Patients with colon cancer have learned over the last two years that we have now a genetic marker which can predict efficacy of antibodies against EGFR which are used in patients with metastatic colon cancer.

We have learned that tumors with mutations in KRAS will not benefit from this treatment. All patients should be tested for KRAS mutation if they have advanced or metastatic disease.

However patients who have mutations of the KRAS gene don’t do worse than patients with wild type. The only difference is that the drugs which target EGFR will not work.

We really have had no marker which identifies patients who have a tumor which is very aggressive and grows independently of whatever treatment we initiate. Recent data suggest we may have identified a marker like this. The marker is called BRAF.

Only about 5 percent of patients with metastatic disease carry a mutation in this gene. Preliminary studies suggest that patients with tumors harboring this mutation do much worse. However more studies are needed to validate these findings.

The reason I am sharing this with you is because we have now therapies available which may inhibit this particular mutation. BRAF mutations are common in melanomas and bile duct cancers, and recent developments show that we may have very powerful inhibitors for patients with this mutation.

In our practice we are screening for these mutations since we have a number of clinical trials allowing patients to be tested with a BRAF inhibitor.

Please discuss these options with your oncologist if your first line therapy is not working to see  if you are eligible for clinical trials when you have either a mutant KRAS or mutant BRAF gene in your tumor.

When we see patients in our offices with metastatic colon cancer which is confined to the peritoneal cavity and the histology of the cancer shows mucinous carcinoma, we consider not only chemotherapy but also think about specialized surgery to remove the cancer in the abdomen and combine this with hyperthermia and chemotherapy given directly into the cavity during surgery.

Why is that?

This subtype of colorectal carcinoma accounts for 10 – 20 % of all colorectal neoplasms. Compared to the more common nonmucinous variety, mucinous tumors metastasize to lymph nodes with increased frequency and are more prone to spread to the peritoneal cavity. These mucinous colorectal adenocarcinomas (MCA) are a recognized subgroup of colon cancer and usually spread to peritoneal surface without spreading to the liver and lungs.

It is important to know that mucinous tumors are also more often associated with a genetic predisposition syndrome particular when they are located on the right side of the colon.

Since these are very complicated surgeries, these combined treatment procedures should be done only with a highly experienced surgeon.

Nevertheless, an increasing number of international treatment centers have published their results using cytoreductive surgery, and intraperitoneal chemotherapy and hyperthermia in the management of peritoneal surface malignancies of colorectal origin.

Because these patients need to be considered for this special therapy, I want to share with you some of the larger trials using this approach. In the retrospective multicenter study by Glehen et al. of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of PC of colorectal cancer, 506 patients were analyzed. Patients in whom cytoreductive surgery was complete had a significant longer survival than patients with incomplete surgery.

Recently, Elias et al performed a retrospective-cohort, multicenter French-study of peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy including 523 patients which confirmed the results obtained by Glehen.

The risk of surgery is high and should be only be performed in high volume centers familiar with this surgery. When patients with MCA with peritoneal carcinomatosis were treated either with standard therapies and standard surgery or with this novel approach called HIPEC, patients did much better with HIPEC, in fact the study was stopped early because HIPEC was doing so much better.

If you have mucinous colon cancer which is limited to the abdominal cavity please discuss this with your treatment oncologist.

The main criticism against the combined treatment is the lack of nonstandardized treatment techniques. Most of the centers are currently using HIPEC whereas only a few are using EPIC. Both procedures are not standardized and many variations exist in exposure techniques, drugs, drug doses, duration, temperature and flow rates, which may contribute to the differences in the results. Finally, a proper patient selection is essential to benefit from combined cytoreductive surgery and intraperitoneal chemotherapy.

Genomic Health has commercialized a new test which has been shown to be associated with risk of tumor recurrence for stage II colon cancer. The test came on the market in January of 2010.

I wanted to review with you the limitations of this test, which is  not as good by far as the test they have developed for breast cancer.

Stage II colon cancer is usually a T3 N0 lesion meaning there are no lymph nodes involved. Oncologists look very carefully at the pathology report to make sure there are no aggressive features seen such as invasion into the nerves or blood vessels or tumor cells which are poorly differentiated (which means you can’t really see where the cell comes from). These features would already indicate a higher risk of tumor recurrence.

We have other clinical features such as signs of bowel obstruction or when the surgeon removed less than 12 lymph nodes that tell us the patient has higher risk, and we usually recommend 6 months of chemotherapy.

For patients who have none of these risk factors the risk of tumor recurrence for stage II colon cancer is about 15 percent. The dilemma is what we don’t know whether the individual patient will recur or not.

The Oncotype DX®  for colon cancer measures 12 genes in the tumor tissues and separates the tumor into  low, intermediate, and high risk for recurrence. Low risk is 12%, intermediate 18% and high risk is 22%. The distinction between risk levels is much less than for breast cancer where low risk is 7% and high risk is 31%, and therefore is much less clinically helpful.

However the biggest difference between the breast and colon tests is that in the breast test the benefit from adjuvant chemotherapy is known, but for colon we don’t know if chemotherapy has any benefit in any of the risk categories.

