraoperative decision change.

The patient demographics that were statistically significant on univariate analysis in relation to those who had no change versus those who had a change in reconstruction included smoking (p<0.001), obesity (p<0.01), and breast weight (p<0.0001). Age, diabetes, and history of chemotherapy or chest wall radiation were not statistically significant (Table 2). Patients who did not have a change in reconstruction were more likely to have undergone a SSM versus a NSM (p<0.01) and have a ‘good’ SPY result (p<0.0001) compared to those who underwent a change in reconstruction (Table 2). There was a statistically significant increase in complications including necrosis (p<0.01), infection (p<0.01), and seroma (p<0.0001) for patients who had a change in reconstruction based on SPY results compared to those who did not (Table 3).

Table 2. Demographic and intraoperative variables for patients with no change in reconstruction compared to change in reconstruction.

Table 3. 60-day outcomes for no change in reconstruction compared to change in reconstruction.

A multivariable analysis was performed adjusting for significant co-variates including preoperative factors and intraoperative factors if a variable produced a p<0.1. Predictors of necrosis within 60 days of surgery included those who had a ‘questionable’ SPY result (p<0.01 OR: 8.1 95% CI 2.1–32.2) and current smoker (p<0.01 OR: 5.7 95% CI 1.5 – 21.2) (Table 4). Predictors of infection included those who underwent a change in reconstruction (p<0.01 OR: 34.6 95% CI 2.7 – 448) and obesity (p<0.001 OR: 79 95% CI 6.1 – 1000) (Table 5). Predictors of seroma included those who underwent a change in reconstruction (p < 0.05 OR: 4.3 95% CI 1.2–14.7) (Table 6). There were no significant predictors of explantation after multivariable analysis (Table 7). Predictors of one or more complications were significant for patients who had a change in type of reconstruction (p<0.05 OR: 4.5 95% CI 1.4–14.9) and those who had a “questionable” SPY result (p<0.01, OR: 4.4 95% CI 1.6 – 12.1) (Table 8). There were no mortalities within 60 days.

Table 4. Multivariable logistic regression model predicting necrosis within 60 days of surgery.

Table 5. Multivariable logistic regression model predicting infection within 60 days of surgery.

Table 6. Multivariable logistic regression model predicting seroma within 60 days of surgery.

Table 7. Multivariable logistic regression model predicting explantation within 60 days of surgery

Table 8. Multivariable logistic regression model predicting any complication within 60 days of surgery.

* = significant, p < 0.05
** = 3 decimal places needed to accurately show OR and CI
OR = odds ratio
CI = confidence interval
SSM – skin sparing mastectomy, ALND – axillary lymph node dissection

Discussion

To date, this has been the first study describing how SPY angiography impacts intraoperative decision making with respect to reconstruction after mastectomy. In this study, nearly 20% of patients underwent excision of compromised tissue and 16% had a change in reconstruction due to findings on SPY angiography (Table 1). Our study also found that SPY results strongly affected the plastic surgeon’s intraoperative decision making, where 100% of ‘bad’ SPY results resulted in a change in type of reconstruction and 40% in the ‘questionable’ SPY group (Table 1). Furthermore, a change in reconstruction type was predictive of infection, seroma, and any complication, while established risk factors such as smoking and obesity increased risk of necrosis and infection. Interestingly, ‘questionable’ SPY results were an independent risk factor for postoperative necrosis and other complications while ‘bad’ results were not.

Studies have shown that Immediate Breast Reconstruction (IBR) has increased complication rates compared to delayed reconstruction with flap necrosis being reported as the most common complication [8–10]. Flap necrosis rates after IBR have been noted to range anywhere from 3.8% up to 42% [8,9,11]. However, morbidity rates for IBR have decreased over time even with nipple sparing technique [12]. This improvement is likely multifactorial and has been largely attributed to increased surgeon experience and technique modification. Our study found a necrosis complication rate of 8.9% for all patients undergoing mastectomy with reconstruction, which is consistent with prior studies [8,9,11]. While preoperative risk factors for complications have been well studied, the intraoperative evaluation for necrosis with SPY angiography is the next potential area of intervention to reduce morbidity [13].

Our study found that 15.7% of breasts with planned IBR ultimately underwent a change in reconstruction intraoperatively based on SPY results either by undergoing TE placement rather than implant, TE with less volume, or no reconstruction at all. While patients who had a change in reconstruction were at increased risk of a complication on univariate analysis, our study also shows that patients who are smokers or had a ‘questionable’ SPY result are at greater risk for necrosis on multivariate analysis (Table 4). Smoking has been established as a known independent risk factor for skin and flap necrosis [7,10,13]. This was seen within our patient population as well and stresses the importance of SPY for these smokers who undergo IBR. Those patients with a ‘questionable’ SPY were more likely to have necrosis compared to those with a ‘good’ result, while those with a ‘bad’ or ‘had areas excised’ result were not. This is likely because excision of skin for a ‘questionable’ spy was not performed. This confirms the utility of SPY intraoperatively in identifying ischemic areas that can be excised in order to reduce postoperative complications and suggests that a more aggressive approach for ‘questionable’ areas should be taken. After multivariable analysis, patients with SPY results that were not clearly identified as “under-perfused/bad” or “well-perfused/good” were at the greatest risk for necrosis complications.

