Chemotherapy strategies in patients with metastatic colorectal cancer (CRC)

Our panel proposes to adopt the ESMO guidelines as a pragmatic guideline for systemic therapy in metastatic colorectal cancer. The key recommendations are listed below:

Patients can be divided into treatment groups. Systemic treatment recommendations are listed based on these groups:

Group 0: Upfront R0 resectable liver lung metastases

Group 1: Potentially resectable metastatic disease after systemic treatment

Group 2: Non-resectable, Intermediate intensive treatment (e.g. extensive disease, tumour-related symptoms)

Group 3: Non-intensive/sequential treatment

When patients undergo upfront resection of metastases (including primary resection in cases of synchronous presentation), postoperative adjuvant FOLFOX for 6 months could be considered. Postoperative chemotherapy with FOLFOX for 6 months is generally recommended. However, adjuvant 5-FU has not shown significant benefit in two small randomized trials and no data is available for FOLFOX. The use of FOLFOX in this situation is supported only by the indirect evidence with regard to the potential value of FOLFOX in the perioperative situation.

Upfront resection of metastases followed by adjuvant systemic chemotherapy may be a preferred option in good prognosis patients with a single small (<2 cm) liver metastasis since this lesion may not remain visible during surgery if responding well to chemotherapy.

For initially R0 resectable metastatic disease, perioperative chemotherapy is another option. In this situation 3 months pre- and postoperative FOLFOX should be applied analogous to the EORTC 40983 trial.1

Achieving complete response (CR) to chemotherapy is of major prognostic importance for liver metastases but should be avoided in order to enable resection (before complete disappearance). Therefore, close follow-up with imaging and multi-disciplinary discussion is mandatory. If an anatomical resection can be performed, CR is not a major problem, because resection will be based on initial sites of liver metastases. In case of CR on CT and no option for anatomical resection, different imaging methods might be used (MRI, PET scan, contrast enhanced ultrasound) or resection might be delayed until relapse occurs.

Although never prospectively proven, it seems evident, that the achievement of a disease-free status after downsizing by induction chemotherapy or enabling secondary surgery is the only means of giving the potential of long-term survival or cure in an otherwise incurable/palliative situation. For this aim, the most active induction chemotherapy which is able to induce downsizing as much as possible in as many patients as possible should be selected upfront.

If metastases become resectable, surgery for the metastases (and the primary) should be performed, followed by postoperative continuation of the same regimen for a total of 6 months of systemic therapy (including preoperative). If metastases remain unresectable, treatment should be continued or switched, depending on quality of response.

Multiple factors should be considered in determining appropriate frontline chemotherapy in patients with metastatic CRC.

Tumour Biology-related Factors

Localization and extent: Liver- or lung-only metastases versus multiple sites; Potentially R0-resectable lesions after induction chemotherapy and sufficient downsizing versus massive disease extension; Imminent relevant tumour symptoms should be considered

Growth dynamics: Aggressive versus indolent growth

Asymptomatic versus symptomatic disease:

Possibility that patient may not be fit/able to receive second line therapy following ineffective first line therapy

Prognostic molecular or biochemical markers (e.g. BRAF mutation)

Patient-related Factors

Biological age


Physical capacity to tolerate more intensive treatment

Eligibility for potential secondary resection of liver/lung

Psychological capacity/willingness to undergo more intensive treatment

Treatment Factors

Potential to induce maximal regression of metastases size/number

Drug efficacy/toxicity profile of chemotherapy

Potential to prolong progression-free survival (PFS) or OS

Toxicity profile

Drug sensitivity/predictive biomarkers

Drug availability and cost

For Group 2 patients, where there is significant disease bulk or treatment related symptoms, reliable and rapid regression of metastases is important. In this situation, an escalation strategy (single agent followed by combination) might have the risk that the first-line treatment is not effective, and switching to more effective second-line treatment may not be possible. Therefore, very active first-line treatment that has a high likelihood to induce metastases regression in a short time seems to be appropriate for most of Group 2 patients. It should be noted that there may be individual cases whereby surgery becomes feasible following exceptional response despite initial assessment of unresectability. For the majority of patients, the treatment aim is palliative rather than curative. The duration of any response, time to progression and OS are also relevant in choosing the most optimal regimen.

For Group 3 patients, maximal shrinkage of metastases is not the primary treatment aim. Rather, without present or imminent symptoms and limited risk for rapid deterioration, prevention of tumour progression with symptom disappearance and prolongation of life with minimal treatment burden is the aim. Therefore, an escalation strategy seems to be appropriate, starting with single agent or well tolerated two-drug combination.

Local ICER analyses were not available for all drugs. While ICER analyses have been performed by NICE( (, these cannot be extrapolated due to different costs of molecular testing, surgery and infusional therapy. NICE did not provide precise estimates for anti-VEGF first line or second line therapy.

The workgroup members unanimously support the general adoption of the ESMO guidelines.

The workgroup members unanimously support the following statements as modifications to the ESMO guidelines:

A recent UK study found that addition of cetuximab to chemotherapy and surgery for operable colorectal liver metastases in KRAS exon 2 wild-type colorectal cancer patients results in shorter PFS.2(PFS at 12 months 60% in group receiving chemotherapy plus cetuximab vs 72% in group on chemotherapy alone; median PFS 14.1 months (95% CI 11.8-15.9) in the group receiving chemotherapy with cetuximab compared with 20.5 months (95% CI 16.8-26.7) in the chemotherapy alone group (HR 1.48; 95% CI 1.04-2.12; p=0.030)) Cetuximab should be used with caution in patients with upfront resectable colorectal cancer.