David Fogelman, M.D.
Assistant Professor
Department of Gastrointestinal Medical Oncology
The University of Texas MD Anderson Cancer Center
Hello. I am Dr. David Fogelman from The University of Texas MD Anderson Cancer Center. Thank you for participating in our Colorectal Cancer Survivorship Course. My job today is to describe to you the various chemotherapeutic agents that we use in colon and rectal cancers. I would like to thank my friend, my colleague, and pharmacist, Hoyt Slade, for helping develop these slides with me.
My role today is to discuss with you the various drugs used in colon and rectal cancers. I'm also going to talk with you about the various settings in which you might use these, particularly the neoadjuvant, the adjuvant, and metastatic settings in colon and rectal cancer. Finally, we'll be talking about the various strategies and combinations that we use of these drugs. And we will discuss some of the patient factors that you might consider when choosing chemotherapeutic regimens.
The different chemotherapeutic drugs that are now available include 5-fluorouracil, capecitabine, oxaliplatin, and irinotecan. There are targeted agents that have more recently been approved. These are bevacizumab, cetuximab, and panitumumab. Finally, leucovorin is worth mentioning. This is a version of folinic acid which we use intravenously to augment the effect of 5-FU.
Looking at the timeline of drug approvals, you will note that the first drug, 5-FU, was approved in 1962 by the FDA and we still use it to this day. It represents the backbone of chemotherapy for colon and rectal cancers. In 1990, leucovorin was studied and was found to improve the effect of 5-FU and so it's become a modulating agent for this drug. This is noteworthy in that there has been a shortage of this recently in the United States. In 1996, irinotecan, the first of the camptothecins was approved for colon and rectal cancer. In 2001, capecitabine, an oral version of 5-FU, was approved. Following this, in 2002, oxaliplatin, a DNA damaging agent, was approved for use in the United States, and then finally in 2004, we began to see the approval of biologic agents for the treatment of colon and rectal cancers. Bevacizumab is an anti-VEGF monoclonal antibody which we use in treatment in combination with the other therapeutic drugs. Cetuximab is an anti-EGFR agent. And, finally, panitumumab, another anti-EGFR agent, was produced in 2006.
We will come back to this slide later and we will go through, later on, the specific combinations. But, for the moment, I do want to demonstrate to you that since the advent of 5-FU the increasing numbers of drugs that we've had available for colon and rectal cancers has really and truly lengthened the survival of patients with metastatic disease. You'll note that at the top bars with using just 5-FU median survival ranged between 11 and 12 months. Nowadays, using all the new agents that we have available, median survival ranges at approximately 24 to 26 months. This is a huge improvement for patients.
The role of leucovorin is worth noting. Leucovorin is folinic acid. It's a reduced form of folic acid and in 1990 had replaced levamisole as the primary biomodulator used with 5-FU and enhances the activity of 5-FU. It's been studied in combination with regimens such as FOLFOX which we'll get to in a moment and FOLFIRI. Lately, there has been a shortage of this in the United States. We at MD Anderson have gotten very comfortable omitting leucovorin from the 5-FU regimens that we currently employ and there is actually data now to support this practice.
There are different settings in which you might find yourself using chemotherapy. You might find yourself using neoadjuvant chemotherapy or chemoradiation, particularly in rectal cancer to improve local disease control, to decrease the risk of local recurrence of cancer, and then finally to improve the resectability of cancers, and to improve the rates at which we can preserve the anal sphincter, which represents a big quality of life factor for patients. We use chemotherapy in the adjuvant setting both to improve survival, to decrease the risk of recurrence, and finally to eradicate microscopic metastatic disease. Finally, in the metastatic setting, chemotherapy can help us gain control over the disease. It can help us improve response and survival to treatment. It can facilitate the use of other treatments and strategies, such as metastasectomy, as well as radiofrequency ablation of lesions. And finally it's been very effective at helping palliate symptoms of cancer.
In the neoadjuvant setting, which is primarily in the rectal cancer group, we use 5-FU or capecitabine in combination with radiation.
Here is an example of a patient, a 38-year-old gentleman, whose rectal cancer, you can see within the circle, was found to abut the prostate. This patient received neoadjuvant chemoradiation and upon completion of the chemoradiation underwent surgery. At the time of surgery, happily for him, he was found to have no cancer at the prostate. In his case, the chemoradiation given upfront was very helpful in minimizing the extent of his disease and allowing for a successful surgery.
Here's another example of a patient, a 41-year-old gentleman, who had a mesorectal deposit, which is visualized both before the MRI on the left, as well as after, on the right, radiation. This patient had a close but negative margin with acellular mucin suggesting that his - that the cancer that might otherwise have been at the margin of resection had been destroyed by the chemotherapy and radiation given upfront.
