On Monday, May 16th, 2011, Dr. Andrew Kennedy, a well-known researcher in liver metastases, led a Fight Colorectal Cancer webinar discussing an issue that affects thousands of colorectal cancer patients.

Colorectal cancer often metastasizes first to the liver, so learning how to manage growth of those tumors can help with patient survival.  

Treatment of liver mets has come a long way in the last two decades. You can learn about these developments in an archive of the webinar below.

Our thanks to Dr. Andrew Kennedy for leading the discussion. His extensive knowledge of this issue is highly respected in the field of radiology. He graciously donated his time to bring this information to patients.

Webinar: Treating Liver Metastases from Fight Colorectal Cancer on Vimeo.

Fight Colorectal Cancer is giving you the opportunity to talk to researchers and medical professionals in April and May through online webinars designed to bring the science of treating colorectal cancer down to the personal.

The latest news from the petri dish
Wednesday, April 20, 2011
8 – 9 PM Eastern

Dr. Yaeger at work in her lab

Dr. Rona Yaeger will discuss the research she has been conducting over the past year with the grant she received as part of Fight Colorectal Cancer’s Lisa Fund research program.

Dr. Yaeger’s research focused on inhibiting the AKT pathway in colorectal cancer cells. She conducted basic research to determine how inhibitors to the pathway might affect cells of patients who have mutated KRAS and are resistant to EGFR inhibiting drugs. Dr. Yaeger has also been conducting a phase II clinical trial with an AKT inhibitor for patients with metastatic colorectal cancer who have normal (wild type) KRAS.

If you are interested in learning more about the future of cancer treatments, or if you’ve ever donated to the Fight Colorectal Cancer Lisa Fund, do not miss this webinar!

Personalizing personalized medicine
Monday, April 25, 2011
8 – 9 PM Eastern

Carolyn Grande, CRNP, AOCNP

Oncology nurse practitioner Carolyn Grande will make personalized medicine a little more personal during this webinar. If you’ve ever heard your doctor mention “tumor markers,” “biomarkers,” “KRAS”, “BRAF,” or “tumor pathways” and wondered what he or she meant, this webinar is for you. In fact, Carolyn may even be able to explain why Rona Yaeger’s pathway research (above) could mean big answers for colorectal cancer patients some day.

Carolyn is a member of Fight Colorectal Cancer’s Medical Advisory Board. In March, she presented this information to the advocates who participated in our Call-on Congress. Her presentation was so popular, we asked and she graciously agreed to make it a part of our webinar program. Don’t miss out!

Treating liver mets
Monday, May 16, 2011
8 – 9 PM Eastern

Dr. Andrew Kennedy

The liver is usually the first place where colorectal cancer metastasizes, so learning to manage tumors in the liver can help stage IV patients survive longer. Fortunately, liver directed therapies have evolved over the last two decades so patients with metastatic or primary liver tumors now have many new treatment options.

We are pleased that one of the leading researchers on liver metastases in the country has agreed to speak about these new options with us and our webinar participants. Join Dr. Andrew Kennedy and learn about how you may be impacted by these new discoveries. Register today.

Don’t worry if you’ve missed some of our webinars.

We archive them! You can watch and listen to the following patient webinars any time (in descending chronological order):

If there is a KRAS mutation in the primary colon or rectal tumor, there is almost always a matching mutation when that tumor spreads to the liver.

Researchers in the Netherlands tested both tumors for KRAS mutations in over 300 patients whose cancer had spread to their livers.

They found about a third of patients had KRAS mutations and KRAS status matched in 96 percent of the cases, making it possible to test either tumor to make decisions about treatment with Erbitux® (cetuximab) or Vectibix® (panitumumab)

Out of 305 tumors:

• 108 had a KRAS mutation in either the primary colorectal or metastatic liver tumor (35.4 percent)
• KRAS mutations didn’t match in 11 of the 108 (3.6 percent)
• Of those:
  • 5 had a wild-type (normal) primary and KRAS mutation in the liver metastasis
  • 1 had a KRAS mutated primary and the liver met was wild-type
  • 5 had different KRAS mutations in the primary and liver tumors.

