Friday, 27 March 2015

Advanced cryoablation therapy to treat lung cancer and metastasis

What is cryoablation, percutaneous ablation, cryosurgery or cryotherapy?

A minimally invasive method that will perhaps be one of very few promising options for cancer patients with advanced metastatic disease.

Cryoablation is a form of treatment which aims to kill cancer cells with extreme cold and is sometimes also referred to as percutaneous ablation, cryosurgery or cryotherapy.

Cryoablation is a relatively new cancer treatment that destroys cancer cells with extreme cold. However at this time, cryoablation is not often used as a first line therapy, instead it is used when surgery isn't an option or when standard surgery has failed. Depending on the available facilities and disease status, cryoablation may in some circumstances be the preferred treatment option for solid tumors, such as cancer of the kidney, liver, lung and prostate. In addition, cryoablation / cryosurgery may be employed to relieve the pain of different types of metastatic cancer (i.e. cancers that have spread to the bone, liver, lungs or other organs). 

Recent long-term follow-up studies show that cryosurgery is an important option for a wide range of unresectable cancers. These clinical studies also demonstrate that this form of therapy provides the potential for long-term survival.

cryosurgery / Cryoablation cancer therapy to achieve remission lung cancer patients / tumor or other metastatic cancers

Cryosurgery may have fewer side effects than other types of cancer treatments, and is in most cases less expensive. In addition, it requires shorter recovery times.

Should cryoablation therapy be used as a first line treatment for solid tumors such as lung cancer, liver cancer, or prostate cancer, including metastasis?

I will address the following points within this short article about Cryosurgery as a treatment for cancer:
  1. What is the difference between first line and second line treatment? 
  2. How does cryosurgery work? 
  3. Why is image guided cryosurgery for metastatic lung tumors not available in more hospitals and cancer centers? 
  4. Links to clinical trials that are currently taking place 
* If you represent a manufacturer of cryoablation / cryosurgery equipment, compatible MRI scanners, or a medical facility that offers cryosurgery to cancer patients, then please get in touch if you would like to have your organisation listed in this article.


What is the difference between a first line and second line cancer treatment?

First-line treatments are:

First-line therapy or treatment regimen / regimens are generally accepted by the medical establishment for initial treatment of a given type and stage of cancer. It is sometimes also referred to as primary treatment or primary therapy. Contrary to popular / patient believe it does not necessarily constitute the best treatment available for a given disease. Rather, it is the most common practice for a given disease and very much related to which drug or therapy got accepted first instead of the best possible treatment available. In other words, it would be terribly short-sighted to refuse a therapy because it is not labelled as a “first-line” or “primary” therapy.

First line therapy vs second-line treatment

Currently, second-line therapies are used mainly when the first line therapies do not work adequately or when they have completely failed. Managing a disease such as cancer requires regular tests (blood tests, MRI scans, etc…) to enable analysis of treatment strategy and to assess whether or not a given treatment regimen is working. When the primary treatment is discontinued while a new treatment regimen is adopted it often signals “second-line treatment”. As mentioned before, in those circumstances the first-line therapy may not have worked, it may have had limited effect, or worse; it may have resulted in side effects such as damaged organs, inability to heal wounds or may have even jeopardized the patient’s life. While first-line therapies can initially result in reducing tumour burden for a period of time they often are followed by continued growth of the cancer (if first-line therapy was working well, then more than 8.000.000 people would not die every year from cancer; see WHO world cancer report 2014).

Please note, that although physicians, such as oncologists, have the freedom to use “second-line” drugs as a first-line treatment (they are only “labeled” as second-line treatment), some insurance companies may not pay for "second-line" therapies when they are used as a first-line treatment.


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How does cryoablation / cryosurgery work as a treatment for cancer patients?

In order to describe how cryoablation is utilised in cancer patients today, I will use a more difficult to treat type of cancer; lung cancer, as an example in this article. The reason for using this cancer as an example is simply because it demonstrates the enormous progress that has been made in the field of cryosurgery in recent years (until recent breakthroughs in cryoprobe diameter, cryoablation therapy for lung cancer was almost impossible).

One other reason to use lung cancer as an example is because next to no progress has been made by the scientific and medical community for this type of cancer even though worldwide 1.59 million people die of lung cancer every year (that is more than all yearly deaths as a result of breast cancer, colon cancer, and prostate cancer combined. I.e. it is the leading cause of cancer related deaths worldwide).

First line treatment / standard of care for stage I Non-Small Cell Lung Cancer (NSCLC) today is pretty much the same as it was in the seventies; surgical resection with lobectomy (i.e. removal of partial or entire lung). Many patients (more than 20%), however, are not eligible for this type of surgical treatment because of comorbidities (additional diseases occurring simultaneously) or because of insufficient lung reserve.
In patients who are unsuitable for surgery of both primary and metastatic lung tumours, image-guided cryoablation may be an attractive alternative. For patients or medical professionals considering this technique, it is perhaps interesting to note that the area of image guided percutaneous cryoablation is a rapidly evolving field of precision surgery. Interestingly, this rapidly advancing surgical technique, called cryoablation, possesses several properties such as low intra-procedural pain (extreme cold is an anaesthetic), good visualisation under magnetic resonance imaging (MRI) guidance, and preservation of collagenous architecture. As such, cryosurgery can be seen as a preferred treatment option.

