Does adding Erbitux to chemotherapy help people whose colorectal cancer has spread beyond the colon or rectum to distant body sites?

The answer is yes, according to a pooled analysis of two large randomized clinical trials comparing chemotherapy alone to chemotherapy plus Erbitux® (cetuximab).  However, benefits depend on whether or not patient tumors have mutations of two genes, KRAS and BRAF.

Previous studies have shown that only patients with normal or wild type KRAS get any benefit from EGFR inhibitors Erbitux or Vectibix™ (panitumumab) so a combined analysis of the CRYSTAL and OPUS studies looked only a outcomes in KRAS wild type tumors.  In addition, the research team studied the effect of mutations to BRAF.

They found that adding Erbitux to initial chemotherapy improved overall survival time, time until cancers got worse (progression-free survival), the percent of tumors that shrank with treatment (overall response rate) for tumors with wild-type KRAS.  The best outcomes were in patients who had both wild-type KRAS and wild-type BRAF.

Overall, benefits were smaller for both chemotherapy and chemotherapy plus Erbitux when BRAF was mutated.  But even in patients with BRAF mutations, adding Erbitux appeared to help.

The pooled analysis of KRAS wild type patients showed:

• Adding Erbitux to chemotherapy added four months to median survival time for the entire group of KRAS wild-type patients. With chemo alone, median overall was 19.5 months while it improved to 23.5 months with chemo and Erbitux.
• Progression-free survival was 7.6 months with chemo alone and 9.6 months with the combination of chemo and Erbitux.
• 38.5 percent of chemo only patients had tumors shrink at some point during their treatment compared to 57.3 percent of patients who also got Erbitux.

When just patients with both wild type KRAS and wild type BRAF were reviewed:

• Overall survival time was 21.1 months with chemo alone and 24.8 months with chemo plus Erbitux.
• Progression–free survival was 7.7 months with chemo and 10.9 months with the combination of chemo and Erbitux.
• Overall response rate was 40.9 percent for chemo and 60.7 percent for chemo and Erbitux.

Prognosis appeared to be poorer when KRAS wild type patients had mutated BRAF, but the researchers noted that there were too few BRAF mutated tumors to make the results statistically significant.  However, adding Erbitux did improve outcomes. In those patients.

• Median overall survival was 9.9 months with chemo and 14.1 months with the addition of Erbitux.
• Progression-free survival was 3.7 months versus 7.1 months.
• Overall response was 13.2 percent for chemo alone and 21.9 percent with Erbitux and chemo.

In presenting the study results at the 2010 ASCO Annual Meeting in Chicago, Carsten Bokemeyer said,

Based on these results, BRAF mutations cannot be used as a relevant predictive marker for the use of cetuximab in first line therapy for metastatic colorectal cancer.

Bokemeyer and his colleagues concluded,

This analysis confirms that the addition of cetuximab to chemotherapy first line in patients with KRAS wild type tumors achieves a statistically significant improvement in overall response rate, progression-free survival, and overall survival compared with chemotherapy alone. The best outcome was observed in patients with KRAS wild type/BRAF wild type tumors (90% of KRAS wild type patients). BRAF mutation status does not appear to be a strong predictive biomarker for the addition of cetuximab to chemotherapy but the sample size may be too small to be reliable.

SOURCE:  Bokemeyer et al., 2010 ASCO Annual Meeting Abstracts, Abstract #3506.

Disclosure:  C3 has received funding from Bristol Myer Squibb and ImClone Systems in the form of unrestricted educational grants.  C3 has ultimate authority over website content.

FOBT screening saves lives, but only when it is done right.

Three out of four primary care doctors did a fecal occult blood test once during an office visit, a method that is ineffective in finding cancer or preventing death from colorectal cancer. One out of four used the in-office test exclusively.

Less than half of doctors had a system in place to be sure that home tests were completed and returned. 

