• Hormone replacement therapy reduces risk of colon cancer.
• Smoking before age 30 increases chances that colon cancer will recur.
• Low CEA levels improve both survival and disease-free survival for stage II colon cancer.
• Most patients want videos of their colonoscopies and are willing to pay for them.

Use of hormone replacement therapy reduces colon cancer

Women in a study of California teachers who were taking hormone replacement therapy (HRT) after menopause had a 36 percent reduced risk of colon cancer over ten years than women who weren’t on HRT at the beginning of the study.  Risk reduction was even greater for women with a first-degree relative who had colon cancer.  Their risk fell 55 percent.

Over 57,000 women were part of the study, about 60 percent of them on HRT at the study start.  Over the next ten years, 444 got colon cancer.

Despite the reduction in colon cancer in the study, doctors caution women about using HRT because of raised risks for breast cancer, heart attack, stroke, and blood clots.  Advice is to use the lowest dose for the shortest time to offset severe menopausal symptoms.

Katherine DeLellis Henderson, PhD, reports the study results in the February 15, 2010 issue of the American Journal of Epidemiology.

Early smoking history reduces disease-free survival after colon cancer

Patients with stage III colon cancer who had a smoking history of 12 or more pack years before they were 30 had almost a 40 percent increased risk of having their cancer return within three years compared to patients who had never smoked.

Among the 1,045 study participants, 46 percent had never smoked, 44 percent were past smokers, and 10 percent were currently smoking.

Disease-free survival three years after treatment was about 18 percent greater for people who had never smoked than for past smokers.

The results, based on questionnaires filled out by patients in the CALGB 80893 adjuvant chemotherapy trial, were published by Nadine Jackson McCleary, MD, MPH,and her colleagues in Cancer, February 15, 2010. They wrote,

Total tobacco usage early in life may be an important, independent prognostic factor of cancer recurrences and mortality in patients with stage III colon cancer.

CEA levels before surgery important for stage II prognosis

Patients whose CEA (carcinoembryonic antigen) blood levels before surgery were low — below 5 ng/ml — had significantly better overall and disease free survival than those whose CEA’s were 5 or higher.  For those with low CEA, overall survival at five years was 81.7 percent compared to 69.9 percent for high CEA.  Disease-free survival was 82.4 percent for low CEA and 70.6 percent for CEA that was 5 ng/ml or higher.

However, CEA levels only made a difference in stage II patients.  There was no significance for stage I or III.

Writing in the Journal of Surgical Oncology, Korean surgeon Jung Wook Huh, MD and colleagues concluded,

Preoperative serum CEA is a reliable predictor of recurrence and survival after curative surgery in patients with colon cancer, particularly in those classified as having stage II disease.

Patients want videos of their colonoscopies

Eight out of ten patients having colonoscopies said that they would like to have a video recording of their colonoscopy, and more than 6 of 10 (63 percent) were willing to pay for it.  After reading a brief paragraph explaining missed lesions during colonoscopy, over half (54 percent) were more interested in a video and none were less interested.

Meghana Raghavendra surveyed 248 outpatients at the Indiana University School of Medicine and reported the results in the World Journal of Gastroenterology, in an early online article January 28, 2010.

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.

Information from 17,641 colon cancer patients in the German Colon/Rectum Cancer Study Group found that people with cancers on the right side of the colon were older, had more chronic illness, and were more likely to be women.  There were significantly more deaths in this group.

While the rate of metastastic cancer spread was similar for both right and left sided tumors, spread to the liver or lungs was more common in the left-sided cancers and peritoneal carcinomatosis from tumors on the right.

Right-sided tumors were more often poorly differentiated and found in nearby lymph nodes (stage III.)

Even after adjusting for risk factors, survival was worse for cancers on the right side.

Right-sided tumors (proximal) included those in the the ascending and transverse colon, while the left side includes the descending and sigmoid colon nearest to the rectum (distal).

Frank Benedix, MD and the team from the Colon/Rectum Carcinomas Study Group concluded,

We found that right- and left-sided colon cancers are significantly different regarding epidemiological, clinical, and histological parameters. Patients with right-sided colon cancers have a worse prognosis. These discrepancies may be caused by genetic differences that account for distinct carcinogenesis and biological behavior. The impact of these findings on screening and therapy remains to be defined.

SOURCE: Benedix et al., Diseases of the Colon and Rectum, Volume 53, Issue 1, pp 57-64, January 2009.

Image courtesy of the National Cancer Institute Visuals Online.

BRAF mutations, which are less common, don’t help with prognosis for relapse-free survival, but do provide information about overall survival in some tumors.   Patients with BRAF mutations and microsatellite-low or stable tumors had poorer overall survival than those without mutations.

As colon cancer develops, changes in genes accumulate that affect cell division and cell death.  When cells no longer divide or die normally, tumors get larger and some cells may break off and move to new and dangerous sites.