Nikki Knijn and her team at the Nijmegen Medical Centre in the Netherlands concluded,

We observed a high concordance of KRAS mutation status of 96.4% (95% CI 93.6–98.2%) between primary colorectal tumours and their corresponding liver metastases. In only six patients (2.0%; 95% CI 0.7–4.2%), the discordance was clinically relevant. In this largest and most homogenous study to date, we conclude that both primary tumours and liver metastases can be used for KRAS mutation analysis.

SOURCE:  Knijn et al., British Journal of Cancer, Published online March 1, 2011.

SIRT Microspheres

When surgery is not possible to remove colorectal cancer that has spread to the liver, inserting radioactive beads into the liver through its large artery may reach tumors and destroy them.

Called Selective Internal Radiation Therapy or SIRT, either resin carrying radioactive Yttrium-90 are inserted into the liver through a catheter in the hepatic artery in the groin. The tiny microspheres travel through the artery into the rich system of blood vessels that feed liver tumors. The beads get trapped in the tiny blood vessels near tumors and emit radiation that destroys cancer cells.

Radiation continues for about 14 days. After that the tiny beads, each less than a third of the diameter of a single strand of hair, remain safely within the liver.

Radiation from microspheres affects only tumors within the liver and doesn’t harm other parts of the body.

Before treatment begins, a planning angiogram is necessary. Resin beads without radioactive Yttrium are inserted through the hepatic artery and followed to be sure that the system of liver blood vessels will let them reach the tumors and not go beyond the liver where radiation could hurt other parts of the body.

SIRT treatment is delivered by an interventional radiologist with special training and experience with the procedure. Find a center where the procedure is done.

Currently, SIRT is covered by Medicare and many insurance companies for people whose colorectal cancer has already gotten worse on chemotherapy and who are not appropriate for liver surgery.

Where Can You Go for More Information

• View a recording of our patient webinar, “Treating Liver Metastases” 
• SIRTEX, the manufactures of SIR-Spheres resin microspheres has information especially for patients on their website, including frequently asked questions and some excellent videos.
• Support and information for patients by patients is available from YES, both online and via toll-free telephone.

Patients with liver tumors, including those that have spread from colorectal cancer, can enroll in a clinical trial at the National Institutes of Health Clinical Center in Bethesda.

The trial will test the effectiveness of infusing the drug melphalan through the artery that feeds the liver.

Colorectal cancer patients with liver metastases are eligible for the trial if they have already had chemotherapy including irinotecan or oxaliplatin.  Limited cancer outside of the liver is acceptable if the most serious problem is within the liver itself.

Treatment involves placing catheters in both the hepatic artery and hepatic vein.  Melphalan is pumped through the hepatic artery for about  15 to 30 minutes and the liver bathed in the chemo drug (hepatic perfusion). The infusion will be repeated every 3 to 8 weeks up to 4 times.

The trial and its treatment takes place at the NIH Clinical Center in Bethesda, MD, just outside of Washington, DC.

There is no cost for care received at the NIH Clinical Center.  Travel expenses and reasonable costs for meals and lodging are also paid to trial participants.

Patients with primary liver cancer, neuroendocrine tumors, or liver metastases that have spread from other gastrointestinal cancers are also eligible for the trial.

For more information, you can contact:

• Itzhak Avital, MD
• Principal investigator
• Phone: 301-402-0083
• Fax: 301-496-0734
• avitali@mail.nih.gov

Or make a referral through:

• Carole Webb, RN
• Research Nurse
• Phone: 301-451-6940
• Webbcc@mail.nih.gov

More information for patients about the trial is available on the National Cancer Institute website.

NCI-04-C-0273: A Phase II Study of Hepatic Arterial Infusion of Melphalan With Venous Filtration via Peripheral Hepatic Perfusion (PHP) for Unresectable Primary and Metastatic Cancers of the Liver

Patients under 40 appear to have more aggressive liver tumors from colorectal cancer and poorer long-term outcomes.

After surgery to remove the cancer that had spread to their liver, patients who were 40 or younger had poorer overall survival and shorter time until cancer returned.