What Primary Care Doctors are Doing

The 2006–2007 National Survey of Primary Care Physicians Recommendations and Practices for Cancer Screening conducted by the National Cancer Institute in collaboration with CDC and the Agency for Healthcare Research and Quality surveyed a sample of primary care doctors about their recommendations for colorectal cancer screening.  Family physicians, general practitioners,obstetrician-gynecologists, and internists were included.

Over ninety percent of surveyed doctors said that they used an FOBT for colorectal screening at least once a month.  Of those 24.8 percent performed the test only in their offices, 52.9 percent used both office and home tests.  Three out of five doctors used a test that is no longer recommended because of its low sensitivity.

A single in-office test during a rectal exam will miss 95 percent of cancers and advanced polyps.

In other practices that reduced the value of fecal occult blood tests:

• Almost 1 in 5 doctors (17.8 percent) repeated a positive FOBT rather than refer a patient for colonoscopy immediately.
• Of those doctors who repeated FOBT, nearly a third (28.8  percent) stopped follow-up evaluation if the second FOBT was negative.
• Most doctors (61.1 percent) were using the least sensitive test, a standard guaiac test, which is no longer recommended.  Only 22 percent used the higher sensitivity guaiac test and 8.9 percent used a fecal immunohistochemical test which is more sensitive and doesn’t require patients to follow a special diet or refrain from certain medications before the test. 14.7 percent didn’t know what test they used.
• Only 44.3 percent had a system in place — chart reminders, telephone calls, or mailings — to follow up on FOBTs that weren’t returned.
• 62.2 percent of doctors had no system in place to be sure that patients referred for follow-up evaluation of a positive test actually got that testing.

Writing in the Journal of General Internal Medicine, CDC scientist Marion Nadel PhD and her team said,

While FOBT done appropriately is an important screening option, in-office FOBT may be worse than no screening at all because it misses 95% of cases of advanced neoplasia, giving many patients a false sense of reassurance.

The researchers concluded,

Although FOBT is an important option for colorectal cancer screening, our study suggests that its potential to save lives is not currently being realized because many physicians are continuing to use inappropriate implementation methods. Intensified efforts to inform physicians of recommended technique and promote the use of systems for tracking test completion and follow-up are needed.

What the Recommendations Are

Both the American Cancer Society and the US Preventive Services Task Force have fecal occult blood testing as a colorectal cancer screening option.

Early Detection of Colorectal Cancer and Adenomatous Polyps, 2008: A Joint Guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology recommend the following as an option for the early detection of colorectal cancer in adults over 50 without symptoms:

Annual fecal immunochemical test with high test sensitivity for cancer.

They further point out:

Because small adenomatous polyps do not tend to bleed and bleeding from cancers or large polyps may be intermittent or simply not always detectable in a single sample of stool, the proper use of stool blood tests requires annual testing that consists of collecting specimens (2 or 3, depending on the product) from consecutive bowel movements.

When a test is positive, follow-up with colonoscopy that examines the entire length of the colon is required:

When performed for CRC screening, a positive gFOBT or FIT requires a diagnostic workup with colonoscopy to examine the entire colon in order to rule out the presence of cancer or advanced neoplasia.

The guidelines specifically specify high-sensitivity guaiac FOBT such as Hemoccult SENSA or fecal immunohistochemical tests (FIT) instead of the older guaiac FOBT.  The test should be done at home on three consecutive bowel movements.   There are some FIT tests that require fewer samples, and most FITs don’t have diet and medicine limits prior to testing, but they still need to be done more than once and at home.

The US Preventive Services Task Force also recommends annual high-sensitivity fecal occult blood testing as one option for colorectal cancer screening in average risk adults from 50 to 75.  USPSTF doesn’t directly address the issue of how to do that screening, but does embrace the idea of choice.

