Colorectal Cancer
could be spared an unnecessary operation. Additionally, primary CRC surgery may alter the host immune response in such a way that tumour growth is increased in the post-operative period.48,49
An
argument against resection is that patients with unresectable metastasis from CRC who have undergone palliative resection of the primary tumour still face the prospect of further intestinal complications, which may require further surgery (see Table 1).34,50 After resection of the primary tumour, these patients may develop local recurrence or adhesions which can result in obstruction and require subsequent surgery.
A decade ago, when patients were treated with single-agent 5-FU chemotherapy, approximately 20 % of patients with mCRC treated with chemotherapy required palliative surgery for symptoms related to their intact primary CRC.39,40,46,50,51
evidence is obtained from case-matched studies. A case-matched study by Benoist et al. compared 27 patients with asymptomatic CRC and unresectable synchronous liver metastases, who received chemotherapy, with 32 matched patients, who were treated by initial resection of the primary tumour. They found no difference in survival between the operative and the non-operative management.
Prospective studies on this topic are currently planned. Recently a protocol has been developed in the Netherlands for stage IV colon cancer patients with unresectable metastases.55
In this trial patients In recent years, combinations with
modern chemotherapy, such as leucovorin–5-FU–oxaliplatin (FOLFOX), capecitabine–oxaliplatin (XELOX) and leucovorin–5-FU– irinotecan (FOLFIRI), have attained response rates of 50 % and disease control rates of 85 % in prospective clinical trials.6,52
With these
modern chemotherapy regimens, approximately 7 % (range 3–22 %) of patients with mCRC required surgical palliation for their intact primary CRC, as stated in an elegant review by Poultsides.43–46
These data
suggest that, with effective chemotherapy, almost 14 asymptomatic patients need to undergo prophylactic resection of their primary tumour in order to save one patient a subsequent operation for obstruction or perforation.46
There are indications that this has led to
a decrease over time in the percentage of resection of the primary tumour in case of unresectable metastatic colorectal disease.13
Survival
Several studies have been performed to analyse OS of patients with stage IV CRC and unresectable metastases, to examine whether to resect the primary tumour or not. Recently, Venderbosch et al. performed a retrospective analysis of two phase III studies (Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer [CAIRO] and CAIRO-2)8,53 and investigated the prognostic and predictive value of resection of the primary tumour in stage IV mCRC patients.54
They demonstrated
that resection of the primary tumour was a significant prognostic factor for survival in these patients. They also performed a review of the literature and identified 22 non-randomised studies, most of which showed improved survival for mCRC patients who underwent resection of the primary tumour. These results were confirmed in a systemic review by Anwar et al.48 presented in Table 2.
An overview of these studies is
However, in all the studies presented a selection bias cannot be excluded. Most studies were not randomised, were performed in single centres and were retrospective in nature. Patients with a good performance status were more likely to undergo surgery, whereas those with extensive disease were more likely to be offered chemotherapy instead. In the absence of randomised controlled trials, the best
1. Jemal A, Bray F, Center MM, et al., Global cancer statistics, CA Cancer J Clin, 2011;61(2):69–90.
2. Mella J, Biffin A, Radcliffe AG, et al., Population-based audit of colorectal cancer management in two UK health regions. Colorectal Cancer Working Group, Royal College of Surgeons of England Clinical Epidemiology and Audit Unit, Br J Surg, 1997;84(12):1731–6.
3. de Gramont A, Figer A, Seymour M, et al., Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer, J Clin Oncol, 2000;18(16):2938–47.
will be randomised to either systemic therapy until progression or unacceptable toxicity or to resection of the primary tumour followed by systemic therapy until progression or unacceptable toxicity. The endpoint of the trial is OS and the trial is powered to identify a survival benefit of six months in the surgery group. Also the National Surgical Adjuvant Breast and Bowel Project has started a Phase II trial using 5-FU, leucovorin and oxaliplatin chemotherapy plus bevacizumab for patients with unresectable stage IV colon cancer and synchronous asymptomatic primary tumour.56
The primary
endpoint is the event rate related to the intact primary tumour requiring surgery. In both trials only patients with colon cancer will be randomised and patients with rectal cancer are excluded. Also a trial from Australia/New Zealand (A randomised phase III multicentre trial evaluating the role of palliative surgical resection of the primary tumour in patients with mCRC [SUPER]) is currently running.57
Patients
will be randomised to compare chemotherapy followed by surgery with surgery alone. The primary outcome is to determine whether surgical resection of the primary tumour in patients with stage IV CRC decreases intestinal complications and improves OS and quality of life. For patients with rectal cancer and unresectable systemic disease, a Phase III randomised clinical trial was recently conducted in the Netherlands. In this trial the role of radiotherapy in providing local control will be studied and patients will be randomised to either standard chemotherapy alone or short-course radiotherapy (5 x 5 Gy) on the primary tumour followed by standard-of-care chemotherapy. The primary endpoint is the number of patients requiring an unplanned surgical intervention related to symptoms of the primary rectal tumour.
Summary
In stage IV CRC with unresectable metastases, the role of resection of the primary tumour remains unclear. Because randomised clinical trials are lacking, it is difficult to draw conclusions from the present literature. With current new chemotherapy regimens, including vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) inhibitors, a relatively low number of patients with mCRC require surgery for their primary tumour. Most studies suggest a survival benefit for patients undergoing surgical resection of the primary tumour compared with those who receive palliative treatment. However, these results are likely to be influenced by selection bias, and therefore prospective randomised controlled trials are needed to address this question. n
4. Douillard JY, Cunningham D, Roth AD, et al., Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial, Lancet, 2000;355(9209):1041–7.
5. Saltz LB, Cox JV, Blanke C, et al., Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group, N Engl J Med, 2000;343(13):905–14.
6. Tournigand C, André T, Achille E, et al., FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study, J Clin Oncol,
2004;22(2):229–37.
7. Seymour MT, Maughan TS, Ledermann JA, et al., Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial, Lancet, 2007;370(9582):143–52.
8. Koopman M, Antonini NF, Douma J, et al., Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial, Lancet, 2007;370(9582):135–42.
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