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LIVER CANCERThe CyberKnife® Robotic
Radiosurgery System was cleared by the U.S. Food and Drug Administration in 2001 to treat tumors anywhere in the body, including
the liver. Despite its name, the CyberKnife System is not a surgical procedure. In fact, there is no cutting involved. Instead,
the CyberKnife System delivers high doses of radiation directly to liver tumors. The CyberKnife System offers patients who
cannot undergo liver cancer surgery due to their poor medical condition, or who refuse surgery, a minimally invasive alternative
treatment for liver cancer. CyberKnife liver cancer treatments are typically performed on an outpatient basis in one to five
days, requiring no overnight hospital stays. Most patients experience minimal to no side effects with a quick recovery time.
What is Liver Cancer?Liver
cancer is the abnormal growth of cells in the liver resulting in a liver tumor. If the abnormal cells originated as liver
cells, the resulting collection of cells is called a primary liver tumor. Some liver tumors are benign, meaning they are not
cancerous and do not spread to other parts of the body. Malignant liver tumors, however, can invade other organs, and spread
throughout the body. Most primary malignant liver cancers are classified as hepatocellular carcinoma or called hepatomas. A
much more common cancer of the liver is a metastatic liver tumor. In this case, cancerous cells from another part of the body
are carried to the liver by the blood or other bodily fluids. Metastatic liver tumors can spread to the liver from the colon,
lung, breast, stomach and pancreas, as well as other sites in the body. More than 21,300 cases of primary liver cancer
are expected to be diagnosed in the United States in 2008. Primary liver cancer is expected to result in approximately 18,410
deaths during that time.1 Five-year relative survival rates for metastatic cancer to the liver is 3.3 percent.1
How is Liver Cancer Detected?Patients
may experience a variety of symptoms including pain in the upper right abdomen, swelling, nausea, jaundice or fever. A physical
exam and blood tests may be used in initial diagnoses. Additionally, doctors may recommend positron emission tomography-CT
(PET-CT) scan, magnetic resonance imaging (MRI) or ultrasound. In some cases an angiogram, which is an X-ray that shows the
blood vessels in the liver, is used to identify the tumor as well. A liver tumor biopsy may be needed to confirm the diagnosis.
Doctors then determine the stage – or extent of the disease – by establishing how big the tumor is and how much
it has spread.
How is Liver Cancer Treated?After liver cancer has been detected and staged, the doctor will discuss different
treatment options. Treatments for liver cancer depend on the type of cancer and the stage. Early-stage primary liver cancer,
and some metastatic tumors, may be treated with surgery, with the goal of removing the entire tumor. Alternatively, the tumor
may be treated by ablation – or destroying it in place – using one of several methods, including the application
of a high-temperature probe (radiofrequency ablation), a low-temperature probe (cryoablation), focused chemotherapy treatment
(chemoembolization), conventional radiation therapy, local alcohol injection or CyberKnife Radiosurgery. In some cases, the
entire liver can be removed and replaced with a donor liver transplant. With more advanced cases of liver cancer, chemotherapy
combined with some of the above mentioned treatments may be used. Surgery Surgery is the common
procedure for treating liver tumors that are localized and have not spread widely throughout the liver. This type of surgery,
often called a partial hepatectomy, involves the surgeon making a large incision in the abdomen and cutting away a section
of liver containing the tumor and some of the surrounding healthy tissue. Liver cancer surgery generally is feasible when
the disease is limited. Under such conditions, resection of a primary liver tumor can lead to a five-year survival rate of
60 percent to 75 percent 2-3, and resection of a metastatic tumor may result in five-year survival rates of 25
percent to 39 percent.4 Unfortunately, only 20 percent to 30 percent of patients with liver cancer are eligible
for surgery because their disease is too advanced and/or their liver functions are extremely poor.5 Liver cancer
surgery may pose significant risk of complications, such as infection, bleeding, respiratory and cardiac problems. Approximately
2 percent to 6 percent of patients have died as a result of liver cancer surgery. Surgery may be the only treatment
necessary or it may be combined with chemotherapy or radiation for patients with widespread cancer or an advanced stage of
their primary tumor. Radiation Therapy Conventional radiation therapy, called external beam radiation
therapy, typically involves delivery of wide fields of radiation that encompass both the tumor and a significant amount of
surrounding healthy tissue. These wide fields of radiation, delivered in small doses over many sessions in the course of several
weeks, are necessary to account for the tumor’s movement as the patient breathes. These wide radiation fields limit
the total radiation dose that can be given in each treatment session because of the toxicity to the normal liver tissue included
in the radiation fields, making it necessary to divide up the total treatment in 30 to 40 sessions given over weeks
This type of damage to normal liver tissue from radiation has been characterized as radiation-induced liver disease (RILD),
a syndrome that may occur in the first few weeks after radiation therapy, and can, in the most severe cases, lead to liver
failure. Recent reports have shown patient survival rates after 1 year ranging from 47 percent to 95 percent and after 5 years
from 11 percent to 25 percent, with generally better outcomes when smaller tumors are treated with higher doses.6 Several
techniques – such as respiratory gating and breath holding– have been developed to better compensate for movement
of liver tumors with breathing. Respiratory gating Respiratory gating is a technique
in which radiation is delivered when the tumor is thought to be in a certain location during a patient’s breathing cycle.
