NIH study finds Cediranib benefits patients with ASPS

An experimental drug, cediranib, may benefit alveolar soft part sarcoma (ASPS) patients, according a recent clinical trial. The trial, carried out by scientists at the National Cancer Institute (NCI), part of the National Institutes of Health, showed that tumors shrank in more than 50 percent of ASPS patients who were treated with cediranib. These findings were presented at the American Society of Clinical Oncology’s annual meeting in Chicago on June 6, 2011.

ASPS accounts for less than one percent of soft tissue sarcomas, and forms in tissues that connect, support, or surround the organs of the body. It is usually diagnosed in children and young adults, developing as a painless mass in the leg or buttock.

ASPS arises due to the breaking and joining of two chromosomes in tumor cells. An X chromosome, one of two sex chromosomes in humans, and one copy of chromosome 17, each lose a small piece, and the X chromosome piece becomes joined to the rest of chromosome 17. This process, called a chromosomal translocation, creates a fusion between two genes, ASPL (on chromosome 17) and TFE3 (on the X chromosome).When this fusion gene is expressed, the result is the formation of an aberrant fusion protein, ASPL-TFE3, not found in normal cells. The detection of this protein is used to confirm a diagnosis of ASPS, which is crucial in distinguishing it from other soft tissue sarcomas, but the protein’s exact role in disease progression is still unknown.

Even though researchers do not know the exact function of the fusion protein in this disease and therefore cannot target it directly, they do know that the cancer relies on the formation of new blood vessels to allow it to grow and spread throughout the body, especially the lungs, where multiple small nodules form. Because of this reliance on the vasculature (arrangement of blood vessels in the body), scientists decided to test cediranib in ASPS, since it’s a drug that blocks the formation of new blood vessels.

AstraZeneca, the drug’s manufacturer, has tested the effect of cediranib in treating a variety of tumors, including lung and colorectal cancers. ASPS is the first solid tumor that has demonstrated substantial tumor shrinkage. NCI’s Division of Cancer Treatment and Diagnosis (DCTD) supported the initial development of this drug using a cooperative research and development agreement, which is a contract between NCI and industry to further develop a technology for commercialization.

“It is unusual to see such high levels of tumor shrinkage in a cancer that traditionally has not responded to standard chemotherapy used for the treatment of sarcomas,” said Shivaani Kummar, M.D., head of early clinical trials development in DCTD. Standard chemotherapy for ASPS has shown no benefit or response.

In this trial, 33 patients ranging in age from 19 to 59 received cediranib. Of these, more than 50 percent had tumor shrinkage, and some continued to receive the treatment more than a year later.

Importantly, the reported side effects of cediranib, that include hypertension and diarrhea, were manageable.

The collaborative abilities of two of NCI’s divisions, DCTD and NCI’s Center for Cancer Research (CCR), played an important role in evaluating this new agent’s potential for the treatment of this rare tumor. The ability to bring ASPS patients from across the country to CCR’s clinical facility on the NIH campus for treatment made patient accrual for a trial in this rare tumor possible, according to Kummar.

A follow up study, coordinated by NCI and conducted at the NIH Clinical Center and at several other research facilities, including two NCI-designated Cancer Centers — Dana-Farber Comprehensive Cancer Center in Boston, and M.D. Anderson Comprehensive Cancer Center in Houston — is planned to confirm these promising results. The trial will compare cediranib with sunitinib, another blood vessel growth inhibitor, in patients with ASPS.

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer, and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site or call NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Reference: Phase II study of cediranib (AZD2171) in patients with alveolar soft part sarcoma. To learn more visit: http://1.usa.gov/la6iqN.

Minimally Invasive Procedures for Tumor Ablation

For Alveolar Soft Part Sarcoms patients the use of aggressive surgery, appropriate diagnostic imaging, and long-term surveillance for metastases are critical to achieve long-term survival (Kayton et al 2006). When surgery is not possible, then local treatment like tumor ablation may be considered. In the past we discussed the benefits of Stereotactic Radiosurgery (SRS).
There are different ablation techniques that can be used to treat tumor locally: cryoablation (cryosurgery), radiofrequency ablation (RFA), laser-induced thermal therapy (LITT), microwave ablation, and focused ultrasound (FUS). Some of them are widely available – like RFA, and some are not avail. everywhere (like cryo and LITT) and some are only started to get used by a few doctors. The medical specialist that performs local tumor ablations is called Interventional Radiologist. Local tumor ablations are used when there is a need/reason to avoid the open surgery and have the advantage of the minimal pain, scarring, and cost.