However, one of the reasons cryoablation for lung tumors was not deemed suitable up until recently was because of the large 11G cryoprobes (3mm diameter) with a blunt-tip. Nevertheless, current technological advances have resulted in ultra thin 17G cryoprobes (1.47mm diameter) which has made cryoablation of lung tumours a more straightforward procedure to perform.



Killing cancer cells with Joule-Thomson effect

The first cryoprobes were developed in the early sixties by Cooper and Lee and were liquid nitrogen (LN2)-containing cryoprobes (where nitrogen boiling is essentially the driving mechanism of cooling). These cryoprobes heralded a paradigm shift within the cryosurgery field as it enabled surgeons to treat deeper tissues with cryoablation. However, a technique introduced subsequently (argon based cryoablation), resulted in another quantum leap given that with this technique the diameter of cryoprobes decreased substantially (from 3mm to 1.47 mm), which in turn has made percutaneous (through the skin) cryoablation of internal organs a more realistic option. With the argon gas (which can reach temperatures of -140°C as a result of the Joule Thomson effect) cryoablation temperatures of between -20°C to -40°C are generated at the end of the cryoprobe tip which creates a lethal environment for cancer cells.

How do freezing temperatures cause cancer cell death?

Cancer cell death as a result of freezing (cryoablation) is caused by several mechanisms during the freeze thaw cycles as well as complex inflammatory mechanisms hours and days after cryosurgery. As such, these mechanisms can be categorised into three distinct phases. These include the heat transfer, cellular injury (following the freeze-thaw cycle), and finally an inflammatory immune response phase.

The process of cryoablation causes a plethora of changes at a cellular and molecular level which results in necrotic cell destruction. This destruction is a consequence of osmotic shifts in intracellular and extracellular water, protein denaturation (i.e. unfolding and inactivity of enzymes, signalling molecules, and structural proteins) and tissue ischemia (from microvascular thrombosis).
Perhaps it is important to note that the level of cancer cell death depends on four thermal parameters. As many molecular biologists or research scientists will be able to tell you from tissue culture experience; cooling rate (how fast cells are frozen), end temperature, time held at the minimum temperature, and thawing rate (how fast cells are defrosted) are important determinants in how viable a cell will be afterwards.


MRI guided cryoablation of (metastatic) lung tumors

Benefits MRI vs CT scan guided cryosurgery

MRI

  1. is safe and does not use ionizing radiation
  2. allows for visualization of the extent of disease and surrounding anatomy, as well as high contrast visualization of the complete extent of the iceball during the procedure.
  3. MRI is capable of acquiring these images in an arbitrarily oriented anatomic plane, which minimizes the need for patient repositioning

CT scans

  1. require the use of a large dose ionizing radiation
  2. do not offer high quality soft tissue contrast or iceball contrast
Development of MR-compatible equipment will expand the role of MRI in image-guided procedures further. As such, soft tissue contrast can be exploited for more accurate planning, targeting, monitoring, and post-treatment evaluation of procedures (e.g. in renal (kidney) cryoablation).

Why is cryosurgery to treat cancer not offered by more hospitals and cancer centers?

As mentioned earlier, small 17 G needle-like probe(s) are guided through a nick in the skin to cancerous tumors inside the lung with the help of medical imaging guidance (preferably MRI). Once these cryoprobes are in position, the tip of the needle (which at that point is inside the tumor) is cooled with gas to as low as 100 degrees C below zero. The resulting ball of ice crystals can destroy cancer by interrupting its cellular function, whilst simultaneously protecting nearby healthy, delicate lung tissue.
Unfortunately, these relatively new 17G cryoprobes (and associated equipment) have not been adopted by every hospital or clinic at this stage. Also, keep in mind that cryoablation is usually performed by an interventional radiologist who requires specialist training and supervision before the hospital is allowed to provide this service.
In addition, MRI availability may also be an issue.
Currently, there are two commercially available percutaneous argon-based cryoablation devices: Cryohit (Galil Medical) and Cryocare (Endocare). Interestingly these systems can activate multiple thin-diameter probes simultaneously (which is useful for mimicking the shape of tumours as well as being able to accommodate larger size tumors.


Links to cryosurgery clinical trials that are currently taking place

  1. Clinical trial cryoablation for lung cancer http://clinicaltrials.gov/show/NCT01957787
  2. Clinical trial cryoblation pancreatic cancer https://clinicaltrials.gov/ct2/show/NCT01335945?term=cryosurgery&rank=5
  3. Clinical trial cryoablation prostate cancer: https://clinicaltrials.gov/ct2/show/NCT02250014?term=cryosurgery&rank=38
For information about Antibody drug conjugates (ADC) and / or clinical trials with ADCs, please go to http://www.pvanuden.com/2014/04/antibody-drug-conjugates-adcs-new-type.html. At the bottom of that page you will find an extensive list with links to clinical trials that investigate Antibody Drug Conjugates for the treatment of many different cancers / tumors.
On that page you will also find a lot of information about Antibody Drug Conjugates in general and how they work (as a treatment for late stage cancers), as well as a list (at the bottom) that shows you which antibody drug conjugate / ADC can be used for a particular cancer.
Please note: Any medical or scientific information published on this website is not intended as a substitute for informed medical advice from a physician and you should not take any action before consulting with a health care professional. For more information, please read my terms & conditions.