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

A new study says it does.

Waiting more than 2 months, doubles the risk that patients will die. 

When adjuvant chemotherapy was delayed more than 60 days past surgery, patients were more likely to die within five years.  However, there wasn’t a significant decrease in relapse-free survival.

Doctors at the Sylvester Comprehensive Cancer Center at the University of Miami in Florida reviewed information on 186 stage II and III patients, 49 (26 percent) of whom started chemotherapy more than 60 days after their surgery.  Thirty percent of those cases were system-related:  late referrals or insurance issues, for instance.

The relative risk of dying within five years (overall survival) was 2.17 — a little over double that of patients who began their chemo earlier.

Recurrence-free survival favored patients with earlier chemo, but wasn’t statistically significant.

Ulas Darda Bayraktar, MD and the Sylvester team concluded,

Adjuvant chemotherapy delay >60 days after surgical resection of colon cancer is associated with worse overall survival.

SOURCE: Bayraktar et al., Cancer, Early View, December 17,  2010.

We were all convinced that when we added Erbitux and Avastin to our chemotherapy, it would work in the adjuvant setting, which means with FOLFOX for 6 months after the successful removal of colon cancer.

But it did not work. Neither Avastin nor Erbitux showed any benefit. How is that possible?

This forces us to go back to the drawing board and get smarter and learn from these experiences. What we must assume is that when you treat with these antibodies, it does not work when you only have microscopic disease.

The reason tumors recur is because some cancer cells are left behind. Some of these cells are stem cells and can’t get killed with chemotherapy.

We have demonstrated benefit in patients with metastatic disease. When you take Avastin, tumors that are visible and big and need to grow up regulate VEGF which is bound away with Avastin.  But what can Avastin do when the cancer cells are very small and don’t need VEGF to survive?

One discussion asks whether we should give adjuvant Avastin for a longer time.  However there are also side effects seen when treatment with Avastin was extended to one year.

Erbitux also did not work. Why not?

I don’t think we have the answers, but it forces us to think about the difference of cancer and its microenvironment between cancer which has spread and is active and cancer which only exists in the form of a few cells somewhere.

We need to develop smarter therapies and how to select the effective therapy like we have begun to do in metastatic patients.  Interestingly, KRAS mutation did not help to select patients who benefitted from Erbitux in the adjuvant setting . Maybe EGFR is not the right target? These results, even through disappointing will force us and industry to rethink and use our molecular biology of cancer to come up with more effective strategies.

Also, I want to mention diet, exercise and supplements in this setting. We need to invest more resources and research to understand what else we can do to reduce cancer recurrence. There are interesting data on exercise, aspirin, vitamin D and diet rich in vegetables. We need to systematically test these possible interventions.

In addition we need to develop a complete new class of medications which attack the colon cancer stem cells, because if they are not removed, they will cause recurrence. Research is going on at USC which may be successfully address this ongoing problem.

The data suggested that there was no benefit with the addition of Avastin, which was given not only for 6 months along with chemotherapy but 6 months in addition to FOLFOX for a total of 12 months.

Despite showing this was a negative clinical trial, when the investigators and Genentech looked at the 1 year disease free survival it appeared there was a potential transient benefit which lasted longer than the 1 year Avastin was given. Whether this is real or a fluke no one knows. However even considering that this is a real benefit, it would be very small may be 5 percent in 3 years. That means a 5% decrease of recurrence with one year of Avastin, but also means that many patients will be treated with no benefit.

Recent data have suggested that when Avastin was given  6 months longer some concerning side effects have been see in up to 10% of patients such as body pain interfering with daily function, dizziness, and central nervous system symptoms raising questions of the safety of Avastin given for a long time, particularly compared to little benefit at all (that benefit would be possible only under the best conditions). It became clear that studies using even longer administration of Avastin would be not indicated.

Fortunately there is a similar trial which was completed in Europe. The data will be hopefully available next year at ASCO and will answer whether this “transient” change is real which is more exciting for the tumor biology than clinical benefit or all a fluke.

Another question, of course, is will the clinical trials using Erbitux become effective in the adjuvant setting. In the US  N0147 is again open and only enrolling wild-type KRAS for this trial.

French patients who were at least 75 responded to questionnaires about their quality of life and emotional health three, six, and twelve months after their diagnoses.  Overall health and emotional functioning improved between the first questionnaire at three months and the twelve month survey for people with colon cancer.  For rectal cancer patients, scores improved between six months and twelve months.

Anne-Marie Bouvier, MD, PhD and her team at the Burgundy Digestive Cancer Registry wrote,

To the authors’ knowledge, the current study is the first to examine trends over time with regard to the influence of adjuvant treatments for colon and rectal cancers on quality of life (QoL) in a general aged population. Providing evidence that adjuvant chemotherapy for colon cancer has no negative impact on the QoL of elderly patients is of great significance in encouraging clinicians to treat this population.

SOURCE: Bouvier et al.,Cancer, Volume 113, Number 4, August 15, 2008.