1.   Cryoablation (formerly known as Cryosurgery) is the application of extreme cold to destroy abnormal or diseased tissue. It can be used percutaneously (as a minimally invasive procedure) and during the open surgery as an additional tool in case when resection is complicated. The most common method of freezing tumors is by using liquid nitrogen as the cooling solution. Other freezing agents are carbon dioxide and argon gas to drive ice formation. The cryoablation has the advantage of the continued direct visualization of the ablation quality during the ablation process using CT-scanner.
Click the following link and read about Cryosurgery in Cancer on the National cancer Institute website

Few ASPS patients had their tumors cryoablated at the Karmanos Cancer Institute with Dr. Peter Littrup

Click the following link to read a scientific article that supports cryosurgery over other tumor ablation methods

2.   Radio frequency ablation (RFA) is the application of the heat that is produced by the current and used to locally destroy a tumor. It can be used percutaneously (as a minimally invasive procedure) and during the open surgery as an additional tool in case when resection is complicated. Tumors in Lung, liver and kidney are the main tumors treated with RFA. The procedure is done by placing a needle-like RFA probe inside the tumor.

Click the following link and read about Radio frequency ablation in Cancer on the National cancer Institute website

Few ASPS patients had their tumors RFA-ablated.
3.   Laser-induced thermal therapy (LITT) is the application of the high temperatures generated by the local absorption of laser energy. It can be used percutaneously (as a minimally invasive procedure) and during the open surgery as an additional tool in case when resection is complicated. Organs or tissues in which LITT has been used for this purpose include brain, head and neck, liver, kidneys, and prostate. Laser applicators for LITT may be inserted into target tissue using a number of image-guided techniques including x-ray fluoroscopy, ultrasound imaging, magnetic resonance imaging, or stereotaxic approaches. LITT has the advantage of the tiniest applicator possible between the all ablative techniques, but it is rarely available technology.

One ASPS patient had her brain metastasis ablated by using LITT technology at the Dana Farber clinics in Boston, but the most experienced intervenional radiologist in using LITT is located in Europe in Frankfurt University Hospital, Dr.T.J.Vogl.
Click the following link to read about Lasers in Cancer on the National cancer Institute website

4.   Focused ultrasound (FUS) and microwave ablation are currently under development technologies. They use a microwave or focused ultrasound medical devices to heat and destroy tissue. Among the tumors destroyed by FUS are solid tumors of the bone, brain, breast, liver, pancreas, rectum, kidney, testes and prostate. When the procedure is done by MRI guidance it may be called Magnetic Resonance-guided Focused Ultrasound, or MRgFUS.
Click the following link to read about Focused ultrasound on the Focused Ultrasound Surgery Foundation website

The insurance coverage for the locally ablative procedures varies, consult your insurance guides for the up-to-date information as whether it is covered for your specific case as the coverage of these procedures is evolving as more data about its efficacy became available. Some of our patients had to pay out of pocket to have their tumors ablated in order to get an access to the technology that is able to locally destroy the tumors not treatable otherwise.
______________________________________________________

Yosef Landesman, Ph.D.
President & Cancer Research Director
Cure Alveolar Soft Part Sarcoma International (iCureASPS)
e-mail:
landesmany@yahoo.com

Laser Assisted Resection of Multiple Lung Metastases

Lung metastases affect a significant part of the ASPS patients at some point of their life, they can be very multiple and wide spread. It is very important to detect them early for an optimal management so all ASPS patients have to be monitored for the possible lung metastases development. For ASPS patients the use of aggressive surgery, appropriate diagnostic imaging, and long-term surveillance for metastases are critical to achieve long-term survival (Kayton et al 2006). If recurrent lung metastases appear, repeated surgeries to remove these tumors are recommended as their removal has been shown to improve survival (Liebl et al 2007).

Generally there are two ways to remove or destroy lung metastases:

1. Resection – by a standard open lung surgery (by a thoracotomy or sternotomy approach) or VATS (video-assisted thoracic surgery). It is a challenging task and not always technically feasible, each case is different due to the size, number and location of the metastases and only thoracic surgeon will be able to say based on a CT scan if a given case is resectable. To be eligible for a resection lungs have to be the only active metastatic organ with the primary tumor resected and other metastases successfully treated before.

2. Ablation – a local treatment done percutaneously by an interventional radiologist using one of the less invasive methods (cryoablation, radiofrequency ablation or LITT) or by non-invasive methods (stereotactic radiosurgery (SRS) or tomotherapy).Previously, we reviewed the use of stereotactic radiosurgery (SRS) here.

