1. Will recurrence rates go down if both FOLFOX and celecoxib (a non-steroidal anti-inflammatory drug similar to aspirin) are used for treatment?

2.  Will recurrence rates stay the same and long term side effects decrease if FOLFOX is used for three months?

FOLFOX can cause short- and long-term neuropathy, a numbness and tingling in hands and feet that makes activities like buttoning shirts hard.  Long-term neuropathy seems to be related to the total amount of FOLFOX received. Celecoxib has been shown to prevent the formation of polyps, and the development of colon cancer in patients who have had polyps.

Patients in the trial will be randomized to one of four treatment arms:

• Six months of FOLFOX (standard of care)
• Six months of FOLFOX plus celecoxib for three years
• Three months of FOLFOX
• Three months of FOLFOX plus celecoxib for three years

Patients will be monitored for the course of the clinical trial by the treating physicians.  Overall patient safety and treatment efficacy will be monitored by a Data Safety Monitoring Committee. As always, patients who participate in clinical trials may or may not directly benefit from the trial.  They contribute to the treatment of future patients, whose treatment will be influenced by the results of this trial.

This trial is called the CLEAR Colon Trial. It is being conducted by a national, publicly-funded clinical trial network called the Cancer and Leukemia Group B (CALGB) and is supported by the National Cancer Institute. For more information, read or download this informational document or visit the Fight Colorectal Cancer Clinical Trial Matching Service.

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.

All of the patients in the NO147 trial had cancer that had spread to their lymph nodes and had surgery before beginning chemotherapy. They had normal or wild-type KRAS genes in their tumors.They were randomly assigned to FOLFOX chemotherapy for 6 months or FOLFOX plus Erbitux. 

The trial was closed before the planned number of patients were enrolled because an analysis showed that there was no benefit to the additional Erbitux and continuing the trial would not help patients.

NO147 randomized 1,760 patients with wild-type KRAS to either FOLFOX — oxaliplatin, leucovorin, and continuous infusion 5-FU — or FOLFOX plus cetuximab for 12 treatments.   The primary goal of the trial was to discover which therapy resulted in the best disease-free survival three years later.  Researchers also wanted to measure three-year overall survival and compare serious side effects.

They found:

• For all patients there was no difference in disease-free survival with 74.1 percent of patients getting FOLFOX alone disease-free at 3 years compared to 73.3 percent on the FOLFOX plus cetuximab regimen.
• FOLFOX only patients had a trend toward better overall survival with 87.3 percent alive at 3 years compared to 82.1 percent when cetuximab was added.
• Disease-free survival for patients over the age of 70 was worse in the cetuximab arm with 63.8 percent alive without colon cancer at three years compared to 78.0 who only got FOLFOX.

Serious side effects were worse with cetuximab.  65 out of every 100 patients had a grade 3 or worse side effect when they got both FOLFOX and cetuximab compared to 45 of every 100 on the FOLFOX only treatment. In addition to a skin rash that is typical for Erbitux, patients on the drug also had more risk for severe diarrhea.

Fewer patients were able to complete all 12 treatment cycles when cetuximab was added.

Both serious side effects and differences in disease-free and overall survival were increased in patients who were 70 and over.

Erbitux has shown benefits both as a single drug and when it is combined with chemotherapy for patients with metastatic colorectal cancer that has already spread to sites beyond the colon so it was unclear why this benefit didn’t extend to patients without metastases.

Dr. Stephen Alberts, the Mayo Clinic oncologist who led the trial said,

The sum of data to date from trials for metastatic colorectal cancer suggested that cetuximab would provide benefit in these stage III patients with KRAS wild-type tumors, and so our findings are unexpected. It is difficult to understand how an agent that helps patients with metastatic cancer is not beneficial to those with less advanced disease. At this point we are focusing our efforts on identifying a biological explanation for these findings.

He went on,

Based on what we found, any use of cetuximab in stage III colon cancer is not supported by the results of our trial.

Dr. Alberts and the trial team concluded,

In this randomized phase III trial the addition of cetuximab to modifiedFOLFOX6 was of no benefit for patients with resected stage III wild-type KRAS colon cancer.

SOURCE:  Alberts et al., 2010 ASCO Annual Meeting Abstracts, #CRA3507

Dr. Alberts discusses the trial and its results below.

Disclosure:  C3 has received educational grants from Bristol-Myers Squibb, ImClone, sanofi-aventis, and Pfizer who were sponsors of the NO147 trial in addition to the National Cancer Institute. C3 has ultimate control over content of our website.

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.

Studying KRAS in the tumors of about half the patients in a large clinical trial of chemotherapy for stage III colon cancer, researchers found no differences in disease-free, recurrence-free, or overall survival.  This remained true no matter which chemotherapy the patients received.

Between 1999 and 2001, almost 1,300 patients took part in a clinical trial that compared standard treatment at the time — bolus 5-FU and leucovorin– to adding irinotecan to 5-FU/leucovorin.  That trial didn’t find a difference between the two chemotherapy arms in preventing recurrences or increasing survival for stage III colon cancer.

