1. Case presentation Mr PR 58 year-old male

2. Initial Presentation Apr 2012 attending Golf Masters in America change in bowel habit was once daily, then increased in frequency and decreased in quantity and caliber attributed this to diet change nil other symptoms e.g. tiredness, PR bleeding

3. Initial Presentation routine blood donor, donates blood every 3/12 turned away on this occasion due to anemia advised to attend GP for further investigation of anemia developed weight loss of 4 kg (86 kg to 82 kg) latest health check-up in Feb 2012 with GP NAD

4. Presented to GP investigated for iron deficiency anemia referred to Gastroenterologist (Michael Merett) for OGD and colonoscopy Colono (9/8/12): sessile polyps- 3 in ascending colon, 1 in distal rectum- all removed; circumferential neoplasm with distal margin 12 cm from anal verge Bx: moderately differentiated adenocarcinoma

5. Staging CT TAP: -multiple lung nodules up to 7mm in size; -extensive liver metastases; largest measuring 8cm in segment II/III and 7cm in segment VII/VIII; masses appeared confluent and not confined to one lobe MRI rectum: -widespread liver metastases and enlarged porta hepatis lymph node -mass at rectosigmoid junctionn 16cm from anal verge -ill-defined posterior margin with infiltration into adjacent fat (T3 tumour) CT-PET Whole body: -consistent with CT and MRI findings

6. Diagnosis AJCC Stage IV Rectal Cancer cT3N1M1 Histo: moderately differentiated adenocarcinoma Kras wildtype Braf wildtype

7. Referral presented at colorectal MDM referred to colorectal surgeon and hepatic surgeon to assess for resectability referred to radiation oncologist for ?radiation to primary referred to medical oncologist for chemotherapy opinion

8. Medical History Nil significant; previous hernia repair No regular meds Nil supplements, complementary therapies NKDA Nil significant FHx of cancer Both parents alive and well (Fa 87, Mo 83)

9. Social History CEO of golf club separated from wife; two daughters gym 5x/week; gold 1x/week balanced diet, nil excessive red meat social drinker non-smoker

10. Progress Lesions deemed unsuitable for resection at this stage MDM decisioned for chemotherapy FOLFOX-6 with bevacizumab (Avastin) Port sited on 3/9/12

11. Chemotherapy responded well after first four cycles completed 20 cycles of FOLFOX-6 with Avastin minimal side effects or disability except mild mouth ulcers, minimal peripheral neuropathy ECOG between 0 and 1 throughout therapy dramatic fall in CEA good radiological response to chemo

12. CEA Index CEA (3/9/12) 458 ➔ 301 ➔ 163 ➔ 108 ➔ 71 ➔ 44 ➔ 27 ➔ 16 ➔ 14 ➔ 12 ➔ 13 ➔ 15 ➔ 19 ➔ 22 ➔ 18 ➔ 32 ➔ 30 ➔ 37 ➔ 39 ➔ 50 ➔ 58 ➔ 95 latest LDH 262 ➔ 265 ➔ 364 7/9/13 UECr, FBC, LFT NAD

13. Progress Currently switched to maintenance chemo with capecitabine (Xeloda) and Avastin presently on fourth cycle planned for re-staging CT after sixth cycle KIV surgery if obstruction or further response KIV radiation

14. Clinical question The role of bevacizumab in metastatic colorectal cancer

15. Median OS on best supportive care: 5-6 mo systemic chemo with 5-FU and oxaliplatin or irinotecan: ~2 years

16. Treatment aims Palliative: -prolong survival -maintain QOL -aim to halt progression Curative: -conversion therapy (conversion of apparently unresectable disease to resectable disease) -aim for response rate

17. Chemo for mCRC 5-fluorouracil, capecitabine oxaliplatin irinotecan bevacizumab cetuximab, panitumumab aflibercept regorafinib

18. The “angiogenic switch” inhibition of tumor growth in experimental animals by selective inhibition of VEGF via anti-VEGF monoclonal antibodies (MoAbs), VEGF receptor small molecule kinase inhibitors or MoAbs, or soluble VEGF receptors inhibition of one or more of the molecules that stimulate VEGF expression (eg, EGF and its receptor, platelet-derived growth factor [PDGF] and its receptor, HIFs, cyclooxygenase-2 [COX-2] inhibitors, and IL-1beta) efficacy of endogenous inhibitors of angiogenesis (eg, endostatin, angiostatin) in xenografts