Now, we will discuss laser assisted surgery for the removal of multiple lung metastases in a surgical procedure. Open lung surgery (by a thoracotomy or sternotomy approach) is a gold standard if the goal is to resect all lung metastases. Lung metastases smaller than 2 mm often cannot be seen on the CT scan. Open surgery allows the surgeon to visually inspect the lungs, as well as palpate (explore by touch) the lung tissue. An experienced surgeon can find a metastasis as small as 0.5-1 mm by this method. Traditionally, lung metastases are removed by “wedge” or “lobe resection”. In that type of surgery, tumor (or tumors) are removed from the lung by stapling and clamping devices. Due to the geometric straight lines and angles of the stapler, the removal of lung metastases by this method results in a considerable loss of healthy lung tissue. Loss of a large amount of lung tissue can ultimately lead to a decrease in lung function. Another downside of this technique is the limitation of the location – there has to be an open edge to use a stapler. This means that tissue is removed in the shape of a pizza slice. If the metastases are centrally located or deep seated they are not accessible for this surgical tool. Hence, metastatic disease to the lungs is considered to be unresectable unless a whole lobe or a lung is being removed. ASPS is often a very disseminated disease, with all of the lobes affected. In this case, resection is not feasible using the conventional stapler assisted method. In some cases, complete resection can still be done by a new technique – laser assisted resection. To use this technique, the surgeon employs a special medical laser. The advantages of this tool are a high degree of precision and an ability to resect deep seated and centrally located metastases without critical loss of lung parenchyma. Using the laser, the surgeon can follow along the contour of the metastasis and remove it, thereby sparing much of the healthy lung tissue and its function. This may be crucial for patients with multiple metastases. It provides the patient with a better quality of life and allows repeated surgery, if needed.

Dr. Axel Rolle, from the Department of Thoracic and Vascular Surgery, Coswig (Dresden), Germany has been working on this laser technique since 1988, developing therapeutic laser technology for the resection of lung tissue (parenchyma). Lung parenchyma contains 80% water, and is of very low density (lots of air chambers). Therefore, in order for the laser to work in this type of tissue, it must have excellent cutting properties, and be able to control bleeding easily (coagulation). The first lasers in use were based on 1064nm wavelength laser. Dr. Rolle has developed and is using since the late 90-ties a longer wavelength laser of 1318nm, which is emitted from Nd:YAG. He found that this laser has both better precision when cutting, preserving the tissue around the metastasis, and improved bleeding control. Dr. Rolle has published these findings demonstrating the clinical benefit of this technique (Rolle et al 2006 (1)). This procedure is an unique opportunity to remove maximal tumor load from the lungs in a parenchyma-saving and lobe-sparing approach.

In a recent scientific publication, Dr. Rolle reported the results of a study, which aimed to define the role of his new 1318-nm Nd:YAG laser, in order to preserve lung tissue for patients with multiple lung metastases (Rolle et al 2006 (2)). During the period of that study: January 1996 to December 2003, a total of 328 cancer patients were treated with the new 1318 nm Nd:YAG laser system. A total of 3267 lung nodules were resected by the laser (an average of 10 tumors per patient (range 2-124). Despite the unusually high number of the resected metastases due to the most difficult cases being referred for his surgery the lobectomy rate was only 7 %.
Dr. Rolle concludes –

“This new 1318-nm Nd:YAG laser facilitates complete resection of multiple bilateral centrally located metastases and thus is lobe sparing. Outcomes are better when metastases are removed completely from the lung for long-term survival than those patients who had incomplete resection”.

Dr. Rolle contact information at the Center for Pneumology and Thoracic and Vascular Surgery, Academic Teaching Hospital of Dresden University:

Dr. Axel Rolle

Dr. Rolle
Fachkrankenhaus Coswig GmbH
Neucoswigerstr. 21
01640 Coswig
Germany

Phone: 0049 (0)3523 – 65 102
Fax: 0049 (0)3523 – 65 103
E-mail:
prof.rolle@fachkrankenhaus-coswig.de


More information about laser surgery:

1. Dr. Rolle performed laser assisted resections on at least two ASPS patients with very multiple lung metastases. You can read one first hand experience at this link. 

2. Patient Education – Lung Cancer Program at UCLA. Click this link.

3. Read more about laser resection at the National Cancer Institute website: http://www.cancer.gov/cancertopics/factsheet/Therapy/lasers

4.  Lung laser surgery at Royal Brompton Hospital in London, England. The Sarcoma team at the Royal Brompton Hospital is the designated exclusive provider for Thoracic Sarcoma Surgery Services in London and the South East of England.