In earlier studies, changes in the KRAS and BRAF genes have been able to predict whether or not advanced colorectal cancer would respond to drugs that target epidermal growth factor receptors (EGFR).  Patients with tumors that have mutated KRAS or BRAF don’t benefit from either Erbitux® (cetuximab) or Vectibix™ (panitumumab).

But it has been unclear whether mutations in these two genes can provide information about whether early stage II or III colon cancer would recur or what the mutations meant for eventual survival.

Using over 1,400 tumor specimens collected during a large, randomized trial of chemotherapy for stage II and III colon cancer, researchers were able to analyze KRAS and BRAF mutations and their impact on both relapse-free and overall survival.  The scientists also looked at microsatellite instability (MSI) and coordinated it with the KRAS and BRAF results.  They had good long-term information about patient relapse and survival.

About 1 in 3 tumors (37 percent) had a KRAS mutation, similar to the percentages found in other studies in metastatic colorectal cancer.  7.9 percent had a BRAF mutation, and the two mutations were mutually exclusive.  Neither KRAS nor BRAF mutations differed between stages II or III.

KRAS mutations

• Were significantly more frequent in l0w-grade tumors and right-sided tumors.
• Were borderline more common in microsatellite-low and microsatellite-stable tumors.
• Did not predict relapse-free survival or overall survival.

BRAF mutations

• Were more frequent in right-sided tumors, high-grade tumors, and tumors that were MSI-high.
• Were more frequent in patients over 60 and in women.
• Did not predict relapse-free survival.
• Did predict poorer overall survival, particularly in patients with MSI-low or MSI-stable tumors.

Arnaud D. Roth, MD and his colleagues concluded,

In stage II-III colon cancer, the KRAS mutation status does not have major prognostic value. BRAF is prognostic for OS in MS-L/S tumors.

SOURCE:  Roth et al., Journal of Clinical Oncology, Early Release, December 14, 2009.

Women followed as part of the California Teachers Study who used NSAIDS regularly had more than 40 percent reduction in colorectal cancer deaths and a 30 percent  reduced chance of dying overall.

Among women in the study, there were 621 women wh developed colorectal cancer.  In that group

• 64 percent had no pre-diagnosis use of NSAIDS including aspirin and ibuprofen.
• 17 percent used them 1-6 days a week.
• 20 percent used them daily.
• 17 percent reported less than 5 years of NSAID use.
• 18 percent reported use for more than 5 years.

After adjusting for other colorectal cancer risk factors, regular use (1-3 days a week, 4-6 days a week, and daily) resulted in a 29 percent overall survival (HR 0.71) and 42 percent colorectal cancer survival (HR 0.58) improvement compared to those women who didn’t use NSAIDS at all.

Women who used NSAIDs for five years or more had 35 percent reduced risk  of dying from any disease and a 60 percent increase in colorectal cancer specific survival.

Writing in Cancer, Jason A. Zell, DO, MPH, and his colleagues concluded,

When used regularly or over a prolonged duration before CRC diagnosis, NSAIDs are associated with decreased mortality among female CRC patients.

SOURCE: Zell et al., Cancer, published early online October 13, 2009.

Patients whose cancers had high microsatellite instability (MSI) had significantly better outcomes at every stage, but mutations in the KRAS gene predicted poorer survival.

Scientists in New York cancer centers assessed MSI and KRAS genetic mutations in 532 primary colorectal cancers removed during surgery.  Twelve percent of cancer had high levels of microsatellite instability (MSI), while 36 percent had mutations in the KRAS gene.

MSI was more common in early stages with very little MSI in cancers diagnosed at stage IV where cancer had spread beyond the colon:

• stage I– 15 percent
• stage II — 21 percent
• stage III — 10 percent
• stage IV — 2 percent

KRAS mutations were more evenly distributed across stages:

• stage I– 36 percent
• stage II — 34 percent
• stage III — 35 percent
• stage IV — 40 percent

Patients with MSI were much less likely to die of cancer within five years of their diagnosis.  More than 9 out of ten (92 percent) were alive five years later compared to 6 of 10 (59 percent) of those who didn’t show MSI.

KRAS was the opposite story.  Mutations in KRAS led to poorer five year survival with 55 percent alive compared to 68 percent of patients with normal KRAS (wild-type).

The researchers noted that there was a group of stage I and II patients who had a particularly poor chance of living 5 years.  Those patients didn’t have MSI but did have KRAS mutations.

Garrett M. Nash from the Department of Surgery at Memorial Sloan Kettering and his colleagues concluded,

MSI and KRAS mutation provide fundamental genetic signatures influencing tumor behavior across patient subsets and stages of tumor development.

SOURCE: Nash et al., Annals of Surgical Oncology, published online October 8, 2009.