Gating makes a number of assumptions about the location of liver tumor. These assumptions are that the tumor is always in
that same location during a specific point in a patient’s breathing pattern; a patient’s breathing pattern does
not change throughout a treatment; and a patient is breathing the same during a treatment as he or she was breathing during
the planning phase. In reality, many patients breathe differently throughout the treatment, particularly if they are nervous
or fall asleep. These changes in breathing patterns may result in errors in radiation delivery. Breath holding Breath
holding involves a patient taking a full breath and then holding it for several seconds. As the patient holds his or her breath,
the radiation beam is switched on and then turned off just before the patient begins to breathe normally again. Breath holding
assumes a tumor will be in a certain location when the patient breathes in. This may not always be the case, depending on
the depth of a patient’s breath. Breath holding also may be very difficult for patients with advanced lung disease. Techniques
such as gating and breath holding have allowed physicians to deliver much higher doses of radiation in as few as three to
five sessions with a procedure called stereotactic body radiation therapy (SBRT). This alternative treatment for liver cancer
has been shown to be more effective than conventional radiation therapy, with tumor control ranging from 70 percent to 100
percent 18 months after treatment, with very low rates of side effects that are generally mild.7 Slightly
better tumor control has been reported for smaller tumors8 and metastatic lesions.9 Although SBRT enables
doctors to spare more normal liver tissue than conventional methods, it still typically requires large margins around tumors
to ensure that the radiation is delivered to the tumor and to account for the inaccuracies of gating and breath holding.
Radiosurgery Radiosurgery
devices, such as the CyberKnife Robotic Radiosurgery System, offer patients a new option for liver cancer treatment.
The CyberKnife System can deliver high doses of radiation with extreme accuracy because of its ability to track the location
liver tumors in real-time during treatment. The CyberKnife System uses the Synchrony® Respiratory Tracking System to track
tumor motion as patients breathe normally, and adjusts the radiation beam accordingly. The Synchrony System correlates the
rise and fall of the chest with the actual location of the tumor in X-ray images. As a result, during CyberKnife treatment,
patients can lie comfortably and breathe normally without any frames, and are not asked to hold their breath or perform any
complex breathing maneuvers. The Synchrony System can track moving targets with an accuracy of 1 millimeter or better, which
allows clinicians to deliver radiation precisely to the tumor and limit exposure to healthy surrounding tissue.10
Chemotherapy
Chemotherapy is used when cancer cells are thought to be located throughout the
body or they are present in a patient’s blood or other fluids, which is often the case with metastatic tumors and advanced-stage
liver cancer. Chemotherapy medication is delivered orally or through an IV, and is given to a patient either as the sole treatment
or in combination with other types of liver cancer treatment. Chemotherapy affects both normal tissue and the cancer cells,
so patients may experience side effects, such as severe nausea and vomiting, infections, fatigue and weight loss. Chemotherapy
has not provided clinical benefit or prolonged survival for patients with advanced primary liver cancer11 and randomized
trials have not shown any benefit of neoadjuvant therapy, a treatment that's given first to help make the next treatment step
go more smoothly, or adjuvant systemictherapy, which is a type of treatment given after surgery to target the entire body
in hopes of destroying any cancer cells that may have traveled to distant body parts, but are below the level of clinical
detection.12 HCC remains a highly lethal disease that is resistant to traditional cytotoxic chemotherapy. The last
30 years of chemotherapy clinical trials for advanced HCC have repeatedly failed to demonstrate any survival benefit for a
long list of drugs. However a survival advantage was recently established for sorafenib, instituting a new standard of care
for inoperable HCC.13
How Does The CyberKnife® Treat Liver Cancer?Treating liver cancer with radiation therapy is a challenge
because liver tumors move with respiration. In addition the tissue surrounding the liver tumors is very sensitive and
can be damaged easily. The CyberKnife Radiosurgery System is able to deliver very high doses of radiation to both primary
and metastatic liver tumors with extreme accuracy. Working in conjunction with the CyberKnife System is the Synchrony®
Respiratory Tracking System, which enables the radiation beam to track tumor movement in real time and allows patients to
breathe normally during their treatment sessions. With the CyberKnife System, doctors can zero in on a moving target –
the liver tumor – and irradiate it without harming the healthy surrounding tissue. As a result, the CyberKnife treatment