And, that's the neoadjuvant approach to chemo --- to chemotherapy. The adjuvant approach is that where surgery is given first and is followed by chemoradiation and chemotherapy afterwards. The benefit of the neoadjuvant approach is that this allows for downstaging of tumor. It allows for better preservation of the anal sphincter. The -- One study suggests improved disease-free survival, although neither study that looked at the comparison of neoadjuvant nor adjuvant actually found an overall survival difference.
There are multiple strategies that we use in combination with radiation. Originally, we had been using bolus 5-FU and leucovorin. This was given on the first four days and then the final four days of radiation treatment. More recently, we began using continuous infusion 5-FU both throughout radiation therapy and in some cases on the Monday through Friday of radiation therapy. And finally most recently we've adopted the use of capecitabine, the oral version of 5-FU, as a pill Monday through Friday, twice daily dose of chemotherapy which patients have found to be significantly easier to tolerate than the infusional 5-FU.
In the adjuvant setting, chemotherapy has been used for stage III colorectal cancer and in some high risk stage II cancers to reduce the risk of recurrence. We free --- we are very comfortable using oral capecitabine which studies have shown to be the --- essentially the equivalent of intravenous 5-FU in the treatment of colorectal cancer.
And in the adjuvant setting, there is data to support the use of oxaliplatin in addition to 5-FU or capecitabine. This doublet, which was published in the New England Journal in 2004, has been shown to improve both disease-free and overall survival.
There are different adjuvant regimens that we use. The bolus regimen FLOX is given over a 56-day cycle for three cycles. It's composed of weekly 5-FU and oxaliplatin. More recently, though, we're using FOLFOX. The original FOLFOX4 regimen included oxaliplatin given on the first day, leucovorin and 5-FU boluses given on the first and on the second day, and then intravenous 5-FU given continuously as a continuous infusion through a pump over 40 --- 22 hours on both days one and two; in other words, over 46 hours essentially.
More recently, though, we've started using FOLFOX6. The difference between FOLFOX6 and FOLFOX4 is that FOLFOX6 omits the boluses after the first day. The benefit there is that patients don't have to return to the cancer center in between days of chemotherapy. They simply come on the first day to start the chemo and they come back on the third day to get disconnected from the chemo. Patients have found this to be much more convenient for them and we have adopted this regimen in our routine clinical practice. Finally, capecitabine has been studied as an adjuvant therapy. This agent, when given at 1000 mg twice --- twice daily for 14 days, seems to be the equivalent of 5-FU. We do frequently give oxaliplatin in addition to capecitabine for those patients who do choose to take capecitabine over intravenous 5-FU.
Finally, in the metastatic setting, we employ all the agents that we possibly can. The --- you'll see at the bottom of our tree that 5-FU remains the backbone of chemotherapy. We've gotten very comfortable substituting capecitabine instead of 5-FU and patients use these interchangeably. In addition to the fluoropyrimidines pat --- we also routinely add irinotecan or oxaliplatin and, on rare instances, both, to the 5-FU or capecitabine chemotherapy. This has the effect of improving response rates and, as you saw from the initial slide, survival. Finally, the targeted agents bevacizumab and cetuximab are also available and we use these in combination with iIrinotecan, oxaliplatin, and the --- and 5-FU and capecitabine. Bevacizumab has been studied in combination with FOLFOX and has been shown to improve survival. Likewise, cetuximab spec --- specifically for those patients whose tumors do not harbor a KRAS mutation can be very helpful and can improve survival in metastatic disease.
In considering which treatments to give to a particular patient, we take into account the patient's age. We look at hepatic and renal function, as both the irinotecan and the oxaliplatin can damage the liver. We look at comorbidities and in particular we pay a lot of attention to performance status. Those patients who are more vigorous and more vibrant are generally able to tolerate more chemotherapy than those patients who are weak or frail. Finally, we look at molecular markers, in particular KRAS. And more and more, we are looking at markers such as B-Raf and others to determine which patients might benefit from a given chemotherapy.
As you'll see, if you look at the lower bars on this graph, the role of FOLFOX, FOLFIRI, and then the addition of bevacizumab and EGFR agents are demonstrated and you'll see that with increasing use of more and more drugs patients are living longer and longer.
So, in summary, intravenous 5-FU or oral capecitabine is currently used in combination with radiation in the neoadjuvant as well as adjuvant settings. Following resection of patients with localized colon cancers, in other words stage II or stage III, adjuvant chemotherapy with 5-FU by itself or in combination with oxaliplatin has been shown to decrease the risk of recurrence and death. And finally combining the various chemotherapeutic drugs with chemotherapy can improve overall survival with patients with metastatic disease. Thank you so much for your attention. We welcome any feedback you may have.
The Role of Chemotherapy video
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