The objective methods by which SPY can be reported have varied in the literature, with studies investigating anatomic blood flow patterns and the quantitative measurements of perfusion including intensity of fluorescence (also known as absolute perfusion or relative perfusion.) [3,5,14] These studies were limited by small sample size, and because SPY angiography is an “instantaneous index of perfusion” it can be impacted by variations in blood pressure or possibly during the operation [1,3,4,5,14]. In addition, because images are black and white with shades of gray defining areas of perfusion, SPY angiography may be subject to user interpretation and operator experience.⁶ Overall, most studies have made a consensus that SPY should be used in conjunction with clinical assessment to assess perfusion [3–6,14]. Our study confirms SPY is helpful in assessing flap perfusion but there continues to be a need for standardization of perfusion measurements. While 100% of patients with a ‘bad’ SPY result underwent a downgrade in reconstruction, only 40% of those with a ‘questionable’ SPY result had a change, suggesting that surgeons should be more vigilant in downgrading reconstruction options, delaying reconstruction for patients, or excising areas of skin that are compromised with a questionable SPY result. This is further supported by the finding that intraoperative change in reconstruction was not an independent risk factor for necrosis (Table 4).

Obesity is another known risk factor for postoperative complications [10]. In this study, obesity and a change in reconstruction were independent risk factors for infection. Those who underwent a change in reconstruction were at higher risk for infection as well as seroma formation (Table 4, Table 5). The increased risk of infection in those who underwent a change in reconstruction may have been related to ischemia or necrosis while the increased risk for seroma formation may have been due to placement of a TE with minimal expansion instead of placement of an implant.

SPY angiography continues to be an important adjunct in assessing tissue perfusion and can guide intraoperative decision making including excision of ischemic tissue and change in reconstruction options. While changing reconstruction may result in increased seroma formation, it may reduce other complications when there is indeterminate or ‘questionable’ SPY imaging result. There are multiple limitations to our study. The single institution and retrospective nature of our study are limitations as well as the small sample size. As with many other studies, the subjective nature of a SPY result interpretation by the surgeon continues to be present. Since SPY was introduced at our institution in 2014, operator experience may have affected our study as other studies have demonstrated that there is a learning curve for surgeons [6]. In addition, long term and oncologic outcomes were not assessed. Further prospective studies using a standardized measurement to assess tissue perfusion with SPY angiography are needed.

Conclusions

SPY angiography can influence intraoperative decision making for reconstruction, and whether direct to implant reconstruction is possible or expanders are necessary. The patients who were at greatest risk for flap necrosis or other complications in this study were those with ‘questionable’ SPY results as interpreted by the surgeon. Further studies are needed using a SPY angiography standardized perfusion measurement to identify patients who are at risk for post-mastectomy complications.

References

1. Venturi ML, Mesbahi AN, Copeland-Halperin LR, Suh VY, and Yemc L (2017) SPY Elite’s Ability to Predict Nipple Necrosis in Nipple-Sparing Mastectomy and Immediate Tissue Expander Reconstruction. Plastic and Reconstructive Surgery. Global Open 5: 1334.
2. Diep GK, Hui JYC, Marmor S, et al (2016) Postmastectomy Reconstruction Outcomes After Intraoperative Evaluation with Indocyanine Green Angiography Versus Clinical Assessment. Annals of Surgical Oncology 23: 4080.
3. Newman MI, Jack MC, and Samson MC (2013) SPY-Q analysis toolkit values potentially predict mastectomy flap necrosis. Annals of Plastic Surgery 70: 595–598.
4. Komorowska-Timek E, Gurtner GC (2019) Intraoperative perfusion mapping with laser-assisted indocyanine green imaging can predict and prevent complications in immediate breast reconstruction. Plastic and Reconstructive Surgery 125:1065–1073.
5. Duggal CS, Madni T, Losken A (2014) An outcome analysis of intraoperative angiography for postmastectomy breast reconstruction. Aesthetic Surgery Journal 34: 61–65.
6. Sood M and Glat P (2013) Potential of the SPY intraoperative perfusion assessment system to reduce ischemic complications in immediate postmastectomy breast reconstruction. Annals of Surgical Innovation and Research 7: 9.
7. Munabi NCO, Olorunnipa OB, Goltsman D, et al. (2014) The ability of intra-operative perfusion mapping with laser-assisted indocyanine green angiography to predict mastectomy flap necrosis in breast reconstruction: a prospective trial. Journal of Plastic, Reconstructive & Aesthetic Surgery : JPRAS 67: 449–455.
8. Alderman AK, Wilkins EG, Kim HM, and Lowery JC (2002) Complications in postmastectomy breast reconstruction: two-year results of the Michigan Breast Reconstruction Outcome Study. Plastic and Reconstructive Surgery 109: 2265–2274.
9. Sullivan SR, Fletcher DRD, Isom CD, and Isik FF (2002) True incidence of all complications following immediate and delayed breast reconstruction. Plastic and Reconstructive Surgery 122: 19–28.
10. McCarthy CM, Mehrara BJ, Riedel E, et al (2008) Predicting complications following expander/implant breast reconstruction: an outcomes analysis based on preoperative clinical risk. Plastic and Reconstructive Surgery 121: 1886–1892.
11. Phillips BT, Lanier ST, Conkling N, et al. (2012) Intraoperative perfusion techniques can accurately predict mastectomy skin flap necrosis in breast reconstruction: results of a prospective trial. Plastic and Reconstructive Surgery 129:778–88.
12. Wang F, Peled AW, Garwood E, et al. (2014) Total skin-sparing mastectomy and immediate breast reconstruction: an evolution of technique and assessment of outcomes. Annals of Surgical Oncology. 21: 3223–3230.
13. Mlodinow AS, Fine NA, Khavanin N, and Kim JYS (2014) Risk factors for mastectomy flap necrosis following immediate tissue expander breast reconstruction. Journal of Plastic Surgery and Hand Surgery. 48: 322–326.
14. Moyer HR and Losken A (2012) Predicting mastectomy skin flap necrosis with indocyanine green angiography: the gray area defined. Plastic and Reconstructive Surgery 129: 1043–1048.