19. Bevacizumab humanized monoclonal antibody directed against VEGF extremely long circulating half-life ~17 to 21 days taken up by platelets; virtually complete neutralization of platelet VEGF first proven to have efficacy in advanced colorectal cancer

20. Bevacizumab Benefit first shown in a trial of 813 patients who were randomly assigned to IFL with or without bevacizumab improved objective response rate (45 versus 35 percent) and median survival (20 versus 16 months) significantly improved time to tumor progression (11 versus 6 months) N Engl J Med. 2004;350(23):2335

21. limited data available on adding bevacizumab to FOLFIRI trials on bevacizumab plus oxaliplatin- based regimens generally showed benefit Bevacizumab

22. XELOX-1/NO16966 randomized trial of XELOX and FOLFOX4 later modified to allow for further randomization to bevacizumab versus no bevacizumab addition of bevacizumab to either regimen significantly improved PFS however, there was no impact on response rates

23. ECOG 3200 829 patients with previously treated mCRC FOLFOX4 versus bevacizumab versus FOLFOX4 plus bevacizumab bevacizumab/FOLFOX4 group had a significantly better PFS (7.3 versus 4.7 months) and median overall survival (12.9 versus 10.8 months) compared to FOLFOX4 alone

24. CAIRO3 trial Dutch trial that randomly assigned 558 patients with stable disease or better after six cycles of XELOX plus bevacizumab who were not eligible for potentially curative metastasectomy to continued capecitable plus bevacizumab versus observation alone Upon first progression (PFS1), patients in both arms were supposed to be treated with XELOX plus bevacizumab until the second progression (PFS2) per protocol

25. CAIRO3 trial maintenance therapy was associated with a significantly longer PFS1 (median 8.5 versus 4.1 months, HR 0.44, p<0.0001) and PFS2 (11.5 versus 10.5 months, HR 0.81, p = 0.028) also longer time to second progression trend toward improved overall survival (median 21.7 versus 18.2 months, HR 0.87, p = 0.16)

26. STOP and GO trial Turkish trial that randomly assigned 123 patients who received six cycles of XELOX plus bevacizumab to to continued therapy or discontinuation of oxaliplatin median PFS was significantly better in the group without oxaliplatin i.e. maintenance therapy with bevacizumab plus capecitabine (11 versus 8.3 months) (preliminary results) also less morbidity in group without oxaliplatin

27. MACRO trial Spanish trial in which patients received six cycles of first-line XELOX plus bevacizumab followed by randomization to continued therapy or bevacizumab maintenance therapy alone until progression or treatment intolerance median PFS and OS in patients treated with bevacizumab alone were not significantly worse but failed to achieve its primary endpoint of non- inferiority similar result in Swiss SAKK 41/06 trial

28. anti-EGFR agents three trials (BOND-2, PACCE, CAIRO2) showed worse survival with simultaneous targeting of both VEGF and EGFR reason for lack of synergy unknown suggestion that bevacizumab prevents delivery of the drugs to the tumor cells; reducing tumor targeting of anti-EGFR antibodies

29. Adjuvant therapy NSABP C-08 trial; 2672 patients with stage II (25 percent) or III colon cancer experimental arm received bevacizumab concurrent with FOLFOX for six months, and then as monotherapy for an additional six months; the control arm was six months of FOLFOX alone no significant benefit with the addition of bevacizumab in terms of DFS or OS

30. Adjuvant therapy AVANT trial; European multi-center trial 3451 patients with resected stage III or high-risk stage II colon carcinoma FOLFOX4 alone versus FOLFOX plus bevacizumab or XELOX plus bevacizumab failed to show DFS or OS benefit suggestion of possible detrimental impact of adding bevacizumab to oxaliplatin-containing regimen

31. Summary For patients treated with a first-line bevacizumab-containing chemotherapy regimen, the use of bevacizumab beyond progression in conjunction with a second-line fluoropyrimidine-based chemotherapy regimen can be considered a standard approach. However, for patients with K-ras wild- type tumors who are receiving irinotecan-based second line regimens, bevacizumab should not be used in conjunction with an anti-EGFR antibody. irinotecan