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Overcoming challenges in management of mCRC
Eric Van Cutsem
Dr Van Cutsem opens his session on metastatic colorectal cancer with a case study involving a 66-year old female. She has arterial hypertension that is controlled using an ACE inhibitor. For the previous 3 months she exhibited a change in stool pattern, intermittent blood loss and anemia, a weight loss of 3 kg, but no obstruction. Her performance status was ECOG 1. She was diagnosed with a malignant tumour in the sigmoid (i.e., a left-sided colon cancer), which was a moderately differentiated adenocarcinoma that on molecular analysis was found to be RAS and BRAF wildtype.
A baseline scan revealed large liver metastases, but no lung metastases. Dr Van Cutsem asked the audience to choose their preferred treatment regimen for this patient from the following list:
- Surgery of the primary tumour
- Irinotecan-based doublet
- Oxaliplatin-based doublet
- Irinotecan-based doublet + anti-EGFR antibody
- Oxaliplatin -based doublet + anti-EGFR antibody
- Irinotecan-based doublet + bevacizumab
- Oxaliplatin -based doublet + bevacizumab
- Chemotherapy triplet + bevacizumab
About half of attendees voted for either an irinotecan-based doublet + anti-EGFR antibody or an oxaliplatin-based doublet + anti-EGFR antibody. About 20% chose chemotherapy triplet + bevacizumab. Few selected surgery of the primary tumour.
Dr Starling commented that there is a role for conversion therapy and you would want to choose a therapy with a high chance of a response. She thinks the chemotherapy triplet + bevacizumab is a good option (except there is a barrier in that bevacizumab is not reimbursed in the UK), but the next best option would be the oxaliplatin-based doublet + anti-EGFR antibody.
Dr Lordick makes an interesting comment on a surgery-based trial underway in Germany, but he agrees that it would not be a therapy of choice at this time. He agrees with using an oxaliplatin-based doublet + anti-EGFR antibody. Dr Van Cutsem adds that in Belgium, BRAF testing is done as BRAF+ tumours do not benefit as strongly from anti-EGFR antibody therapy. BRAF testing is now part of the new ESMO clinical practice guidelines for metastatic colorectal cancer. The panel engages in an extensive discussion on the current status of BRAF testing in each country.
Dr Van Cutsem asks attendees how they would treat a primary tumour that is caecum adenocarcinoma (i.e, a right-sided colon cancer). He offers the same list of 1st-line treatment choices as in the previous question. The attendees’ top choice was an oxaliplatin-based doublet + anti-EGFR antibody, followed by oxaliplatin-based doublet + bevacizumab, and then an irinotecan-based doublet + anti-EGFR antibody.
Dr Lordick has become cautious on using anti-EGFR antibodies in tumours that come from a right-sided colon cancer due to some unfavourable clinical data and the likely presence of some resistance mechanisms such as BRAF mutations. Dr Starling would ideally select oxaliplatin-based doublet + bevacizumab, but again is faced with the cost-recovery issue in the UK of using bevacizumab.
After 4 months of treatment with chemotherapy (FOLFOX + anti-EGFR antibody), this patient had a good partial response with some remaining metastasis. The attendees were then asked what would they do next?
- Surgery of the primary tumour
- Surgery of the liver metastases (reverse strategy)
- Combined surgery of the primary tumour and liver metastases
- Continue same treatment (FOLFOX + anti-EGFR antibody or FOLFOX + bevacizumab )
- Downgrade chemotherapy to maintenance treatment with fluoropyrimidine + bevacizumab
- Downgrade chemotherapy to maintenance treatment with fluoropyrimidine + anti-EGFR antibody
Attendees voted 55% in favour of combined surgery of the primary tumour and liver metastases, second most-popular was surgery of the liver metastases (reverse strategy), and third choice was to continue the same treatment. The panel agreed that in this case surgery was a reasonable approach.
Dr Van Cutsem then reviews the new ESMO clinical guidelines for the treatment of metastatic colon cancer, which divides patients into fit or unfit categories. Unfit patients are given best supportive care, or if deemed suitable can be given fluoropyrimidine + bevacizumab at a reduced-dose doublet + anti-EGFR.
For fit patients, surgery is recommended for the group with clearly resectable metastases (with or without peri- or post-operative chemotherapy). The goal in the second group is cytoreduction and treatment selection is based on the molecular profile of each patient. If cytoreduction is achieved, surgery may be an option. For those patients where the goal is disease control/limiting progression then as is the case for the second category, treatment selection is also based on the molecular profile of each patient. Monitoring is done on a 2 or 3 month basis, and if response is adequate then the choice is to continue, maintain or pause. In the case of progressive disease, the guidelines state moving onto 2nd-line therapy.
The ESMO clinical guidelines do not address tumour sidedness, but it is becoming an important distinction. Right-sided (proximal) colon cancer derives from midgut, whereas left-sided (distal) colon cancer derives from hindgut. They have different molecular characteristics, such as BRAF mutations being more prevalent in right-sided colon cancers and APC, K-RAS, DCC and p53 mutations in left-sided colon cancers.
Based on retrospective analyses of the 1st-line CRYSTAL and FIRE-3 trials, left-sided metastatic tumours had a better prognosis (for overall survival, progression-free survival and overall response rate), compared to right-sided metastatic tumours in patients with RAS wildtype metastatic colon cancer in all groups treated with FOLFIRI + cetuximab, FOLFIRI + bevacizumab or FOLFIRI alone.
In terms of predicting response to treatment, there were many differences observed in a retrospective analysis of 6 RCTs with 2,159 evaluable patients. For example, in right-sided cancers, chemotherapy + bevacizumab was superior to chemotherapy + anti-EGFR, but the opposite was true in left-sided cancers. In future clinical trials, sidedness should be incorporated into stratifying patients, but many challenges including diagnosis and quotation remain.
Dr Van Cutsem presents another case study in a 62-year old male who has a primary tumour (adenocarcinoma, RAS and BRAF wildtype), of the colon descendens with metastases in the liver and lung. He was treated for 6 months with FOLFOX + bevacizumab with good tolerance and developed Grade 2 neurotoxicity at 6 months. Maintenance treatment with fluoropyrimidine + bevacizumab was continued for 4 months and progression of metastases was observed at 10 months with persisting neuropathy.
What is the best option for 2nd-line treatment after 10 months of 1st-line treatment?
- FOLFIRI + bevacizumab
- FOLFIRI + aflibercept
- FOLFIRI + ramucirumab
- FOLFIRI + cetuximab
- FOLFIRI + panitumumab
- Reintroduce FOLFOX + bevacizumab
- Reintroduce FOLFOX + anti-EGFR antibody
The attendees most popular choice was FOLFIRI + ramucirumab followed by FOLFIRI + cetuximab. Dr Lordick and Dr Starling suggest in a general sense to change the chemotherapy to FOLFIRI and keep the patient on an anti-angiogenic treatment. Any of bevacizumab, aflibercept or ramucirumab would be valid options. They would consider saving the anti-EGFR antibody until the 3rd line. In this case, reintroduction of FOLFOX was not an option due to neurotoxicity.
Dr Van Cutsem finishes this session by discussing the ESMO guidelines recommendations for maintenance therapy and for 2nd-line combinations with targeting agents.