The percentage of younger patients who were alive without cancer five years later was similar to older patients, which the research team attributed to more aggressive treatment for the young patients, along with repeated surgery. 

All patients who had surgery to remove colorectal cancer that had spread to their livers (liver resection) at the French Hôpital Paul Brousse from 1990 through 2006 were studied.  56 of 806 (7 percent) were 40 years old or younger.

They had more liver metastases when they were diagnosed  than older patients, and liver tumors were more often found at the same time as their primary tumor in colon or rectum.

Comparing younger and older patients:

• Half of older patients (51 percent) were alive at five years (overall survival) compared to a third (33 percent) of the younger ones.
• Only 2 percent of  young patients didn’t have cancer get worse during the five years after surgery (progression-free survival) compared to 16 percent of older ones.
• Disease-free survival at five years was similar in both groups (17 percent for young, 23 percent for older.)
• Being 40 or younger independently predicted poor progression-free survival.

Robbert J. de Haas, MD and his colleagues concluded,

In young patients, colorectal liver metastases seem to be more aggressive, with a trend toward lower overall survival, more disease recurrences, and a significantly shorter progression-free survival after hepatectomy. However, disease-free survival rates were comparable between young and older patients, owing to an aggressive multimodality treatment approach, consisting of chemotherapy and repeat surgery. Therefore, physicians should recognize the poor outcome of colorectal liver metastases in young patients and should consider an aggressive approach to diagnosis and early treatment.

SOURCE: de Haas et al., Cancer, Volume 115, Issue 3, Pages 647 – 658, February 1, 2010.

How useful is radiofrequency ablation (RFA) in treating liver metastases from colorectal cancer?

To answer that question, American Society for Clinical Oncology scientists included two C3 advocates, Rob Michelson and Dr. Andrew Guisti, on an expert panel looking at published RFA research.

In appreciation, the panel dedicated their Clinical Evidence Review to Michelson who died in January, 2008.

The Expert Panel wishes to dedicate this Clinical Evidence Review to Rob Michelson, who served as the patient representative at the Panel meeting in October 2007 and passed away early in 2008. His contributions at the meeting and as a reviewer of the first draft were substantive and thought provoking.

While the panel could not find sufficient evidence to establish an evidence-based practice guideline for RFA to treat cancer that had spread to the liver from the colon or rectum, they did complete a review of existing studies and called for more research into the usefulness of RFA to improve outcomes for patients with liver metastases from colorectal cancer.

In reviewing existing medical literature, the panel focused on three important questions:

• The effectiveness of RFA versus surgical resection for those tumors that could be surgically removed  (resectable).
• The usefulness of RFA to treat tumors that could not be surgically removed (unresectable).
• RFA approaches (open, laparoscopic, or percutaneous).

Radiofrequency ablation uses metal probes  and low frequency electric current to heat and destroy tumor tissue.  Radiofrequency also seals small blood vessels to reduce bleeding risk.  Because heat is confined to the cancerous tissue, patients don’t feel it and normal liver tissue is protected.

RFA can be performed during an open surgery, laparoscopically, or through the skin percutaneously.  During all treatments, good imaging is critical to be able to see the tumor being ablated.  CT scans, MRI, or ultrasound can be used during percutaneous RFA, but intraoperative ultrasound is used during an open or laparoscopic operation.

Postablation syndrome occurs in about 30 to 40 percent of patients, usually beginning three days after an RFA procedure and lasting about five days.  Patients experience low-grade fever, chills, malaise, achiness, pain, and nausea and vomiting.  It is more common when large tumor volumes are treated and is probably due to inflammation as treated tissues die.

Other complications from RFA were relatively low and were more common in open as opposed to percutaneous methods.  There were fewer complications among more experienced doctors and in hospitals with more RFA experience.

The Expert Panel included an Appendix to help doctors discuss options with patients to manage liver metastases from colorectal cancer.

Panel members concluded,

There is a compelling need for more research to determine the efficacy and utility of RFA to increase local recurrence-free, progression-free, and disease-free survival as well as overall survival for patients with colorectal hepatic metastases. Clinical trials have established that hepatic resection can improve overall survival for patients with resectable colorectal hepatic metastases.