While overall patients with stage I or IIA colon cancer (early stage) have a lower risk of cancer returning than patients with stage IIB or III (later stage), careful surveillance after surgery is as effective in finding and treating cancer in both groups.

About one in three patients in both the early and late stage who had a recurrence detected during surveillance were able to have surgery with the goal of curing their cancer.  

Using information from the Clinical Outcomes of Surgical Therapy (COST) study, researchers divided 872 patients without metastatic colon cancer into two categories:

• Early stage disease: stages I or IIA
• Late stage disease: stages IIB and III

All patients in the study, no matter their stage at diagnosis, followed the same surveillance plan after surgery.

• History and physical exam every 3 months for 1 year then every 6 months to 5 years
• Carcinoembryonic antigen (CEA) blood test every 3 months for 1 year then every 6 months to 5 years
• Chest x-ray every 6 months for 2 years then every 1 year to 5 years
• Annual colonoscopy if positive for polyps or cancer; exam every 3 years if first one was negative
• CT scan of abdomen at discretion of physician for symptoms, signs, or increased CEA

Results found:

• By five years, about 1 in 10 early stage patients had a recurrence of their cancer (9.5 percent) compared to about 1 in 3 late stage patients (35.7 percent).
• Sites where cancer had spread were similar in both groups, although late stage patients were more likely to have spread to more than one site.
• Median survival after surgery for recurrence, when possible, was 51.2 months for early stage and 35.8 months for late stage patients.

There was little difference between groups  in how the recurrence was initially found:

• Elevated carcinoembryonic antigen (CEA) test found 29 percent of early versus 37 percent of late stage recurrent cancers and was the most common way of finding recurrences, particularly in the second year when it found more recurrences than CT-scan, chest x-ray, and colonoscopy combined.
• CT-scans uncovered 24 percent of early versus 26 percent of late stage recurrences.
• Chest x-rays found 7 percent of early versus 12 percent of late stage recurrence.
• Colonoscopy found 13 percent of early versus 9 percent of late ones.

Of the entire group of 537 patients with an early stage diagnosis (stage I and IIA), 55 had a recurrence.  20 of them went on to a second surgery and had a median survival of 51 months after their operation.  Those for whom surgery wasn’t possible had a much shorter survival of about 9 months.

There were 254 patients initially diagnosed as late stage (stage IIB and III).  Of those, 91 experienced a recurrence and 32 were able to have a second surgery.  Like the early stage patients, a second surgery led to much longer survival — 36 months versus 11 months without surgery.

Vassiliki L. Tsikitis and the study team concluded,

Patients with early-stage colon cancer have similar sites of recurrence, and receive similar benefit from postrecurrence therapy as late-stage patients; implementation of surveillance guidelines for early-stage patients is appropriate.

SOURCE: Tsikitis et al., Journal of Clinical Oncology, Volume 27, Number 22, August 1, 2009.

The National Comprehensive Cancer Network provides online treatment summaries for people with cancer, and new rules from the Department of Health and Human Services require that patients be notified when HIPAA rules are broken and their privacy is compromised.

Research Reports

• Unmarried cancer patients who are separated from their spouses at the time of diagnosis but not widowed or divorced have worse five year survival and ten year survival.  We’ve known for a while that married patients do better than unmarried ones, perhaps because support helps compliance with treatment.  However, review of SEER data for nearly 4 million cancer patients from 1973 through 2004 found that separated patients had the worst survival, followed in order by the  widowed, divorced, and never married.  For reasons yet undetermined, separated patients were 72 percent less likely to be alive five years after diagnosis than married people with cancer and 64 percent less likely after ten years.  Gwen C. Sprehn, PhD and her team at Indiana University School of Medicine report their study in Cancer online August 24, 2009.
• When cancer spreads to nerves near rectal and colon tumors, patients are four times as likely to die of cancer within five years of their diagnosis and twice as likely to experience a recurrence of stage II or III disease.  Perineural invasion or PNI was found in about 1 out of every 5 colorectal cancers by a research team at the VA Medical Center in Houston.  In particular, stage II (node-negative) patients with PNI had significantly worse outcomes than even stage III patients without PNI.  Although the researchers didn’t have enough information to draw a firm conclusions, it appeared that those stage II patients with PNI who got chemotherapy after surgery did as well as stage II patients without PNI.   PNI was more common as the cancer stage increased, with no cases in stage I and 57 percent in stage IV.   Catherine Liebig and her team report their study results in the Journal of Clinical Oncology Early Release September 8, 2009.

