1. Alexander Stein University Cancer Center Hamburg, Germany
ESMO Consensus Conference: Interactive Session on Colorectal Cancer Guidelines A clinical case presentation on advanced colon cancer (first and second line therapy)
Alexander Stein
University Cancer Center Hamburg, Germany

2. Disclosure
Honoraria from Roche and Merck

3. Case presentation male, 64 years of age, ECOG 0
no relevant comorbidity
routine abdominal ultrasound revealed suspicious liver lesions
CT chest/abdomen
3 liver lesions up to 2.5cm
3 suspicious pulmonary lesions up to 1cm
single bone lesion 1.8cm mixed osteoplastic/osteolytic (left os ileum)
thickening of colonic wall (descendens)

5. Case presentation
colonoscopy: non obstructive tumor without bleeding signs colon descendens
histology: adenocarcinoma
CEA value 245 ng/ml
colon carcinoma with synchronous liver and lung metastates and potential bone involvement

6. Further diagnostics
PET scan  liver and lung lesions positive, bone lesion negative
bone scan  weakly positive
determination of KRAS status  wildtype
ESMO consensus guidelines for management of patients with colon and rectal cancer 2012.
KRAS mutation precludes efficacy of treatment with anti-EGFR antibodies and KRAS status determination is therefore mandatory before treatment [I, A].

7. Acc. to ESMO guidelines next step should be ...
start pure palliative chemotherapy for metastatic disease
discuss patient within MDT according to clinical presentation and determine treatment aim and clinical grouping

8. Definition of treatment strategy
The optimal strategy should be developed according to the characteristics of the patient and be discussed in the multidisciplinary team and should incorporate the (potential) view of the patient as well.
Patients can be individually divided into the 4 clinical groups, by parameters describing localization, extent, and resectability of the disease, tumour dynamics, co-morbidity, potential of the patient to tolerate chemotherapy and secondary surgical treatment [IV, B].

9. Clinical groups for first line treatment stratification
clinical presentation
treatment aim
treatment intensity
clearly R0-resectable liver and/or lung metastases
cure, decrease risk of relapse
nothing or moderate (FOLFOX) 1
liver and/or lung metastases only
which
might become resectable after induction chemotherapy
±limited/localized metastases to other sites, e.g. locoregional lymphnodes
physically able to undergo major surgery (biological age, heart/lung condition)
maximum tumour shrinkage
upfront most active combination regimen 2
multiple metastases/sites, with
rapid progression and/or
tumour-related symptoms/risk of rapid deterioration
co-morbidity allows intensive treatment
clinically relevant tumour shrinkage as soon as possible
at least achieve control of progressive disease
upfront active combination: at least doublet 3
never option for resection
and/or no major symptoms or risk of rapid deterioration
and/or severe comorbidity (excluding from later surgery and/or intensive systemic treatment, as for groups 1+2)
abrogation of further progression
tumour shrinkage less relevant
low toxicity most relevant
treatment selection according to disease characteristics and patients preference re toxicity and efficacy:
“watchful waiting”
sequential approach: start with
single agent, or
doublet with low toxicity
exceptional triplets

10. Clinical course
Patient was considered potentially curative (group 1) by MDT despite the unclear single bone lesion.

11. Acc. to ESMO guidelines primary tumor should be managed by ...
resection of primary tumor before chemotherapy
upfront chemotherapy and delayed resection in case of major response (but still unresectable mets)
upfront chemotherapy and resection only in case of local symptoms

12. Clinical course primary tumor was left in situ
Potentially resectable metastatic disease after chemotherapy (group 1)
For initially unresectable metastatic disease, most active available induction treatment should be chosen [V, C]. If metastases become resectable surgery for primary and metastases should be performed.
Palliative surgery, stenting, laser ablation, or (chemo)radiation in case of unresectable disease, even after systemic treatment should be confined to bleeding or obstruction and as minimal invasive as possible and non invasive measures applied first [V, C].

13. Treatment algorithm for synchronous metastatic colon cancer
synchronous metastatic colon cancer with intact primary
R0/R1 resectable metastases
unresectable metastases
single, <2cm
liver met
3 months preop FOLFOX
intensive upfront chemotherapy
resectability achieved?
yes no
resection of primary and metastases (simultaneous or delayed)
continue chemotherapy
resectability achieved?
6 months postop FOLFOX
3 months postop FOLFOX
continue initial treatment for a total of 6 months
yes no
surgery of primary: individual decision (e.g. complications or emergency)

14. Clinical course FOLFOX + bevacizumab
restaging after 2/4 months: partial response (RECIST)
restaging after 6 months (PET/CT):
liver mets: one remaining with 1.4cm (PET positive)
lung lesions: complete response
bone lesion: unchanged
colonoscopy witout macroscopic evidence of residual primary tumor, biopsy negative (local CR)
decreased tolerability with peripheral neuropathy G2 and asthenia G1

16. Clinical course
 major response liver and complete response lung-metastases and primary tumor
Decision was made by MDT to classify the patient as potentially curative based on age, ECOG, major response and unchanged bone lesion. However, resection or RFA of remaining central liver met. seemed technically difficult.

17. Further management? maintenance (5FU/Cape and/or bevacizumab)
complete stop of treatment
consider locally ablative procedure

18. followed by complete stop of treatment
helical tomotherapy with 10x 4Gy for liver metastasis and as a precaution for the bone lesion
followed by complete stop of treatment
If metastases are not resectable due to their location additional measures like radiofrequency ablation or stereotactic body radiotherapy (in specialized institutions) should be considered, although the benefit is not formally proven [III, B].

19. Clinical course
no evidence of disease for 10 months, followed by progressive disease with 4 new liver and disseminated pulmonary lesions, single bone lesion unchanged
remaining toxicity: PNP G1 (12 months after last oxaliplatin administration)

20. Acc. to ESMO guidelines further treatment should be ...
restart FOLFOX + bevacizumab
change to irinotecan based second line (FOLFIRI +/- targeted agent)

21. Reinduction reinduction FOLFOX + bevacizumab
In first line treatment patients should be treated as long as possible by restart of the former first line regimen (reinduction), when the toxicity (especially neurotoxicity) allows such reinduction.
restaging after 2 months: stable disease
restaging after 4 months: progressive disease (multiple new liver lesions)

22. Further treatment? FOLFIRI + panitumumab
FOLFIRI/irinotecan + cetuximab
FOLFIRI + bevacizumab (beyond progression - TML)
FOLFIRI
single agent EGFR antibody

23. Course of second line FOLFIRI + panitumumab
restaging after 3 months: stable disease (SLD -25%), dose reduction FOLFIRI 80% due to neutropenia
restaging after 6 months: partial response (SLD -8%)
side effects: asthenia G2, cutaneous tox. G1

24. Thank you