Highlights:

• While adding oxaliplatin to 5-FU improves five year survival slightly for stage II colon cancer, it increases side effects, particularly tingling and numbness in the feet.  An analysis of several NSABP trials found that two or three more stage II patients out of every 100 would be alive five years later if they were given oxaliplatin in addition to 5-FU than if they only got 5-FU.  Risk of cancer returning was similar with an absolute improvement of 3 to 5 percent, depending on risk factors.  Doctors and patients need to think about whether the small benefit is worth the risk of neuropathy that may become permanent.
• Two speakers at the Saturday colorectal cancer oral abstract session addressed adding oxaliplatin to 5-FU as part of pre-surgical chemoradiation treatment for rectal cancer.  NSABP R-04 found that oxaliplatin did not help increase complete response rates, avoid colostomies, or downstage cancers. It did increase diarrhea significantly. On the other hand, early results from a German trial did find an increase in complete responses with oxaliplatin, and they didn’t see worse side effects.
• In the PRIME phase III clinical trial, patients receiving their first treatment for advanced colorectal cancer who had normal or wild-type KRAS genes in their tumor did better when Vectibix® (panitumumab) was added to FOLFOX chemotherapy.  But those patients whose tumor KRAS was mutated actually did worse than patients who only got chemotherapy.
• Side effects, while difficult for patients, may predict better outcomes from treatment.  Patients who got capecitabine as part of pre-surgical chemoradiation and developed hand-foot syndrome had fewer recurrences three years later and better survival at five years.  In another study of breast, lung, and colorectal cancer, patients who got high blood pressure while on Avastin® (bevacizumab) lived longer and it took longer before their cancer got worse.

The Cost of Cancer Care

In an editorial in the ASCO Daily News, published every day for ASCO attendees, Jeffrey M. Peppercorn, MD, MPH, discussed the rising out-of-pocket costs of cancer care for patients and their families.  Although cancer care costs overall are growing fast, the costs that patients bear are growing even faster.  About a third of cancer patients say they have trouble paying their bills, and one out of four have exhausted their savings.

Although the ASCO Task Force on Cost of Cancer Care calls for oncologists to discuss out-of-pocket expenses with patients, few do, and a survey found that about half of oncologists are uncomfortable talking about costs in deciding on treatment.

To learn more, join us for our next patient webinar:

The Big News in Colorectal Cancer from the 2011 ASCO Annual Meeting
June 20, 2011
8 – 9 PM Eastern time
Register to join us.

 

For people diagnosed with stage III colon cancer, stage II rectal cancer, or stage II colon cancer showing certain high-risk features, researchers found that each four-week delay in starting chemotherapy after surgery was associated with a 12% lower rate of survival five years later.

One important caveat: All of these studies were done when 5-FU was the only available treatment, before oxaliplatin was added to standard chemotherapy. It’s too early to know long-term results for today’s typical regimines.

Based on this review, though, the researchers concluded that it is indeed best to avoid unnecessary delay in starting chemotherapy, and that there may in fact still be benefits for giving chemotherapy even if it must be delayed several months after surgery.

The most likely causes for delay the researchers noted are complications and healing time needed after surgery, or “system delays” in appointments between surgeon, medical oncologist, and treatment sessions.

Dr. James J. Biagi and associates at Queen’s University in Kingston, Ontario were testing two clinical assumptions: First, that chemotherapy should begin as soon as possible after surgery — which they found to be true; and secondly, that chemotherapy offered beyond three months after surgery might not offer benefits — which they found to be not necessarily true.

Those assumptions “haven’t been, and won’t likely be tested in randomized trials,” Biagi noted, because that kind of trial would require intentionally delaying chemotherapy in eligible patients. Using mathematical meta-analysis, they compared outcomes for 14,000 patients in nine clinical studies reported between 1975 and 2009. They found that, among patients fit enough to start chemotherapy four weeks after surgery, treatments delayed until eight weeks showed a 12% higher five-year mortality, or 25% higher mortality when treatment started at 12 weeks.

Translating those statistics into a typical patient (using Adjuvent! Online—a tool that helps doctors and patients evaluate risks and benefits of adjuvant therapy), Dr. Biagi described how a 65-year-old man diagnosed with stage III colon cancer who started chemotherapy at four weeks would have a 60% survival chance of surviving five years; the same person would have a 55% survival rate starting treatment at eight weeks; or 50% survival rate starting treatment 12 weeks after surgery. (Again, these survival rates are from earlier 5-FU-only treatments.) This compared to an estimated 45% chance of five-year survival with no chemotherapy at all.