Because several screening strategies have similar efficacy, efforts to reduce colon cancer deaths should focus on implementation of strategies that maximize the number of individuals who get screening of some type. The different options for colorectal cancer screening tests are variably acceptable to patients; eliciting patient preferences is one step in improving adherence. Ideally, shared decision making between clinicians and patients would incorporate information on local test availability and quality as well as patient preferences.

SOURCE: Nadel et al. Journal of General Internal Medicine, online first April 10, 2010.  Open Access.

What This Means for Patients

Fecal occult blood testing (FOBT) is a recommended colorectal screening option for people of average risk.

It is especially useful for screening where there is limited access to sigmoidoscopy or colonoscopy.  Some patients may prefer it over options that are more invasive or require bowel preparation.  It  should be choice for you to consider.

However, it is critical that it be done right.

• Don’t accept a single test done in your doctor’s office during a rectal exam.  It will find so few cancers that it is useless.
• Ask for a high sensitivity guaiac FOBT or a fecal immunohistochemical test (FIT).  Medicare and most insurances will cover either one.
  
• Be sure to follow instructions carefully in the days before starting the test.  Complete all samples, and mail the test back.
• If your doctor doesn’t follow-up, call and find out if the results were normal.
• If the test is positive, insist on a colonoscopy.  Don’t accept a second test or a less complete examination of your entire colon.
  

Then repeat the test in a year.

In a surprising results, doctors studying surgical complications and hospital deaths after colorectal surgery found that diabetic patients do better than non-diabetics after surgery.

There was a 23 percent reduction in deaths after surgery for diabetics and 18 percent fewer complications.

Unfortunately, this improvement in outcomes did not extend to the uninsured or to people under 50.

About 219,000 patients in the Nationwide Inpatient Sample (NIS) had colorectal cancer in the years between 1995 and 2005.  Fifteen percent had diabetes, one percent with complicated diabetes with serious problems like kidney disease or vision loss.

Dying in the hospital after surgery were:

• 3.2 percent without diabetes
• 2.5 percent with uncomplicated diabetes
• 4.2 percent with complicated diabetes

Nitasha Anand and her colleagues concluded,

In patients undergoing colorectal cancer surgery, those with diabetes had a 23% lower mortality and fewer postoperative complications compared to non-diabetics. The mechanisms underlying this unexpected observation warrant further investigation.

In an interview with Reuters Health, Dr.Geoffrey C. Nguyen, of the University of Toronto and a lead researcher for the study said,

We were really expecting to find the opposite.

Considering the fact that uninsured and younger diabetic patients didn’t have the same advantage,  Dr. Nguyen speculated that special care before and after surgery made the difference for insured and older diabetics.

SOURCE: Anand et al.,Journal of General Internal Medicine, Online First March 30, 2010.

German scientists have identified a gene that has higher levels in colon cancer patients whose tumors are destined to spread. By initiating a signaling pathway in the cancer cell, MACC1 (Metastasis-Associated in Colon Cancer 1) promotes faster cell growth and cancer spread  to distant sites in the body (metastasis) .

Their research was published online in Nature Medicine.

About a third of patients whose cancer is found in early stages will eventually have it spread to other organs.  Measuring MACC1 may help doctors identify those patients, treat them more aggressively, and follow them  more closely.

Cancer researchers at the Max Delbrück Center for Molecular Medicine in Berlin studied tumor tissue from 103 patients with colorectal cancer.  Sixty of those patients didn’t have any sign of cancer spread when they were diagnosed. Of the 60, 37 were alive and cancer-free five years later.  They had low levels of MACC1 in their tumors.

On the other hand, 23 patients had cancer spread.  They had higher tumor levels of MACC1.

Ulrike Stein and his colleagues concluded,

For clinical practice, MACC1 will be useful for the identification of poor prognosis subjects with colorectal cancer and is a promising new target for intervention in metastasis formation.

SOURCE: Stein et al., Nature Medicine, Advance Access December 21, 2008.

Patients who developed hypertension with Avastin® (bevacizumab) had better response to treatment for colorectal cancer.  More had tumors shrink, and it took significantly longer for their cancer to get worse.