To see if KRAS status made any difference in outcomes for stage III colon cancer, a research team analyzed tumor tissue from 508 of the 1,264 patients who were enrolled in the CALGB 89803 clinical trial.  They found mutated KRAS in 178 tumors, 35 percent of all participants.

Five-year outcomes between KRAS mutant and KRAS wild-type tumor tissue were very similar:

• Disease-free survival was 62 percent for KRAS mutant versus 63 percent for KRAS wild-type.
• Recurrence-free survival was 64 percent for mutant vs wild-type.
• Overall survival was 75 percent in mutant and 73 percent in wild-type tumors.

In addition, the research team found no correlation between KRAS status and clinical features of the cancer, which chemotherapy arm the patients were on, or microsatellite instability (MSI).

Writing in Clinical Cancer Research, Shuji Ogino and colleagues concluded,

In this large trial of chemotherapy in stage III colon cancer patients, KRAS mutational status was not associated with any significant influence on disease-free or overall survival.

SOURCE:  Ogino et al., Clinical Cancer Research, online first November 24, 2009.

• 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.

The PETACC-3  (Pan European Trial Adjuvant Colon Cancer)  trial was designed to see if adding irinotecan to 5-FU and leucovorin could increase the percentage of stage III patients who were alive and cancer-free (disease-free survival).  It also studied overall survival and relapse-free survival.

In a randomized Phase III trial over 2,000 patients with stage  III colon cancer received either:

• Twelve standard treatments every two weeks of LV5FU2 (a two-hour infusion of leucovorin followed by a 400 mg/m² bolus injection of 5-FU and a 22 hour continuous infusion of 5-FU each day for two days — the deGramont regimen)
• Twelve treatments every two weeks  LV5FU2 (standard deGramont regimen)with an additional infusion of 180 mg/m² of irinotecan on the first day.

Patient characteristics were well-balanced between the two groups, with more men than women (55 percent vs 45 percent), a median age of 60, and about a third of patients in both groups over 65.  About two thirds had cancer found in fewer than 4 nearby lymph nodes.  None had any sign of cancer elsewhere in their bodies.

Results found no significant differences in survival for stage III patients between the two treatments:

• Five-year disease-free survival was 56.7 percent with the added irinotecan, 54.3 percent without.
• Five-year overall survival was 73.6 percent with irinotecan, 71.3 percent without.

Serious (grade 3 and 4) side effects were more common in the irinotecan group:

• Any  severe adverse event:  24.3 percent in LV5FU2 only group versus 37.7 percent with added irinotecan
• Diarrhea: 5.6 percent with standard treatmnet, 11.9 percent with irinotecan
• Neutropenia (lowered white cells counts): 6.0 percent versus 28.2 percent with irinotecan
• Nausea:  1.2 percent versus 5.5 percent with added irinotecan

About half of patients in the irinotecan arm had some hair loss compared to about one in five patients receiving infusional 5FU.

The results of the trial are similar to those found by Dr. Leonard Saltz and colleagues in the CALGB 89803 clinical trial that compared bolus 5FU with leucovorin to the same bolus regimen with irinotecan (CPT-11).  In that study adding irinotecan did not increase either disease-free or overall survival and did result in more serious side effects and some unexpected deaths.

The addition of CPT-11 to weekly bolus FU plus leucovorin did not result in improvement in DFS or OS in stage III disease, but did increase both lethal and nonlethal toxicity. This trial demonstrates that advances in the treatment of metastatic disease do not necessarily translate into advances in adjuvant treatment, and it reinforces the need for randomized controlled adjuvant studies.

The ACCORD-2 trial compared infusional 5FU (LV5FU2) with and without irinotecan and found no difference in disease-free survival, even after adjusting for higher-risk colon cancers in the group of patients who received irinotecan.  ACCORD-2 also found substantially higher levels of grade 3 and 4 neutropenia in the irinotecan group — 4 percent versus 28 percent.  Marc Ychou wrote,

Adjuvant LV5FU2 + IRI compared with LV5FU2 alone in patients at high risk of relapse showed no improvement in DFS and OS.

Irinotecan, also known by its original scientific designation CPT-11 and its brand name Camptosar®, was approved by the FDA in 1998 to treat colorectal cancer that had progressed on standard treatment with 5-FU and leucovorin.  It is now available in generic form.

Writing in the Journal of Clinical Oncology on May 18, 2009 Eric Van Cutsem and the PETACC team concluded,

In summary, PETACC-3 has failed to demonstrate a statistically significant DFS, RFS, or OS advantage for the addition of irinotecan to infusional FU/LV in the adjuvant treatment of stage III colon cancer.

SOURCES: Van Cutsem et al.,Journal of Clinical Oncology, JCO Early Release, May 18, 2009.

Saltz et al., Journal of Clinical Oncology, Volume 25, Number 23, August 10, 2007.

Ychou et al., Annals of Oncology, Volume 2, Number 4, April 2009.