Patient take-away:  Avoid unnecessary delay starting chemotherapy after surgery

• To help avoid complications from surgery that could delay healing, patients may want to seek colorectal surgery specialists.
• Patients can and should work to avoid delay between the surgeon’s referral to the medical oncologist who determines your chemotherapy treatment, and beginning scheduled treatments. If you’re considering delaying chemotherapy until after an important event (e.g. child’s wedding), talk with the oncologist and oncology nurse about how chemo might affect both your short-term lifestyle and long-term outcome.
• Also know that if delay is necessary (e.g. to heal from surgery complications), you still may benefit from chemotherapy, even as long as three months after surgery.

Source: J Clin Oncol 29: 2011 (suppl 4; abstr 364)

Previously: Delaying Chemotherapy After Surgery

Dr. Edith Mitchell

Last night, Dr. Edith Mitchell of Thomas Jefferson University Kimmel Cancer Center in Philadelphia, PA, updated colorectal cancer patients on the latest research and treatment news in an online webinar.

Dr. Mitchell highlighted the most important news for colon and rectal cancer patients to come from the 2011 Gastrointestinal Cancers Symposium held in San Francisco last month. She answer such questions as…

“Can doctors determine the chances that my cancer may return?”

“Can my doctors determine if I need chemotherapy?”

“Does Avastin or Erbitux benefit my stage III cancer treatment?”

“Are there any promising new treatments on the horizon?”

You can view the webinar online here.

The patient webinars are a program of the Colorectal Cancer Coalition and are offered to patients at no cost. If you would like to support this program through a financial donation, visit our Donate page.

But one in five will have cancer spread beyond their colon.

Better information about which patients will relapse could spare many from the risks of chemotherapy.

A new gene test announced at the 2011 Gastrointestinal Cancer Symposium in San Francisco helps provide answers to which patients are at highest risk and could help patients and their doctors make better decisions about follow-up chemotherapy after surgery.

ColoPrint, an 18 gene tumor tissue signature, found that three out of four patients with stage II colon cancer had only about a 5 percent risk of recurrence, very similar to stage I patients.  For the remaining high risk patients, one in five (20 percent) had cancer return.

In a series of 135 patients with stage II colon cancer, ColoPrint identified

• 73 percent at low risk of recurrence.  After  a median 97 months of followup, only 5 percent experienced a relapse.
• 27 percent at high risk.  During the 97 month follow-up, 20 percent had cancer return.

ColoPrint was developed by searching the whole genome for a fingerprint of genes that predicted recurrence from colon cancer.  The study reported at the GI Symposium is the second one to validate the test.  A third validation study of 600 patients is now underway at MD Anderson Cancer Center in Houston, with results expected later this year.

In a press briefing, surgeon Robert Rosenberg, MD, an assistant professor at the University Hospital of the Technical University in Munich, Germany said,

The ColoPrint gene expression test was the only significant factor that predicted the development of distant metastasis in our patient series, In this validation study, the performance of ColoPrint seemed to be independent of known clinical factors. ColoPrint was able to predict outcome in stage II patients, and this facilitates the identification of patients who may be safely managed without chemotherapy.

SOURCE: Rosenberg et al,, Independent validation of a prognostic genomic profile (ColoPrint) for stage II colon cancer (CC) patients, Abstract #358, 2011 Gastrointestinal Cancers Symposium.

Coalition staff Kate Murphy and Kim Ryan were joined by Dr. John L. Marshall of the Georgetown Lombardi Comprehensive Cancer Center to discuss this issue and took questions from patients at the end. You can view the webinar here:

Stage II Colon Cancer: Chemo or Not? Find Your Solution

Stage II colon cancer patients face tough decisions about whether the possible benefits of chemotherapy outweigh its risks and challenges. The Coalition is grateful to Dr. Marshall for helping patients explore this issue.

Of every 100 people with colon cancer, about 15 will have cancers that arise when mistakes in DNA during cell division are not caught and fixed.  Scientists call this defective mismatch repair or dMMR.

More often, colon cancer occurs when mutations in chromosomes accumulate but DNA repair pathways remain intact and mismatch repair is proficient (pMMR). This is true for about 85 percent of colon cancer.

Both prognosis and the potential benefit from FU-based chemotherapy appear to be very different for these two types of colon cancer. Knowing mismatch repair status of colon tumors can help patients and their doctors make better treatment decisions.

