Treatment with systemic chemotherapy is one of the presently used possibilities for cancer treatment. However, substances that are effective in this kind of treatment are often harmful to the system of the body as a whole. Particularly, the treatment of cancer of the liver presents a serious clinical problem, and the success rate when treating liver cancer is today very low.
Although primary liver cancer (hepatoma) is rather uncommon in northern Europe and United States, hepatoma is prevalent in other parts of the world, e.g. in Southeast Asia, Japan, the Pacific Islands, Greece, Italy and parts of Africa. Also, many patients with cancer in the gastrointestinal tract develop isolated hepatic metastases, since the liver is the primary target for dissemination. Due to the distribution of the metastases within the liver, only few patients with liver cancer can be cured by resection.
Liver cancer is today mainly treated with systemic chemotherapy. However, no substantial increase in the time of survival of the patients is following this treatment (L. M. De Brauw “Isolated liver perfusion. An experimental modality in the treatment of hepatic metastases.” Thesis, University of Leiden, Leiden, The Netherlands). A reason for these discouraging results seems to be the fact that the toxicity of the chemodrugs limits the possible dosage due to the systemic effects. Local administration by infusion in the hepatic artery does not solve this problem, since the chemodrugs are distributed in the system also during this procedure.
Therefore, it has been suggested that therapeutic drugs should be administered locally by isolation of a vessel wall, by performing perfusion of the liver or other selected isolated organs.
To be therapeutically successful, a treatment session must be applicable one or several times in a treatment cycle (1 to 6 times or more) during a predetermined time interval. Individual treatment sessions can have durations of several minutes to hours, and can have intervals of several days or weeks. The technique must, therefore, be repeatable and the devices used for each individual treatment should be retrievable to reestablish the pre-interventional situation after each treatment session. To realize repeatability, the technique has to be least traumatic which requires minimally invasive i.e. percutaneous techniques.
Examples of techniques for isolating and perfusing organs are found for example in the following prior art documents.
In EP-0 364 799 to BGH Medical Products, a process of perfusing a high concentration of an agent through an organ is described. The agent is infused arterially in the organ and on the venous side of the organ the blood is removed from the body using a specially designed double balloon catheter. In this process there is a leakage to the systemic blood flow, since there are numerous blood communicating vessels besides the main artery and the main vein.
A similar catheter is used in the U.S. Pat. No. 5,817,046 to Glickman et al., showing a system for perfusion of the pelvic cavity. The pelvic cavity is isolated between a double catheter, placed in the iliac vein, and bilateral thigh tourniquets. The thigh tourniquets, which are used to restrict the flow of blood between the legs and the pelvic cavity of the patient, limit the time during which perfusion can be performed.
In U.S. Pat. No. 4,714,460 to Calderon, feedback methods and systems for retrograde perfusion in the body are described. A double balloon concentric catheter, with an inner infusion lumen and an outer suction lumen, is used for perfusion of the venous side of the vascular network. The therapeutic agent for treatment is infused inside the vein in the opposite direction with respect to the ordinary blood flow, also called retrograde infusion. The described method is, thus, designed to operate in back pressure and the perfusion fluid is continuously diluted by arterial blood.
U.S. Pat. No. 4,883,459 to Calderon describes a method for perfusion where a carrier medium dye is injected into the tumor. The flow of the dye is monitored to determine an optimal retrograde perfusion path through the tumor.
A balloon catheter with closed tip and device for perfusion with such catheters, are described in U.S. Pat. No. 5,746,717 to Aigner. The catheter has at least one contrast marking which enables the position of the catheter inside the body to be determined.
The perfusion processes and apparatuses described above all include the return of the blood, which has been contaminated with drugs, to the systemic circulation. This requires treatment to remove the contaminants before this blood can be returned to the body. Also, by not isolating the organ in a perfusion circuit, as is the case in some of the above mentioned procedures, perfusion fluid may easily leak into the systemic circulation. Furthermore, most catheters explained above have the disadvantage that they remain in the body of the living being after termination of the perfusion process.
WO 83/03535 to Cromie describes a liver perfusion bypass member defining three flow conduits. The first conduit, formed by one or more lumens extending along the entire length of the member, provides a flow path for the systemic blood. The second flow conduit, formed by a sealed longitudinal lumen, receives the blood of the liver which is recycled back to the liver by the third conduit, connected to the second one. In this third conduit a system is provided for delivering the therapeutic agent. After treatment the blood in the second and third conduit is removed and would not be returned to the patient.
A similar double perfusion catheter is provided by U.S. Pat. No. 4,540,402 to Aigner. This catheter also defines two blood flows. The first one is the systemic blood flow which is guided through a first catheter tube. The second flow, the perfusion flow, is conducted to a heart-lung machine by a second catheter tube, mounted on the first tube, and this flow is recycled through the liver.
Both devices described above provide continuation of the systemic blood flow during isolation and perfusion of the liver so perfusion can be performed with higher concentrations of therapeutic agent and during a longer period of time. A major disadvantage however is that said devices have to be inserted and removed by open surgery, only permitting perfusion once due to scars in the tissues and the severe stress on the body of the patient.
U.S. Pat. No. 6,287,273 to Allers et al. describes a system for isolated perfusion without the need for surgery, consisting of a catheter set, a pump apparatus and perfusion control apparatus. The method comprises isolating an organ by placing occlusive seals in the most important blood vessels of the organ and establishing a bypass circuit for the systemic blood and a perfusion circuit connected to the organ. Both circuits are partially extracorporeal, whereby the therapeutic agent is administered to the perfusion circuit outside the body.
WO 03/006096 to Allers et al. provides a catheter, delivered endoluminally, which can replace the occlusive seals used in the method described in U.S. Pat. No. 6,287,273. In one embodiment the catheter stem is fluid permeable while the structure at the end of the catheter is fluid impermeable, thereby restricting venous blood entering the vena cava and allowing the systemic blood to flow through the catheter. Another embodiment describes a fluid impermeable stem and a fluid permeable end structure, thereby allowing delivery of therapeutic agents to the hepatic veins while blocking the systemic blood flow through the vena cava.
A disadvantage of the invention in these documents is the complexity of the method. For example, perfusion of the liver demands positioning of at least four to five catheters. One or two catheters are placed into the inferior vena cava for isolating systemic from liver blood flow, another catheter is placed in the vena porta and guides the systemic blood to the catheter placed in the superior vena cava while conducting the perfusion flow to the catheter positioned in the hepatic artery. Furthermore, the fluid is circulated in the extracorporeal circuits by pumping and has to be monitored carefully by control devices to ensure, for example, blood pressure and temperature. Furthermore, many rely on occlusion using an inflatable balloon, which are prone to leakage.
As can be noticed by the amount of prior art documents mentioned above, much effort has already been made for providing methods, devices and systems for isolating and perfusing an organ affected with cancer with therapeutic drugs. However, all these methods, devices and systems have their limitations and drawbacks, so there is a persistent need for improvement to and/or simplification of the prior art. Especially for treatment of liver cancer strong progress is demanded.
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