In a small Italian study, researchers measured blood pressure in 39 patients receiving Avastin along with irinotecan and 5-FU for the initial treatment of colorectal cancer.  Eight patients (20 percent) experienced grade 2 or 3 hypertension.

• Of those eight patients, six had tumors shrink or a partial response.  On the other hand, only 10 of the 31 patients (32 percent) without an increase in blood pressure had partial responses to treatment.
• Median time before cancer got worse was 14.5 months for patients with hypertension compared to 3.1 months for those who didn’t have high blood pressure.
• Those without hypertension lived a median of 15.1 months, but median survival time hasn’t yet been reached for patients who responded to Avastin with an increase in blood pressure.

Grade 2 or moderate hypertension is defined as systolic pressure from 150 to 179 mm/Hg.  Severe grade 3 is blood pressure over 180.

Dr. Mario Scartozzi and his colleagues in Ancona, Italy concluded,

Our data indicate that bevacizumab-induced hypertension may represent an interesting prognostic factor for clinical outcome in advanced colorectal cancer patients receiving first-line bevacizumab.

SOURCE: Scartozzi et al. Annals of Oncology, Advance Access: October 7, 2008.

Hypomagnesemia, or reduced magnesium levels, is a side effect of Erbitux® (cetuximab) treatment.  Patients with colorectal cancer whose blood magnesium dropped the fastest also had the best response to Erbitux given with Camptosar® (irinotecan) .

Italian researchers measured magnesium levels for 68 patients before treatment began and then 6 hours, 1 7, 14, 21, 50, and 92 days later.  After the seventh day, readings decreased consistently.

Magnesium levels fell at least 20 percent for 25 patients by the third week.  More of these patients responded to treatment, they lived longer before their cancer got worse and had longer overall survival.

Response rates for patients with an early reduction in magnesium were 64 percent,  compared to 25.6 percent of other patients.

Median time to progression for the early hypomagnesemia group was 6 months compared to 3.6 months for those whose magnesium levels fell more slowly.  Overall survival was 10.7 months versus 8.9 months.

Measuring magnesium may provide a way to predict whether or not Erbitux will be successful in treating advanced colorectal cancer.

Bruno Vincenzi and colleagues wrote,

Our results confirm that cetuximab treatment may induce a reduction of Mg²⁺ circulating levels and offer the first evidence that Mg²⁺ reduction may represent a new predictive factor of efficacy in advanced colorectal cancer patients treated with cetuximab plus irinotecan.

SOURCE: Vincenzi et al., Clinical Cancer Research, Volume 14, Number 13, July 1, 2008.

More News from ASCO 2008

Although men and women with metastatic colon or rectal cancer have similar overall survival after their diagnosis, age has an impact.  Women in premenopausal years, 18 to 44, live longer than younger men.  However, after the age of 75, women have significant worse survival than men.

Across all age groups, Hispanics survive the longest, followed by whites, Asians, African Americans, and, finally, Native Americans according to a study from the University of Southern California Norris Comprehensive Cancer Center and reported at ASCO.

USC researchers reviewed information for 56,600 men and women with metastatic colon and rectal cancer in the Surveillance, Epidemiology and End Results (SEER) database from 1988 through 2003.  Independent of age, there was no difference in survival between men and women, but once age was added to the analysis, there were significant differences between how long men lived compared to women. Ethnic background also affected survival.

In a news release from USC, Heinz-Josef Lenz, M.D., professor of medicine at the Keck School of medicine one of the researchers leading the study, said,

This study provides further evidence that estrogen may play an important role not only in colon cancer development but also progression of the disease, and may impact how we develop therapies for women and men with colon cancer.

SOURCE: Abstract 4015, Andrew Hendifar, M.D. MPH, Sex, age, and ethnicity are associated with survival in metastatic colorectal cancer, ASCO 2008.