SOURCE: Wong et al., Journal of Clinical Oncology, Volume 28, Number 3, pages 493-508, January 20, 2010.

What should you and your doctor talk about if your colon or rectal cancer has spread to your liver?

Deciding on the best way to manage liver metastases from colorectal cancer isn’t easy. It’s best done with the involvement of  multidisciplinary team of doctors and thoughtful discussion with the patient.

In developing the ASCO 2009 Clinical Evidence Review on Radiofrequency Ablation of Hepatic Metastases From Colorectal Cancer, the Expert Panel developed points for patients and physicians to consider during an office visit to learn about treatment options.

In an Appendix to their Evidence Review, the Panel wrote the following for physicians meeting with patients:

Discussion Points Between the Patient and Physician: Hepatic Resection and/or Other Treatment Options (eg, Radiofrequency Ablation) for Hepatic Metastases From Colorectal Cancer

• State that the goal of the appointment is to make sure the patient understands all the treatment options and has all the information needed to make a choice. Ask the patient, “What are your goals for this visit?”
• Ask the patient how much prognostic information he/she wishes to hear during the discussion and whether he/she prefers to hear risk and benefits estimates conveyed as numbers (eg, 30%) or as words (eg, very small). It is important to understand the patient’s perceptions of risks and benefits and to discuss other patient/family issues that might influence decision making.
• Tell the patient that treatment for hepatic metastases from colorectal cancer is often performed in stages and may be ongoing.
• Discuss the role chemotherapy may play in determining if and when hepatic resection is recommended and/or if radiofrequency ablation (RFA) or other treatment is considered.
• Tell patients with resectable tumors that hepatic resection is recommended and the prognosis is good (5-year survival for 40% of patients and 10-year survival for 20% of patients). There are differences in survival for patients with single versus many tumors and small versus large tumors.
• If RFA is considered for unresectable tumors, discuss which method (open, laparoscopic, or percutaneous) is indicated and whether the RFA procedure will be performed alone or at the same time as hepatic resection. Discuss imaging, surgery, anesthesia, hospital stay, and recovery issues. Consider patient preferences.
• Any comorbidities and/or patient preferences should be discussed in detail and placed in perspective as to their effect on potential benefit of therapy versus potential risk.
• Discuss possible complications.
• Tell the patient about the importance of high-quality, up-to-date preprocedural imaging as well as the importance of follow-up computed tomography or magnetic resonance imaging scans according to the recommended schedule after the procedure to determine whether the tumor was completely ablated and to plan for additional treatments as necessary. Explain how the appointments will be scheduled.
• Additional potential prognostic and predictive markers should be discussed (eg, carcinoembryonic antigen).
• Talk to the patient about colorectal cancer surveillance and the importance of all follow-up appointments, tests, and scans. Encourage the patient to use the American Society of Clinical Oncology Colorectal Cancer Surveillance Flow Sheets to keep track of follow-up appointments.

SOURCE: Wong et al., Journal of Clinical Oncology, Volume 28, Number 3, January 20, 2010.

Patients with stage IV colorectal cancer live longer when tumors in their liver can be removed surgically, but not all patients have cancer that can be operated on.

Separating patients with liver tumors from colorectal cancer into three groups according to possible liver resectability, British doctors found a wide variation in both overall survival and progression-free survival three years later.

A team of surgeons, medical oncologists, and radiologists at the Royal Marsden Hospital in London divided patients in a clinical trial studying CAPOX chemotherapy into three groups:

• A — those whose treatment was considered to be palliative and not treatable with surgery.
• B — those where chemotherapy might convert initially unresectable metastases and make surgery possible.
• C — patients with resectable liver mets receiving neoadjuvant chemotherapy before surgery.

Among 128 patients who were part of the study, 74 were in the palliative group, 22 in the conversion, and 32 in the neoadjuvant groups.

Patients had scans every four  chemotherapy cycles, and when it was possible liver surgery was attempted after four or eight cycles.

• Ten patients (45 percent) of the conversion group and 19 (59 percent) of the neoadjuvant group eventually had surgery.
• Three years later, 10 percent of the conversion and 37 percent of the neoadjuvant group were alive and their cancer had not gotten worse (progression-free survival).

