colorectal cancer updated august 2017 by dr. doreen...

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COLORECTAL CANCER Updated August 2017 by Dr. Doreen Ezeife DISCLAIMER: The following are study notes compiled by the above PGY-5 medical oncology residents and reviewed by a staff medical oncologist. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College. A) PUBLIC HEALTH

EPIDEMIOLOGY - Incidence: 3rd highest incidence in Canada (after lung and breast); 49 new cases per 100,0001. - Mortality: 2nd highest cause of cancer-related mortality in Canada (after lung); 17.4 deaths per

100,0001.

RISK FACTORS - Environmental/Chemical/Infections: abdominal radiation, renal transplantation, race – African

Americans at higher risk, gender – men have greater mortality from colorectal cancer, obesity, red and processed meat, tobacco, alcohol, use of androgen deprivation therapy, diabetes mellitus and insulin resistance

- Genetic: Familial adenomatous polyposis (FAP), Lynch syndrome (Hereditary non-polyposis colorectal cancer (HNPCC), MUTYH-associated polyposis (MAP), Peutz-Jeghers, Juvenile polyposis, personal or family history of sporadic colorectal cancers or adenomatous polyps, inflammatory bowel disease (ulcerative colitis and Crohn’s disease) acromegaly

PROTECTIVE FACTORS - exercise, high-fiber diet, ASA/NSAIDs/COX-2 inhibitors, statins: evidence is mixed

PREVENTION & SCREENING - Prevention: There is no established chemoprevention method. Although NSAIDs have been

shown to have modest risk reduction in average- and high-risk individuals, clear recommendations for chemoprevention

- Screening: o Average risk individuals:

§ Age > 50 with no other additional personal or familial risk factors § FOBT or FIT testing every 1 to 2 years for asymptomatic individuals between age

50 to 75 years of age. § Positive FOBT, FIT or flexible sigmoidoscopy tests should be followed by

endoscopy evaluation of the entire colon. § Colonoscopy every 10 years

o Inflammatory Bowel Disease: § Guidelines differ slightly but generally recommend annual surveillance

colonoscopy beginning after 8 to 10 years of IBD diagnosis § Colonoscopy should be repeated every 1 to 3 years

o Familial history: § First-degree relative diagnosed age < 60 or >/= 2 first-degree relatives:

• Screen with colonoscopy at age 40 or 10 years before the youngest relative's diagnosis.

• Repeat colonoscopy every 5 years § First-degree relative diagnosed age > 60:

• Same screening guidelines as for average risk individuals § Familial adenomatous polyposis:

• Annual flexible sigmoidoscopy or colonoscopy starting at age 10 to 12 § Lynch syndrome (germline genetic mutations in MLH-1, MSH-2, MSH-6, PMS-1

and/or PMS-2:

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• Use Amsterdam criteria or revised Bethesda guidelines to determine individuals fitting criteria for Lynch syndrome

• NCCN guidelines state Lynch syndrome screening should occur in every individual with CRC at age 70 or younger and those older than 70 who meet Bethesda guidelines

• Screen with colonoscopy every 1 to 2 years beginning at age 20 to 25 years, or 2 to 5 years prior to the earliest age of colorectal cancer in the family, whichever comes first.

B) PRESENTATION & DIAGNOSIS

SYMPTOMS & SIGNS - Common Symptoms: hematochezia, melena, abdominal pain, iron deficiency anemia, change in

bowel habits, occasionally signs of obstruction, rectal cancer can cause tenesmus, rectal pain, and diminished caliber of stools

- Common Signs: rectal bleeding, rectal mass on DRE - Common Presentations: as above. Uncommonly, Streptococcus bovis or Clostridium septicum

bacteremia are associated with colon cancer in 10 to 25% of patients.