Patients with defective mismatch repair have better disease-free and overall survival and don’t seem to benefit from 5-FU at either stage II or stage III.  Stage II patients with dMMR have significantly poorer overall survival if they get chemo after surgery.

Caution:  These results come from studies of 5-FU plus levamisole or 5-FU plus leucovorin.  They don’t include any information from the current standard treatments of FOLFOX or FLOX which contain oxaliplatin in addition to 5-FU and leucovorin.

Defective mismatch repair is uncovered when either tumors have microsatellite instability (MSI) or immunohistochemical tests can’t find the proteins that are expressed by genes that control mismatch repair — MLH1, MSH2, MSH6, and PMS2.  Measuring either MSI or lack of MLH1 or MSH2 expression gives similar results in deciding whether a tumor is mismatch defective or proficient.

Almost all defective mismatch repair tumors are located in the right side of the colon.  They are poorly differentiated, often have lots of mucus, and tend to be infiltrated with immune-system cells (lymphocytes). Some scientists speculate that it is this improved immune-response that gives them their survival advantage.

Daniel Sargent, Ph.D., and his team analyzed mismatch repair status in the tumors of 457 patients in five different clinical trials with stage II or III colon cancer who had received either FU-based chemotherapy after surgery to remove their cancer or surgery alone.  They then pooled their information with a group of 570 patients who had been analyzed earlier.  The entire set included 1,027 patients, including 165 (16 percent) with defective mismatch repair.

They analyzed the impact of either proficient or defective mismatch repair as both a prognosis marker (its effect on survival despite treatment) and predictive marker (if chemotherapy treatment changes outcomes).

Pooled Results

Mismatch Repair Status as a Prognostic Marker

• Patients with defective mismatch repair (dMMR) who didn’t get 5-FU had significantly better disease-free and overall survival than patients with proficient mismatch repair (pMMR).
• When patients got chemotherapy, mismatch repair status had no impact on survival.

Mismatch Repair Status as a Predictive Marker for FU- based chemotherapy

• There was no benefit of FU-based chemotherapy for either stage II or stage III colon cancer patients with defective mismatch repair.
• There was no benefit of FU chemo for stage II patients with proficient mismatch repair.
• Stage III patients with pMMR did benefit from chemotherapy with 5-FU.
• Stage II patients with dMMR had worse overall survival when they got 5-FU than when they had surgery alone.

Graph of Predictive Value of dMMR in Adjuvant Colon Cancer

A — Stage II, dMMR
B–  StageIII dMMR
C — Stage II pMMR
D — Stage III pMMR

Click on graph to enlarge it.

Dr. Sargent’s analysis confirmed an earlier study reported in 2003 in the New England Journal of Medicine by Christine Ribic that found no benefit to treatment with 5-FU for patients with stage II or III colon cancer with high microsatellite stability, who may possibly be harmed by  5-FU-based chemotherapy and have a better overall prognosis after diagnosis.

His team concluded,

In conclusion, this prospectively specified analysis of data from randomized, clinical trials provides independent, supportive evidence of the following: dMMR colon cancers have a favorable stage adjusted prognosis compared with the majority of colon cancers; and patients with dMMR colon cancers do not benefit from FU based adjuvant therapy.

Further, they point out,

These findings support the conclusion that average-risk patients with colon cancer who are considered for FU based adjuvant therapy should have the tumor MMR status assessed to inform the likelihood of patient benefit of chemotherapy. Our conclusions are restricted to patients being considered for single agent, fluoropyrimidine-based therapy (ie, patients with stage II disease), and the conclusions provide guidance as to who should not be treated (ie, the dMMR subset). We believe that dMMR status in the setting of stage II disease should be considered a clinically useful marker of tumor biology and represents an additional step in individualized cancer therapy.

SOURCE: Sargent et al.,  Defective Mismatch Repair As a Predictive Marker for Lack of Efficacy of Fluorouracil-Based Adjuvant Therapy in Colon Cancer. Journal of Clinical Oncology, Volume 28, Number 20, pages 3219-3226,July 10, 2010.

Image:  Figure #2, Sargent et al., JCO

Five years after treatment, 67 percent of patients under the age of fifty hadn’t had their cancer spread beyond the colon (recurrence-free interval), the same percentage that applied to patients who were fifty or over.

Overall survival and disease-free survival were somewhat better for young patients because they had fewer other reasons for dying.  Overall and disease-free survival reflect patients who are alive five years after beginning treatment.  Neither includes people who have died from any cause, including their cancer.