We need a better signature to distinguish between low and high risk.  Twelve to 22 percent is only a small step, and not satisfactory to make treatment decision not knowing if there is any treatment effect. In other words your risk of 12% could mean you benefit from chemo but your risk of 22% may not.

Many companies are working on prognostic markers which can help to select patients at high risk much better for chemotherapy, I have not adapted this test for evaluation for my patients with stage II colon cancer.

Disclosure: Dr. Lenz serves as a consultant to Amgen, Bristol-Myers Squibb, Genentech, ImClone, Merck KG, Novartis, Pfizer, Response Genetics, and sanofi-aventis. He has received honoraria from Astra Zeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, Genentech, ICN, Imclone, Millenium, New Biotics, Novartis Chiron, Pfizer, Roche, sanofi-aventis. His research is funded by the National Cancer Institute and the National Institutes of Health

Disclosure:  Dr. Lenz is a consultant to Response Genetics which markets a genetics test to help patients and doctors make treatment decisions.

Disclosure: C3 has received funding from Genomic Health in the form of unrestricted educational grants.  C3 has ultimate authority over website content.

In the month of March we celebrate Colon Cancer Awareness.

Colon cancer is one of the few cancers we can prevent successfully with colonoscopy, better than breast cancer or any other cancer with the exception of cervical cancer.

It takes usually about 5-10 years to develop colon cancer, which gives us a great window of opportunity to screen. We know that usually we see polyps first, which can develop into cancer, but that normally takes years. With screening we can see polyps and remove them before they develop into cancer.

Because of this prolonged development, the recommendation have been a baseline colonoscopy at age 50 and then every 5-10 years, but if any polyps are seen repeat colonoscopy in a year except if the polyps are hyperplastic.

Yes, we can prevent colon cancer. There is no discussion that we can.

The dilemma we have is that we still see many patients in their twenties, thirties, and forties with metastatic disease who have some symptoms but are told by their physician it is upset stomach and it can’t be colon cancer because they are too young.

We need to take these symptoms seriously! Any ongoing abdominal discomfort which is not explained should include a colonoscopy as a diagnostic tool even in a young patient.

It is also critical to know that any family history, ANY, will increase your risk and particularly if the family member was diagnosed at a young age. Screening should start about 10 years younger than the family member with cancer.

It is also important to know if there is a genetic predisposition, that colonoscopies need to be done yearly, because in these patients colon cancer can develop much faster and it is possible to see cancer within a year. This syndrome is called HNPCC, hereditary non- polyposis colon cancer. As you probably noticed these patients usually have no polyps but flat lesions which are much more difficult to see on colonoscopy. It is critical to have an experienced gastroenterologist who takes his time to evaluate the colon. It has been shown that up to 20% of the lesions in the right side of the colon (the furthest away from the anus) are easily overseen if you rush in and out.

It is also important that the location of the tumor also is important for symptoms. When the tumor is on the right side, patients have some change in bowel movement habits, some abdominal discomfort, and a feeling like an upset stomach. If the tumor is on the left side, symptoms are more typical including like diarrhea, blood in the stool, and pain with bowel movements.

Please make sure you talk to your family and friends about doing a colonoscopy.

Yes we can prevent this disease.

Every year in the month of March we celebrate our patients during a reception at USC.

We invite them for food and wine in the Norris lobby which we convert into a party space. We invite patients and physicians to talk about their experiences and about new developments at our center and the progress we have made in the last year.

• USC Colon Cancer Reception
• Sunday, March 6, 2010
• 12 noon
• Norris lobby

This has always been one of the most exciting days for us because we see our patients not wearing our white coats but with a wine glass in their hands.

We also see family members of patients who have passed away come and enjoy seeing us again and meeting old friends as part of their grieving process.

It is very emotional but also raises a lot of hope for our patients and gives us the important sense we all work together and have the same goal.

If  you live in Los Angeles, please  come and visit us on Sunday March 6th at noon in the Norris lobby (parking is free in Biggy Street).

We have done this for ten years and are very proud of the progress we have made in the laboratory and clinic which directly translated into more cures and longer and better lives.

Our progress is only possible because our patients are willing to give us blood, extra tissue, and participate in clinical trials, which is critical to advance our understanding of this disease. The more we know the better we can develop new treatments.

FIGHT ON.

In this month we don’t want to only raise awareness about prevention of colon cancer. We should be aware of the significant progress we have made in the last 10 years treating it.

With the introduction of irinotecan, oxaliplatin, bevacizumab, and cetuximab, overall survival has tripled to more than two years; but this does not tell us the whole story. In the past patients with metastatic disease all died from their disease. This is not true any longer.

With more active therapies, we have cured more and more patients, particularly those whose cancer has only spread to the liver. There are increasing reports that this is also true for lesions found in one site in the lung.

With genetic testing we now can identify more active therapies, which now have response rates of 70 percent and higher, leading to more conversion of unresectable to resectable tumors.

I wanted to share with you one story of my patient who was diagnosed with metastatic disease with a liver lesion in 1998. We treated him for years with any new drug which came on the market, which translated into seven different therapies. Because of some success, we resected liver lesions three times and lung lesions twice.