INVESTIGATIONS - Laboratory: preoperative CEA - Diagnostic Imaging: preoperative CT chest, abdomen and pelvis - Diagnostic Procedures: Complete colonoscopy for assessment of the entire bowel and to obtain

tissue diagnosis, K-ras/N-ras/B-raf testing of tumours in the metastatic setting, Mismatch repair gene testing of tumours in localized disease (especially in stage II colon cancer)

PATHOLOGY & MOLECULAR BIOLOGY - Common Histology: Carcinomas are the most common: adenocarcinoma (>90%),

adenosquamous carcinoma, spindle cell carcinomas, squamous cell (epidermoid) carcinoma, undifferentiated carcinoma.

- Other histologic types (neuroendocrine neoplasms, hamartomas, mesenchymal tumors, lymphomas) are rare.

- Common Metastatic Sites: regional lymph nodes, lungs, liver, and peritoneum. Colon cancer typically spreads to liver first because the venous drainage of the intestinal system is via the portal system. Rectal cancer may spread to lungs first because the inferior rectal vein drains into the inferior vena cava rather than to the portal system. Therefore, colon cancer drains into the portal system while rectal cancer drains systemically.

- Relevant Molecular Biology: K-ras/N-ras/B-raf testing of tumours, Mismatch repair genes testing of tumours, 18q deletions

STAGING - TNM: - T1: tumour invades submucosa - T2: tumour invades muscularis propria - T3: tumour invades through muscularis propria into pericolorectal tissues - T4a/b: tumour penetrates to the surface of visceral peritoneum/directly invades other organs or

structures - N1: metastasis in 1-3 regional lymph nodes - N2: metastasis in >/=4 regional lymph nodes - M1a/b: metastasis confined to one organ or site/metastasis in more than one organ or site or the

peritoneum - Stage I: T1/2N0M0; Stage IIA: T3N0M0; Stage IIB: T4aN0M0; Stage IIC: T4cN0M0; Stage III:

node positive disease, M0; Stage IV: M1 disease.

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C) TREATMENT LOCALIZED / ADJUVANT / LOCALLY ADVANCED – COLON CANCER

- Bottom Line General Approach: Stage I: segmental colectomy, no role for adjuvant therapy. Stage IIA (T3N0): segmental colectomy, consider 6 months adjuvant fluoropyrimidine in patients with high-risk (at least one of the high-risk features described below) T3N0 disease. Stage IIB/C (T4N0): segmental colectomy, consider 6 months of adjuvant fluoropyrimidine or modified FOLFOX6 in high-risk patients.

- High-risk features include: inadequate lymph node sampling (<12 nodes), T4 disease, clinical perforation, lymphovascular and/or perineural invasion, complete obstruction or poor differentiation.

- Patients with high levels of microsatellite instability have a better prognosis. Adjuvant chemotherapy with a fluoropyrimidine monotherapy in patients with microsatellite instability is not recommended.

- Stage III: segmental colectomy followed by 6 months of adjuvant chemotherapy with a fluoropyrimidine or modified FOLFOX6.

- Stage III colon cancer in patients > 70 years old: There is no clear benefit of adjuvant FOLFOX chemotherapy in patients > 70 years old. However, it is reasonable to consider FOLFOX chemotherapy in this population.

- No role for adjuvant radiotherapy. - Prognosis: - 5 year survival with surgery alone – from ASCO SEP 5: - Stage I – 85% - Stage II T4aN0 – 80% - Stage II T4bN0 (directly invades into or is adherent to other organs or structures) – 60% - Node-positive (Stage III) – 30-50%

- The prognosis of patients with stage II CRC with defective mismatch repair (MSI-H/dMMR,

whether secondary to HNPCC or sporadic MMR mutations) is better than that for patients with proficient mismatch repair (MSS/pMMR) stage II CRC.

- This is not seen in stage III CRC and prognosis for patients with MSI-H or MSS tumours is similar.

- Important Phase III Clinical Trials:

Adjuvant chemotherapy versus observation in patients with colorectal cancer: a

randomised study (QUASAR trial) Lancet. 2007 Dec 15;370(9604):2020-9.