Other Headlines

• The NCCN Treatment Summaries for People with Cancer™ provide information for patients based on the National Comprehensive Cancer Network  Clinical Practice Guidelines in Oncology used by oncologists to guide treatment decisions.  For patients with colorectal cancer, treatment summaries include Colon and Rectal Cancer Overview, as well as Colon Cancer-Stage 0,I,II, and III and Rectal Cancer — Stage 0,I,II, and III. For advanced colorectal cancer patients there is Colon and Rectal Cancer-Stage IV.
• People must now be notified when their health information privacy is violated. New rules from the Department of Health and Human Services require that health care providers, health plans, and other groups covered by the Health Insurance Portability and Accountability Act (HIPAA) notify individuals when privacy is breached.  In cases where a breach covers more the 500 individuals, the media and the HHS Secretary must be told.  For fewer than 500 people, the HHS Secretary must be notified on an annual basis, but individuals must be told immediately.

Aspirin is a very interesting drug which has showed to reduce the risk of cardiovascular disease and colon cancer risk and is a great pain reliever. The mechanism of action is the inhibition of an enzyme called COX-2.

However aspirin also inhibits COX-1 which is thought to be responsible for some of its side effects such as stomach ulcers, bleeding disorders and kidney problems. Therefore major pharmaceutical companies have developed specific COX-2 inhibitors to have the great benefits but not the side effects. These drugs are known as Celebrex and Vioxx.

It was shocking to see the results from the large VICTOR trial testing Vioxx in patients with colon cancer who had successful resection and adjuvant chemotherapy. This trial enrolled 1167 patients and 23 cardiovascular thrombotic events occurred (heart attacks), 16 were in the Vioxx group and 7 in the placebo group. Statistically this was highly significant making it an estimated risk of 2.66 which means increase by 266 percent. These data were the end of the COX-2 inhibitors in the chemoprevention world.

The newest study on aspirin shows clearly that the inhibition of these enzymes may benefit patients with active disease. Dr. Chan showed in 1300 patients with colon cancer were nearly 30% less likely to die from their cancer.

How aspirin works, we don’t know. It can prevent blood clots, but COX-2 is directly involved in inflammation which can be part of cancer, and invasion and metastases. These data warrant further studies of the role of these drugs for patients with colon cancer.

I discuss and use baby aspirin  for many of my patients but also let them know about the potential risk factors. For example someone with bleeding problems or stomach ulcer or kidney function problems would be not great candidate. However for patients on Avastin I do consider aspirin to potentially reduce the risk for heart attack and strokes.

Please discuss these findings with your treating oncologists.

Surgical robots are being developed with a light touch that can tell the difference between normal and tumor tissue.

Research Reports

• About 12 percent of stage I and II colon cancer patients in a German study had one or more clinical characteristics that increased their risk of dying from their cancer.  Overall, cancer-specific survival for the group was 94.8 percent at 5 years and 91 percent at ten years.  However, invasion of lymphatic vessels, poor tumor grade, or length of tumor greater than 6 centimeters reduced survival.  With one poor characteristic, five and ten year cancer-specific survival was 94.8 percent and 88.9 percent.  With all three, survival fell to 87.5 percent at 5 years and 72.9 percent at ten years.  Patients with none of the characteristics had a five year survival of 96 percent.  None of the patients in the study had chemotherapy after their surgery. The study of a prospective Munich database was reported by surgeon Ralf Gertler in the European Journal of Cancer online August 19, 2009.
• Colorectal and breast cancer patients of any race who are treated in hospitals where more than half of patients are black have higher death rates.  For colorectal cancer, the increased risk was almost 30 percent even after adjusting for other risks like age, stage, race, and socioeconomic factors.  “Efforts aimed at increasing early detection through screening and decreasing incidence with preventative services are essential for decreasing racial disparities in mortality, but where a patient receives care after a cancer diagnosis may be equally important,” senior study author Arden M. Morris, MD, MPH said.  The study was published in the July 20, 2009 issue of the Journal of Oncology.
• Acupressure wristbands reduced nausea from radiation therapy.  However, there was no additional effectiveness if patients were given information before using the bands that led them to expect results. Joseph Roscoe, PhD, and his colleagues at the University of Rochester reported their on their study in the Journal of Symptom and Pain Management online March 31, 2009.
• Researchers in Japan found no connection between how much fish an individual eats and colorectal cancer.  Following nearly 40,000 people for 9 years, the scientists found 566 cases of colorectal cancer but no difference in risk between those who ate the most fish and those who ate the least. Y. Sugawara reports study results in the British Journal of Cancer on August 25, 2009.

Other Headlines

• Robots may have a lighter — and better — touch than surgeons.  Tumors usually feel stiffer than surrounding tissue, and in open surgeries, doctors put light pressure on organs to identify areas with potential cancer.  With minimally invasive (laparoscopic) surgery, they cannot feel tissue.  A new robotic system is being developed to replace the surgeon’s hand, systematically putting light pressure on organs to locate tumors.  The robots use less pressure and use it consistently.  Medical News Today on August 22 had an article about the Canadian CSTAR project that is developing the robots.