He was even on a Phase I clinical trial prior to his last lung resection. We cleared both his lungs and his liver but never removed his rectal cancer.

Last year we saw on the PET scan that there was a lesion close to the rectum (colonoscopy was clean). We needed two attempts to biopsy it but found rectal cancer, which was the site of the 1998 tumor. We removed it, and we are now treating with chemo.

We kept this patient alive to have access to new medication which again allowed us to make him live longer and allow another surgery with the intent to cure. It is amazing that there are metastases left after our battle against this disease.

He has no evidence of disease after 12 years. Unfortunately this does not happen to all patients but gives us hope that we have developed a lot of new treatments which will help more patients.

There is hope and cure for more and more patients.  FIGHT ON.

Recent studies from Swedish investigators suggest that blueberries may prevent colon cancer development. They suggest that blueberries should be eaten with probiotic yoghurt to further improve the benefit.

We have known for many years that antioxidants may have protective effects, but no prospective studies have validated these findings. There is a lot of data showing that colored fruits and vegetables affect cancer development, but so far we have not seen trials proving their effect.

However we know that ongoing oxidative stress is a major part of developing colon cancer. Antioxidants can help the normal cells to defend against oxidative stress. We had big hopes for selenium however it did not show the benefit we all hoped for. However we have learned in recent years that the environment in the colon may be very important.

The presence of good bacteria (probiotics) not only help with your bowel movements and regularity (ACTIVA), but these bacteria may influence the way cancer develops. The interaction of the colon mucosa (linings), bacteria, and potential agents which can cause cancer are very important.

We have started to recommend probiotic yoghurt to all our patients because of this impact on the gastrointestinal tract. How the antioxidants and bacteria interact is unclear but these data suggest that we can change the environment with bacteria and supplements and reduce the risk of colon cancer.

We are a long way to better understanding of how to further reduce colon cancer risk successfully. The exciting new data also suggest that these good bacteria may also impact how cancer behaves if it develops.

EAT your yoghurt with blueberries.

At ASCO in June 2009  a study was presented showing potential benefit of a novel inhibitor of AKT and MAPK in patients with metastatic colon cancer in second and third line chemotherapy.  An update at the 2010 ASCO GI meeting in January further confirmed these promising results.

This was a randomized phase II study comparing Xeloda alone versus a combination of Perifosine and Xeloda.

The target of this novel inhibitor are AKT and MAPK and JNK pathways, which are frequently altered in patients with metastatic colon cancer. When AKT is mutated or highly active, colon cancer cells grow and spread more aggressively and are more resistant to chemotherapy.

Perifosine is the first inhibitor of AKT which shows very promising clinical benefit. The time to tumor progression doubled for patients who received perifosine and Xeloda compared to patients who received only Xeloda.

The Keryx Biopharmaceuticals, the company manufacturing Perifosine, is planning a registration phase III trial to get this drug approved for the market.

In the future we hope to have more drugs like this which target colon cancer’s specific genetic make up. What we need to do in the future is select patients who benefit the most from these specific targeted agents. We need to find out what tumors have activated these pathways.

Swedish scientists  reported in the American Cancer Society Journal of Natural Products that cardiac glycosides, which are a family of naturally derived drugs which are used to treat congestive heart failure and arrhythmia, show anti-tumor activity against colon cancer cells.

There is little known how these drugs work as potential anti-cancer agents. These scientists screened several of these glycosides in colon cancer cell lines, and they found that the drugs were all effective, to varying degrees, at killing the cancer cells. The sensitivity, however, was rather low when compared to that of other cancer cell types reported previously.

Several of the drugs also showed increased anticancer activity when combined with certain drugs used for standard chemotherapy. The findings suggest that these heart drugs may affect colon cancer outcome when used alone or combination with conventional chemotherapy drugs.

These drugs are found in the leaves of the oriental foxglove plant and contain digitoxin, a drug used to treat heart disease.

These are very early results and may trigger more research in this family of drugs for further development.

You may know this already, but we have now more proof that physically activity reduces significantly your risk of tumor recurrence.

The study conducted by Dr. Jeffrey Meyerhardt from the Dana Farber Cancer Institute began in January 1986, included 668 men who’d been treated for stage I, stage II or stage III colon cancer that had not spread (nonmetastatic cancer).

Every two years, the men were sent questionnaires that asked them about any new cancer and disease diagnoses, as well as their physical activity. A metabolic equivalent task (MET) score was matched to each type of physical activity, with exercises that burned more energy receiving higher MET scores.

During the study period, which ended in January 2006, 258 of the participants died, including 88 who died from colon cancer. The results show that men who were physically active after diagnosis of nonmetastatic colorectal cancer experienced a significantly decreased risk of colorectal cancer-specific death, as well as death from any cause. This benefit was independent of age, disease stage, body mass index and tumor location and from the pre-diagnosis physical activity.

This manuscript was published in the Archives of Internal Medicine on December 14. These data show that physical activity will help in your fight against colon cancer for anyone.

Turn off your TV and start exercising.