________________________ 

Yosef Landesman, Ph.D. (in cooperation with Olga Tkatcheva)
President & Cancer Research Director
Cure Alveolar Soft Part Sarcoma International (iCureASPS)
e-mail:
landesmany@yahoo.com
      

Stereotactic Radiosurgery (SRS)

Stereotactic Radiosurgery (SRS) is a medical procedure, which is non-invasive surgery to destroy tumors. High dose of ionizing radiation is precisely delivered into a specific area of an organ to kill tumor cells. The beam of radiation is the surgical knife in radiosurgery. The most common forms of ionizing radiation are: proton beams, X-rays and photons.

Unlike conventional surgery that removes tumors by bulk dissection, SRS only distorts the DNA of the tumor cells. Those cells then lose their ability to divide. Tumor shrinkage can be seen often over several months.

Currently there are three basic forms of stereotactic radiosurgery: Cobalt-60 (photon), Linear accelerator (linac) and Particle beam (proton). Each one is different from the other in both the equipment used and the radiation emitted. One type may be more effective than the other depending on the location of the tumor.

1. Cobalt-60 (photon) – also called a Gamma Knife® is an extremely accurate instrument used to treat brain tumors. The Gamma Knife® allows noninvasive brain surgery, sparing tissues adjacent to the target. The beams of gamma radiation are programmed to target the tumor at the point where they intersect. In a single treatment session, 201 beams of gamma radiation focus precisely on the tumor. Over time, most lesions slowly shrink in size and dissolve. The exposure is brief and only the tissue being treated receives a significant radiation dose, while the surrounding tissue remains unharmed. The Gamma Knife® technology is used for tumors which are small, less than 3.5 cm, or in patients who have limited symptoms from the tumor. When Gamma Knife® cannot be utilized or is not available to the patient, radiosurgery with linear accelerator technology can usually be utilized.

Click here to read more about Gamma Knife® at the university of Pittsburg, at the Johns Hopkins, at the University of Virginia.

2. Linear accelerator (linac)
Linac is short for the term “linear accelerator”. The Linear accelerator instruments produce high-energy X-ray radiation. Conventional X-rays are a form of electromagnetic radiation with short wavelength, without charge or mass. The most improved linac technology is based on Intensity – Modulated Radiation Therapy (IMRT). It takes into account the three-dimensional shape of the tumor. This is done through the use of a CT scanner that is incorporated into the IMRT. The CT scans identify the exact tumor location and its shape. The radiation beams in varying intensities are delivered to the tumor with increased accuracy, reducing the harmful effects of the X-rays on normal tissue.
This treatment is very beneficial for large tumor (up to 2.5 cm) in one-session, and tumors greater in size (over 3.5 cm) in several treatment sessions. When several treatments are required this is called fractionated stereotactic radiotherapy. Linear accelerator based machines can be used to treat tumors throughout the body, as well as in the head and neck.

The linac machines are made by multiple manufacturers with common brand names such as: X-Knife®, Axess®, Trilogy®, Novalis®, CyberKnife®, TomoTherapy® .

Read more about Cyberknife:
Cyberknife to treat tumors anywhere in the body
Cyberknife, frequently asked questions
Cyberknife at Stanford
Compare: Gamma Knife versus Cyberknife to treat brain tumors

3. Particle beam (proton) – Also known as Proton beam, is radiation of positively charged particles that impact the tumor cells by way of their mass. The side effects of the treatment with Proton beam are less than those that are caused by X-ray treatment. X-rays affect cells as they travel through the body in a straight line, delivering injury both at the surface of the body where they enter, and in tissues behind the cancer. Proton beams do not travel all the way through the body and can be used very accurately to kill cancer cells without the collateral damage seen with traditional radiation: Proton beams can be controlled to deposit the bulk of their energy at the EXACT tumor location. The Proton beam machines are very expensive and therefore exist only in six centers in the United States: M.D. Anderson in Houston; Loma Linda University Medical Center in California AND Proton treatment at Loma Linda; The Midwest Proton Radiotherapy Institute in Bloomington, Indiana; Massachusetts General Hospital, Boston; The University of Florida Proton Therapy Institute in Jacksonville; and the University of California, Davis Cancer Center in Sacramento.

Click here to Read more about Proton Beam

*This summary aims to introduce you into SRS. Please be aware that we mentioned only some of the centers, which practice SRS. While some centers treat cancer in only few organs, other centers may use the same technique to treat tumors in more locations.

__________________________

Yosef Landesman, Ph.D.
President & Cancer Research Director
Cure Alveolar Soft Part Sarcoma International (iCureASPS)
e-mail: landesmany@yahoo.com