Researchers from the ACCENT Collaborative Group in cooperation with the LIVESTRONG Young Adult Alliance analyzed information from 33,574 individual colon cancer patients who took part in 24 different randomized Phase III clinical trials.

• 1,758 or 5.2 percent were under age 40
• 5,817 or 17.3 percent were under age 5o
• 299 or 0.9 percent were under age 30

Comparing outcomes at 5 years:

• Overall survival was 75 percent for those younger than 40, 76 percent for those under 50, and 71 percent for those 50 and over.
• Disease free survival was 68 percent for patients under 40, 68 percent for those under 50, and 61 percent for 50 and over.
• Five year recurrence-free intervals were experienced by 68 percent under 40, 67 percent under 50, and 67 percent 50 and older.

There were no clinically meaningful differences in serious side effects between younger and older patients.

Mayo Clinic biostatistican, Daniel J. Sargent, PhD, and his team concluded,

Among patients on chemotherapy, young (age 30-50) stage II and III CC patients had similar recurrence-free interval and adjuvant chemotherapy benefit as older patients, with no clinically meaningful differences in adverse events. Young patients have improved overall survival and disease-free survival, likely primarily due to fewer competing causes of death. Adjuvant chemotherapy is beneficial for colon cancer patients aged 30-50 meeting typical chemotherapy eligibility criteria.

SOURCE: Sargent et al., 2010 ASCO Annual Meeting Abstracts, Abstract #3523.

Stage II colon cancer patients have a tough time knowing how likely it is that their cancer will recur and making a decision about having chemotherapy after surgery.

A test is now on the market that can help with that decision.  OncoType DX® Colon Assay analyzes 12 key genes from a tumor sample to produce a recurrence score that indicates how likely stage II colon cancer will return.

While OncoType DX Colon can’t predict whether chemotherapy will reduce the chance that cancer will come back, it can help patients and their doctors decide on chemotherapy in combination with other factors.

Based on many years of studying tumor samples saved in paraffin during clinical trials, OncoType DX analyzes expression of 12 genes in colon tumors.  The resulting recurrence score determines the likelihood that cancer will recur in the following three years.

At ASCO in 2009, development and validation of the 12 gene test was announced, and Genomic Health predicted a commercial launch of the test in early 2010.

Range of recurrence scores:

• Low — About 44 percent of patients will have about a 12 percent risk of recurrence.
• Intermediate — About 31 percent will have an 18 percent risk of recurrence.
• High — 26 percent will have a 22 percent risk

Genomic Health scientists recommend that the actual recurrence core itself be considered, rather than a general low, intermediate, or high.

Two other factors that are important in deciding whether or not to use chemotherapy are

• Mismatch repair status: In about 15 percent of stage II colon cancer, genes that help repair damaged DNA are mutated.  Mismatch repair is deficient (dMMR).  Patients with these tumors have good survival prospects and are much less likely to experience recurrence.  Studies show that chemotherapy doesn’t reduce recurrence or improve survival, and some studies show reduced benefit with chemo, although this remains controversial.  Most tumors, however, are have not lost the ability to repair DNA and are labeled MMR proficient (pMMR).
• T-stage: Stage II colon cancer is either T3 or T4. In T3 colon cancer, the tumor has grown outer muscular layer of the colon and into the outermost layers not through them. It has not reached any nearby organs or tissues. A cancer that has broken through the wall of the colon and may be in nearby tissues is classified as T4.  T4 cancers have almost double the risk of recurrence.

Most oncologists would agree that risk is high for T4 tumors with proficient mismatch repair and chemotherapy is probably warranted after surgery.  For T3 tumors that have deficient mismatch repair, chemotherapy probably has no benefit and may even be detrimental.

But three out of four stage II colon cancers fall into an intermediate risk category of T3 stage and proficient mismatch repair.  For patients with these tumors, the OncoType DX recurrence score can be valuable in helping make a decision about further treatment.

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

Pam’s experience with colorectal cancer research advocacy goes back more than a decade.  She has been a patient advocate with several cancer cooperative groups and now chairs the Radiation Therapy Oncology Group (RTOG) Patient Advocacy Committee.

While most patients with stage II colon cancer are at low risk of recurrence, there are patients in this group who are at increased risk and who may need chemotherapy to reduce their risk.

The average stage II patient has an absolute benefit of only 1 or 2 percent from chemotherapy. In other words, the average Stage II patient will decrease risk of recurrence by only 1 or 2 percent it they have chemotherapy. And since chemotherapy has its own risks, it is important to identify those at increased risk whose potential benefit would be greater than average.