is more comfortable for patients, radiation is delivered more accurately and treatments can be completed in one to five sessions. Liver
cancer treatment with the CyberKnife System involves a team approach, in which several specialists participate. A team may
include: - a Radiation Oncologist
- a General Surgeon
- a Medical Oncologist
- a Medical Physicist
- a
Radiation Therapist
- Medical Support Staff
Once the team is in place, the patient will begin preparation
for CyberKnife treatment. The CyberKnife treatment generally involves four steps: - Fiducial placement
- Set-up
and imaging
- Treatment planning
- CyberKnife treatment
During the first step, the patient is
scheduled for a short outpatient procedure in which three to six fiducials – tiny gold seeds each about the size of
a grain of rice – are inserted into and around the liver tumor using CT guidance, ultrasound or via a camera that is
passed through the mouth into the stomach and small intestine. The CyberKnife System uses those fiducial markers as reference
points to identify the exact location of the tumor during treatment. Once fiducials are implanted, the patient must wait approximately
one week before CyberKnife treatment planning can begin to ensure that fiducial movement has stabilized. During set-up
and imaging, the patient will be fitted for a custom body cradle, which is designed to help keep him or her more comfortable
and ensures consistent positioning for both imaging and treatment. The patient also will be fitted with a special Synchrony
vest, which is worn during CyberKnife treatment and enables the robot to correlate chest motion and breathing patterns with
the tumor position. The data generated with the vest allows the CyberKnife robot to precisely follow the tumor’s motion
as it delivers each beam of radiation, ensuring safe and accurate radiation delivery. While wearing the vest and positioned
in the cradle, the patient then will undergo a series of CT imaging studies, which will enable the CyberKnife team to determine
the exact size, shape and location of the tumor. An MRI or PET-CT scan also may be necessary to fully visualize the tumor,
liver and nearby anatomy. Once the imaging is done, the Synchrony vest and body cradle will be stored for use during CyberKnife
treatment. Next a treatment plan will be specifically designed by a medical physicist in conjunction with the patient’s
doctors. The patient does not need to be present at this time. During treatment planning, the imaging data is downloaded into
the CyberKnife System’s software. The medical team determines the size of the area being targeted by radiation and the
radiation dosage, as well as identifying critical structures where radiation should be minimized. Each patient’s unique
treatment plan will take full advantage of the CyberKnife System’s extreme maneuverability, allowing for a safe and
accurate liver cancer treatment. After a treatment plan is developed, the patient returns to the CyberKnife center for
treatment. Doctors may choose to deliver the liver cancer treatment in one session, or stage it over several days. Liver cancer
treatments are typically completed within one week. For most patients, the CyberKnife treatment is a completely pain-free
experience. Patients dress comfortably in their own clothes and, depending on the treatment center, they may be allowed to
bring music to listen to during the treatment. Patients also may want to bring something to read while they wait, and have
a friend or family member with them to provide support before and after treatment. When it is time for treatment, the
patient will be asked to put on their Synchrony vest and lie on their custom body cradle. The radiation therapist will ensure
the vest is properly adjusted and that the patient is positioned correctly on the treatment couch. As treatment begins,
the location of the liver tumor will be tracked and detected continually as the patient breathes normally. The medical team
will be watching every step of the way as the CyberKnife System tracks the patient’s liver tumor as it moves, and safely
and precisely delivers radiation to it. The CyberKnife System’s computer-controlled robot will move around the
patient’s body to various locations from which it will deliver radiation. At each position, the robot will stop. Then,
special software will determine precisely where the radiation should be delivered by correlating the location of the tumor
using digital images of the fiducials and information from the Synchrony vest. The CyberKnife’s robotic arm will adjust
the radiation source automatically, to follow the liver tumor as it moves. Nothing will be required of the patient during
treatment, except to relax and lie as still as possible. Once treatment is complete, most patients quickly return to
their daily routines with little interruption to their normal activities. If treatment is being delivered in stages, the patient
will need to return for additional treatments over the next several days as determined by their doctors. After CyberKnife
treatments, most patients experience minimal side effects, which typically go away within the first week or two after treatment.
