Dr. Barbara Melosky, MD, FRCPC (biography and disclosures)
What I Did Before
As a medical oncologist who treats metastatic colorectal carcinoma (mCRC), I used to follow certain principles in regards to chemotherapy. The chemotherapy regimens have evolved to include first, second and third line therapy. When I began my practice, the median survival was 6 months and we only had one drug, 5-florouracil (5-FU). We now have 8 different drugs and survival has tripled to over 20 months. This is good news for our patients but it comes with a cost of toxicity. The optimal duration of chemotherapy has not been well defined. I used to treat my patients for six months and if all disease was stable, gave them a holiday. A real holiday. They didn’t need to see me, the clinic, the lab or the radiological department for two or three months. In older patients, I always gave them a longer break thinking that this was important for their quality of life.
What Changed My Practice
As patients live longer, the chemotherapy related toxicities become more bothersome. Oxaliplatin, an effective drug can cause neuropathy which can be a real nuisance. Irinotecan can cause fatigue, diarrhea and nausea. Most recently an antibody against vascular endothelial growth factor called bevacizumab has been added to our first line regimen as it has shown to increase survival. [1] The mechanism of action is complex but likely improves chemotherapy delivery by normalizing tumor vasculature. Side effects are minimal but it is expensive. Because of cost, delivery was previously limited to 12 cycles. Trials showing the highest survival used bevacizumab until disease progressed. Because of that, our approval also changed to progression. [2] However, a caveat was made. If bevacizumab was stopped, it could not be resumed. The duration of chemotherapy has been looked at prospectively in several trials. OPTIMOX 1 randomized patients with mCRC to oxaliplatin and 5-flourouracil until progression or a break from the hard drug oxaliplatin after 8 cycles but 5-FU kept going. Both arms were equal in efficacy but the arm with the break from oxaliplatin had much less neuropathy. [3] I learned from OPTIMOX 1 that breaks from the hard drugs may benefit my patients in reducing toxicity and not sacrifice on efficacy. A second trial looking at this question was CONcePT. [4] CONcePT also tested the intermittent use of oxaliplatin versus continued use with 5FU. No difference was seen in response. Like OPTIMOX 1, the group with intermittent oxaliplatin had less toxicity and were able to tolerate treatment longer. Finally, OPTIMOX 2 randomized patients to a complete break or chemotherapy free interval (CFI) versus an OPTIMOX 1 strategy where there was discontinuation of oxaliplatin but continuation of 5FU. [5] A 6 month survival difference was seen in those patients who did not receive a CFI. Many of us did not believe the data when it was presented at the American Society of Clinical Oncology meeting two years ago, but now do as the data evolves.
What I Do Now
I now do not give as many chemotherapy holidays as I used to. I usually start with combination chemotherapy with bevacizumab and after 10 to 12 cycles, stop the hard drugs either oxaliplatin or irinotecan but keep the 5-FU and bevacizumab going. After 8 cycles or so, I reintroduce the hard drugs. The alternate regimen in a similar fashion is used on progression. I tell patients when they start that they might be on treatment for a very long time. They can miss one or two cycles which is four to six weeks and go travelling but the bottom line is that the chemotherapy continues until they become intolerant of chemotherapy or their disease becomes resistant. I believe this is the best care for my patients giving them the longest survival while keeping their quality of life the highest. This is a real change in my practice.
References: (Note: Article requests require a login ID with the BC College of Physicians website)
[1] Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer, Hurwitz et al., N Engl J Med. 2004 Jun 3; 350:2335-2342 (Article Request Form) (View Article)
[2] D. M. Purdie, J. D. Berlin, et al. The safety of long-term bevacizumab use: Results from the BRiTE observational cohort study (OCS). J Clin Oncol 26: 2008 (May 20 suppl; abstr 4103) (View Abstract)
[3] C. Tournigand, A. Cervantes, et al., OPTIMOX1: A Randomized Study of FOLFOX4 or FOLFOX7 With Oxaliplatin in a Stop-and-Go Fashion in Advanced Colorectal Cancer—A GERCOR Study, J Clin Oncol 24: 2006, No 3 (January 20) (View Article)
[4] A. Grothey, L. L. Hart, et al., Intermittent oxaliplatin (oxali) administration and time-to-treatment-failure (TTF) in metastatic colorectal cancer (mCRC): Final results of the phase III CONcePT trial. J Clin Oncol 26: 2008 (May 20 suppl; abstr 4010) (View Abstract)
[5] B. Chibaudel, F. Maindrault-Goebel, et al., Can Chemotherapy Be Discontinued in Unresectable Metastatic Colorectal Cancer? The GERCOR OPTIMOX2 Study, J Clin Oncol 27:2009, 10.1200/JCO.2009.23.4344, JCO Early Release, published online ahead of print Sep 28 2009 (Article Request Form) (View Abstract)
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Thank you for this update. Although I do not have many patients with metastatic colon cancer at present, and I generally rely on the specialist to direct such complex care, I find it very useful to be informed of the therapeutic choices faced by these patients so that I may support them through these difficult decisions.
This is a well-written, informative article. While I do not routinely care for this patient population, it is useful information to be aware of and to use in order to evaluate chemotherapy options. Thank you.
I guess it all comes down to the severity of the side effects vs the chances of ongoing tumour repression. Often very difficult to balance -especially for the oncologists who don’t really know the patients or their families. It is often a great help to the patient to have a more “neutral” and broad based opinion from their GP – who at the very least, can act as a sounding board for these “rock and a hard place” decisions and who, at least in rural areas, is dealing with the side effects. This , of course, assumes the patient has a GP!