Currently a variety of factors are used to try to identify which stage II patients are at increased risk of recurrence.

• One  is the number of lymph nodes examined. Not only is examination of at least 8 to 12 nodes essential to accurate staging but the number of nodes removed is a strong prognostic indicator. In other words, people with more nodes removed do better than people with fewer.  At the 2010 Gastrointestinal Cancer Symposium it was again confirmed that patients with 12 or more lymph nodes examined had a recurrence risk at 3 years about 5% lower than those with examined fewer nodes. It was further noted that the prognostic value of lymph node number was independent of the 12 gene recurrence score.
• The 12 gene recurrence score (Oncotype DX Colon recently released by Genomic Health) reports patients as at high, medium or low risk of recurrence at 3 years. The recurrence scores range from an average risk of 12 % for low risk, 18% for medium risk to 22% for high risk.
• Also frequently used to evaluate stage II tumors is lymphovascular invasion (the visualization of cancer cells in small vessels within the tumor), T stage (T3 versus T4), and the markers 18qLOH and MSI (microsatellite instability).
• Microsatellite status has been shown to be a prognostic indicator in stage II colon cancer. Patients with pMMR (proficient mismatched repair) have worse outcomes than those who are deficient in mismatch repair (dMMR or MSI-H). The 5 year survival for patients who have pMMR is less than 75% in comparison with those who have dMMR (MSI-H) whose 5 year survival is greater than 90%. About 15% of patients have deficient mismatch repair (are MSI) and are a reduced risk of recurrence. A presentation at the ASCO Gastrointestinal Symposium indicated a need for physician education on the value of mismatch repair testing and use in treatment planning.
• Those who have loss of heterozygosity at 18q, a place on a chromosome, (18qLOH) are at increased risk of recurrence.

Examination of these factors and others can assist patients and their physicians to decide whether or not to have chemotherapy. At this point, no single factor is adequate to guide treatment decisions. When many factors available are used together, though, sufficient information is available to assist physicians and their patients decide whether or not chemotherapy is warranted.

Since patients vary widely in the amount of decreased risk is necessary to justify the toxicity and expense of chemotherapy, the decision must be made on an individual basis. This will require better education of physicians so they can better inform their patients.

• Preserved tissue from the QUASAR study was able to validate  a multiple panel of 7 genes that show the risk of recurrence for stage II colon cancer.  However, it could not prove that another 6 genes could predict who would benefit from treatment with 5-FU and leucovorin over surgery alone.   C3 has previously covered this analysis in depth. Dr. David Kerr in discussing the results emphasized the importance of combining recurrence risk scores with information about tumor stage and MSI status in making decisions about chemotherapy for stage II patients.
• A review of the PETACC-3 randomized clinical trial that compared infusional 5-FU to infusional 5-FU plus irinotecan found that MSI (microsatellite instability) status predicted both relapse free survival at three and five years and overall survival for stage II and III colon cancer.  However, the benefit was much stronger in stage II than in stage III leading Dr. Sabine Tejpar and her team to conclude that there may be biological effects of MSI that happen specifically in stage II.  As a hypothesis, she considered whether MSI prevents or reduces the ability of cancer to move into nearby lymph nodes. In contrast to a previous study that looked at adding irinotecan to bolus 5-FU, the PETACC-3 study found no benefit from irinotecan in stage III colon cancer.
• Prognostic molecular markers were quite different between stage II and stage III colon cancer in an analysis of several different markers in tumor tissue from the PETACC-3 study. While MSI or microsatellite instability was a strong marker of good prognosis in stage II, it lost its value as a prognostic marker completely in stage III.  p53 and the SMAD4 genes had prognostic value for stage III but not for stage II.  A marker previously identified with poor prognosis in stage II disease — loss of heterozygosity at 18q or 18qLOH — lost its prognostic value completely when analysed together with MSI in stage II and had no value in stage III.  In his conclusion Dr. Arnaud Roth questioned whether stage II and III colon cancers are biological different diseases rather than steps in continuous cancer development.

In discussionof the three molecular marker oral presentations at ASCO, Dr. Charles Fuchs pointed out the difference between

• Predictive markers that tell whether a particular treatment will be beneficial for an individual patient or not.
• Prognostic markers that tell how likely cancer is to recur or patients to survive regardless of treatment.

He questioned whether or not the gene analysis from the QUASAR trial is ready to help make clinical decisions about whether or not to treat stage II patients with chemotherapy and called for additional study of benefit from chemo in each of the recurrence risk groups.