Median overall survival for all three groups:

• Palliative treatment — 14.6 months
• Conversion chemotherapy — 24.5 months
• Neoadjuvant chemo — 52.9 months

Patients in the study received CAPOX chemotherapy in three week cycles.  The CAPOX regimen was oral Xeloda® (capecitabine) daily for 14 days after an initial infusion of oxaliplatin on day one.

The team concluded,

This prospective study shows the wide variation in outcome according to baseline resectability status and highlights the potential clinical value of a modified staging system to distinguish between these patient subgroups.

SOURCE: Watkins et al., British Journal of Cancer, Volume 102, pp. 255-261, published online January 19, 2010.

Chemotherapy and Erbitux® (cetuximab) reduced liver tumors from colorectal cancer enough for patients to have them removed surgically.

Although their cancer was initially too extensive to be surgically removed (resected) chemotherapy combined with Erbitux allowed about a third of patients to have surgery that completely removed all visible signs of liver tumors.  Tumor shrinkage occured in about two out of three patients, despite which chemotherapy was used.

During a phase II clinical trial in Germany and Austria, 111 patients with colorectal cancer that had spread to their liver were treated with Erbitux and either FOLFOX6 (oxaliplatin, fluorouracil, and leucovorin) or FOLFIRI (irinotecan, fluorouracil, and leucovorin).  All were considered to have liver tumors that could not be removed surgically.

Every eight weeks, CT scans or MRIs were used to measure any tumor shrinkage (response). After 16 weeks and then every 8 weeks for two years, a local, multidisciplinary team decided whether the situation had changed and patients were able to have surgery.

The study found:

• 38 of 53  patients (68 percent) on FOLFOX6 had a partial or complete response to treatment with measurable tumor shrinkage compared to 30 of 53 (57 percent) of those on FOLFIRI.  This difference between chemotherapies was not significant.
• 20 of 53 patients (38 percent) on FOLFOX were able to have surgery that removed all signs of cancer in the liver, including tumor margins (R0 resection) while 16 of 53 (30 percent) of FOLFIRI patients had an R0 resection.  Again, this was not a significant difference.

The study included patients with both KRAS and BRAF mutations.  Normal or wild-type KRAS made a difference in response to treatment with 70 percent of KRAS wild-type tumors shrinking compared to 41 percent of tumors with KRAS mutations.

Serious side effects included skin rash in 34 percent of patients and lowered white cell counts (neutropenia) in 23 percent.

Dr. Gunner Folbrecht and the CELIM team concluded,

Chemotherapy with cetuximab yields high response rates compared with historical controls, and leads to significantly increased resectability.

After the trial was over, a team of radiologists reviewed patient scans at the beginning and end of treatment to access how many could have had surgery initially and how many after chemotherapy (resectability rate). The radiologists didn’t know which patients had been able to have surgery or what chemotherapy they received.  The team found that the percentage whose tumors could have been operated on almost doubled during treatment from 32 percent initially to 60 percent after chemotherapy with Erbitux.

In a comment in HemOnc Today, Alan Vernook, MD, points out that although all patients had to have unresectable tumors to be included in the trial, the blinded retrospective review found that almost a third could have had surgery initially.  He urges multidisciplinary team involvement in treatment of patients with liver mets.

One interesting finding is that these patients were deemed unresectable at the outset as part of eligibility criteria. Yet, in a blinded independent retrospective review, about 30% of the patients were felt to be resectable. So, on one hand, the treatment effect of this study brings us the hope that in KRAS wild-type patients, cetuximab plus chemotherapy may make more patients resectable. But, it also raises the question that deeming who is resectable at the outset is in the eye of the beholder. So, this study emphasizes the need for more and more multidisciplinary therapy and the idea that one surgeon’s unresectable is another surgeon’s resectable.

SOURCE:  Folprecht et al, The Lancet, early online November 25, 2009.

Disclosure: C3 has accepted funding for projects and educational programs from ImClone Systems and Eli Lilly in the form of unrestricted educational grants. C3 has ultimate authority over website content.