Adjuvant Therapy After Resection of Metastatic Colorectal Cancer: Scant Evidence of a Curative Benefit

January 15, 2016

In all other settings, giving chemotherapy just to make us feel better emotionally in exchange for potential harm to the patient is not the right strategy. We need to find better treatments for this new clinical indication.

Oncologists have a great deal of enthusiasm for adjuvant therapy. In fact, it is one of the few places where we can actually have a curative impact on patients with solid tumors. While there have been great strides in adjuvant therapy in some diseases, such as breast cancer, our success in the setting of colorectal cancer has been more modest. In stage III disease, only 1 of every 4 patients who receive adjuvant therapy experiences significant benefit; in stage II disease, only 1 in 20 appears to benefit.

Unfortunately, we have not been able to predict, using molecular testing, which patients are at risk and which will benefit in a prospective fashion. Nor have we been willing to acknowledge (or document) that when we apply adjuvant therapy to an entire population, knowingly benefiting a small subset, we may in fact do significant harm to some patients. Our enthusiasm for curing the few outweighs our negative impact on the majority.

Over the last 20 years we have created a new clinical setting now known as “stage IV–no evidence of disease.” We all have many of these patients in our clinics. They range from patients with isolated peritoneal nodules or liver metastases that have been resected, to those with multiple metastases that have been resected and ablated. On the one hand, we are delighted that we have gotten these patients to this state; on the other hand, we know that these patients have a very high risk of persistent cancer. Because of our enthusiasm for adjuvant therapy and our belief that our new medicines will have an adjuvant-like effect on these patients, we have treated them perioperatively and postoperatively in the hope of offering additional curative benefit. However, we must recognize that there is absolutely no evidence to support doing this.

As we reflect on the history of adjuvant therapy for colorectal cancer over the past decade, it is striking that agents that have significant impact in the metastatic setting have failed in the adjuvant, curative setting. This has not been the case in other malignancies, which suggests that micrometastatic colon cancer has unique properties not seen in other cancers. Theories involving epithelial-mesenchymal transition[1] and stem cells[2] suggest that the cells we are killing in the micrometastatic setting, which yield the adjuvant effect, may not be the same cells we are treating in patients with stage IV–no evidence of disease colorectal cancer.

In clinic, I typically use the gardening analogy of “seed” and “small plant.” Our two agents with activity in the adjuvant setting, fluorouracil (5-FU) and oxaliplatin, have curative potential on seeds. But I suspect that in the patient with stage IV–no evidence of disease colorectal cancer, any residual cells we are treating are, in fact, small plants-early metastatic disease. Chemotherapy does not have curative potential in metastatic disease. Therefore, giving a set amount of chemotherapy in the hope of offering additional curative impact has little justification in science.

A major failing of the gastrointestinal research community is that we have not done adequate studies of the role of chemotherapy in this setting. But first we must recognize that these are very difficult clinical trials to design. Patients with widely variable risks would all be included, and we have no solid biomarker other than relapse to determine the impact of treatment. We have performed only a few studies, and these studies have failed to demonstrate an overall survival benefit for patients in this setting.

The European Organisation for Research and Treatment of Cancer study is the best trial we have that has examined perioperative FOLFOX (leucovorin [folinic acid], 5-FU, oxaliplatin) in patients who have undergone liver resection.[3] The results demonstrated that there was an 8% improvement in progression-free survival at 3 years; however, this was a small, underpowered study, and it failed to demonstrate an overall survival benefit. Many see this trial as justification for giving FOLFOX chemotherapy in the perioperative liver resection setting, but others-including me-see it as a negative trial. Another study looked at epidermal growth factor receptor–based therapy in the perioperative setting. Unfortunately, this study had negative results that demonstrated potential harm from the addition of biologics in this setting.[4] In both studies, logic dictated that the chemotherapy should have resulted in an improved outcome. However, neither study demonstrated this.

Clearly, what is needed is a new approach to the treatment of patients with stage IV–no evidence of disease colorectal cancer. This is an ideal opportunity for clinical trials to look at novel therapies and approaches. I believe most of these patients should be treated as if they have residual metastatic disease; with this premise, one might adopt a watch-and-wait strategy rather than a maintenance-like strategy. Repeated rounds of intensive chemotherapy with intent of cure do not seem justified based on the literature or scientific logic and therefore should not be given to these patients. The only exception is in the perioperative setting, where demonstration of clinical responsiveness or downstaging/conversion would be of use. In all other settings, giving chemotherapy just to make us feel better emotionally in exchange for potential harm to the patient is not the right strategy. We need to find better treatments for this new clinical indication.

Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Bates RC, Mercurio AM. The epithelial-mesenchymal transition (EMT) and colorectal cancer progression. Cancer Biol Ther. 2005;4:365-70.

2. Kreso A, van Galen P, Pedley PM, et al. Self-renewal as a therapeutic target in human colorectal cancer. Nat Med. 2014;20:29-36.

3. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371:1007-16.

4. Baker H. Cetuximab for liver metastases from colorectal cancer. Lancet Oncol. 2013;14:e204.