Doctors will discuss all possible side effects prior to treatment. In addition, doctors may prescribe medication to control
any side effects, should they occur. After completing CyberKnife radiosurgery treatment, it is important for the patient
to schedule and attend any follow-up appointments. The patient should be aware that his or her tumor will not suddenly disappear.
Response to liver cancer treatment varies from patient to patient. It could take several months or longer to determine the
effectiveness of the CyberKnife treatment. Doctors will monitor the outcome in the months and years following a patient’s
treatment through physical exams, blood tests and imaging techniques, such as CT or PET-CT scans.
1. American Cancer Society, “Cancer Facts & Figures, 2008”
2. Yamanaka
N, Okamoto E, Toyosaka A, Mitunobu M, Fujihara S, Kato T, et al. Prognostic factors after hepatectomy for hepatocellular carcinomas.
A univariate and multivariate analysis. Cancer 1990; 65: 1104-1110
3. Blum HE. Treatment of hepatocellular carcinoma.
Best Pract Res Clin Gastroenterol 2005; 19: 129-145
4. Fong, Y; Blumgart, LH; Cohen, AM. Surgical Treatment
of Colorectal Metastases to the Liver. CA Cancer J Clin 1995; 45: 50-62
5. Tsuzuki T, Sugioka A, Ueda M, Iida S,
Kanai T, Yoshii H, Nakayasu K. Hepatic resection for hepatocellular carcinoma. Surgery 1990; 107: 511-520
6. Hawkins
MA, Dawson LA Radiation therapy for hepatocellular carcinoma: from palliation to cure. Cancer. 2006 Apr 15;106(8):1653-63.
7. Katz AW, Carey-Sampson M, Muhs AG, Milano MT, Schell MC, Okunieff P. Hypofractionated stereotactic body radiation
therapy (SBRT) for limited hepatic metastases. Int J Radiat Oncol Biol Phys 2007;67:793-798.
8. Wada H, Takai Y,
Nemoto K, et al. Univariate analysis of factors correlated with tumor control probability of three-dimensional conformal hypofractionated
high-dose radiotherapy for small pulmonary or hepatic tumors. Int J Radiat Oncol Biol Phys 2004;58:1114-1120.
9. Mendez
Romero A, Wunderink W, Hussain SM, De Pooter JA, Heijmen BJ, Nowak PC, Nuyttens JJ, Brandwijk RP, Verhoef C, Ijzermans JN,
Levendag PC. Stereotactic body radiation therapy for primary and metastatic liver tumors: A single institution phase i-ii
study. Acta Oncol 2006;45:831-837.
10. Wong KH, Dieterich S, Tang, J, and Cleary, K. Quantitative Measurement of
CyberKnife Robotic Arm Steering. TechnolCancer ResTreat. 2007; 6[6], 589-594.
11. Thomas MB, O'Beirne JP, Furuse
J, Chan AT, Abou-Alfa G, Johnson P. Systemic therapy for hepatocellular carcinoma: cytotoxic chemotherapy, targeted therapy
and immunotherapy. Ann Surg Oncol 2008, 15(4):1008-1014.
12. O'Neil BH, Venook AP. Hepatocellular carcinoma: the
role of the North American GI Steering Committee Hepatobiliary Task Force and the advent of effective drug therapy. Oncologist
2007, 12(12):1425-1432.
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Apr;15(4):1008-14. Epub 2008 Jan 31.
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