Advance Abstracts from ASCO 2008

How far a colon or rectal cancer penetrates through the wall of the bowel may be more important in deciding survival risks than current staging that focuses on positive lymph nodes.

Five year survival statistics for a large number of rectal and cancer patients verified an earlier study that found some stage III colorectal cancers had better prognosis than stage II cancers that extended through the bowel wall but did not invade nearby lymph nodes.

The information has implications for treating colorectal cancer after surgery.

Colorectal cancer is staged by looking at how far the tumor extends into and through the wall of the bowel T1,2,3, or 4), whether it is found in lymph nodes (N0, 1 or 2), and whether it has spread to distant organs or metastasized (M0 or M1).  For instance, T3N0M0 is stage IIa, T4NOMO is stage IIb. Information about survival and recommendations about appropriate treatment are based on staging.

Currently stage III cancers are considered to have a higher risk of recurrence and eventual death than stage II.

During the American Society for Clinical Oncology annual meeting in Chicago, Dr. Leonard L. Gunderson, from the Mayo Clinic in Scottsdale, Arizona, will present an abstract of an analysis of SEER (Surveillance, Epidemiology, and End Results) data from 1992 through 2003 with staging and survival information for nearly 36,000 rectal and110,000 colon cancer patients.

According to the analysis, people with stage IIB tumors that extend through the bowel wall and are attached to nearby tissues or penetrate the membrane surrounding the intestines (T4 N0 M0) have poorer survival chances than those with stage III tumors that remain within the bowel wall but have spread to lymph nodes (T1- 2 N1- 2).

In addition, the statistics support a change in staging to separate stage IIB into further substages:  IIB T4a would be tumors had gone through the membrane surrounding the bowels (visceral peritoneum) and IIC T4b where the tumor directly invades or is adherent to other organs or structures. Stage IIC has significantly poorer survival possibilities than IIB or stages IIIA or IIIB.

(Thanks to an alert commentor, we have corrected the above paragraph to reflect the real difference between stage IIB T4a and IIC T4b.  It now reads correctly)

In addition, some tumors that have spread to more than 3 lymph nodes (N2) are less likely to lead to death at five years than previously suspected and are being reclassified as IIIA.

While complicated, the proposed new staging categories will help patients and their doctors made decisions about chemotherapy treatment after surgery.

More specific information about stages and survival is listed in a table included with the abstract.

The study concludes,

This population- based outcomes analysis validates the Rectal Pooled Analysis data and supports the shift of T1-2N2 cancers from IIIC to IIIA/IIIB and T4bN1 from IIIB to IIIC. It also supports subdividing IIB into IIB(T4aN0) or IIC(T4bN0) and shifting favorable TN2 categories from IIIC to IIIA(T1N2a) or IIIB(T1N2b, T2N2a-b, T3N2a, T4aN2a). Outcomes by TN category suggest a complex biological interaction between depth of primary invasion and nodal status.

2008 ASCO Abstract #4020

Patients who have poorly controlled type-2 diabetes and colorectal cancer have worse outcomes than patients whose diabetes is controlled or patients without diabetes.

Poorly controlled type 2 diabetes led to more right-sided tumors, more advanced cancer at diagnosis, diagnosis at a younger age, and poorer five year survival.

Researchers at the Dallas Veterans Medical Center reviewed records of patients with colorectal cancer whose also had type 2 diabetes and matched them to a control group of colorectal cancer patients without diabetes.  Poorly controlled type 2 diabetes was defined as a HbA1c level of 7.5 percent or more.

Patients who diabetes was well controlled were not much different than colorectal cancer patients without diabetes.  However, patients whose type 2 diabetes was poorly controlled — as evidenced by a HbA1c level of 7.5 percent or more — had a clinically more aggressive form of colorectal cancer.

SOURCE: Ali A. Siddiqui et al.,Journal of Digestive Diseases and Sciences, published online April 12,2008.