Regimen • 5-FU/folinic acid chemotherapy vs observation Mechanism of Action of Experimental Drug

• Pyrimidine analog antimetabolite that inhibits thymidylate synthetase to deplete thymidine triphosphate and hence, inhibit DNA synthesis.

Primary Endpoint • All-cause mortality Inclusion/Exclusion Criteria

• Patients with complete resection of colon or rectal cancer without distant mets

• No prior chemo • “uncertain indication for chemotherapy” (determined by patient’s

clinicians, 91% of patients deemed to have an uncertain indication for chemo had stage II disease).

Size (N) • 3239 patients Results • Survival: Relative risk of death from any cause from chemo vs

observation = 0.82 • DFS: Relative risk of recurrence with chemo vs observation = 0.78 • Quality of Life: QOL was worse in the chemo group than the

observation group during the course of chemo.

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Toxicity • Nausea, oral mucositis, diarrhea, neutropenia Conclusion • 5-FU-based chemotherapy can improve survival in patients with

stage II colorectal cancer. The absolute benefit in OS is 2.6%. Other Comments • This trial included both colon and rectal cancer patients, and some

stage III patients, as well as some high-risk stage II patients. • Among the patients with colon cancer, there was only a trend seen

in OS. Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study.

J Clin Oncol. 2015 Dec 10;33(35):4176-87 (10 year update with survival data).

Original study: T Andre et al. J Clin Oncol. 2009 Jul 1;27(19):3109-16.

Regimen • 12 cycles of : Bolus + continuous infusion 5-FU/leucovorin (LV5FU2) vs. FOLFOX4 (5-FU/leucovorin + oxaliplatin)

Mechanism of Action of Experimental Drug

• 5-FU: Pyrimidine analog antimetabolite that inhibits thymidylate synthetase to deplete thymidine triphosphate and hence, inhibit DNA synthesis. Leucovorin allows 5-FU to form a stable ternary complex with thymidylate synthetase to prolong inhibition of the enzyme by 5-FU.

• Oxaliplatin: alkylating agent that binds to DNA forming cross-links which inhibit DNA replication and transcription, resulting in cell death.

Primary Endpoint • DFS in the original study Inclusion/Exclusion Criteria

• Age 18 to 75 • Undergone complete resection of histologically-proven high-risk

stage II or stage III colon cancer • No prior chemotherapy or radiotherapy • Treatment started within 7 weeks of surgery

Size (N) • 2246 patients Results • Survival: 10-year OS rates were 67.1% vs 71.7% (LV5FU2 v

FOLFOX4, respectively, P = 0.043) in the whole population, • 79.5% vs 78.4% for stage II (P = 0.980) • 59.0% vs 67.1% for stage III (P = 0.016) • BRAF mutation was not prognostic for OS, but MMR deficient

tumours were an independent prognostic factor (HR 2.02, P = 0.014).

• DFS/PFS/TTP: 5yr DFS 73.3% vs 67.4% in FOLFOX4 vs 5FU/leucovorin group, respectively (in the original study).

• Response Rate: not reported • Quality of Life: not reported

Toxicity • Grade 3 peripheral sensory neuropathy in oxaliplatin group Conclusion • Adding oxaliplatin to 5FU significantly improves 5yr DFS and 6yr OS

in the stage II and stage III colon cancer patients; FOLFOX should be considered after surgery in stage III colon cancer patients.

Other Comments • (e.g. any criticisms about the study)

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Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): The

IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration.

Shi and Grothey et al. Presented at Plenary Session ASCO 2017.

Design • Prospective pre-planned pooled analysis of 6 concurrently conducted randomized phase III trials SCOT, TOSCA, Alliance/SWOG 80702, IDEA France (GERCOR/PRODIGE), ACHIEVE, HORG) was performed to evaluate the non-inferiority of 3months compared with 6months (control) of adjuvant FOLFOX/XELOX.


• As above

Primary Endpoint • DFS non-inferiority (non-inferiority cutoff was DFS HR for 3months vs 6months < 1.12)

Inclusion/Exclusion Criteria

• Age 18 to 75 • Undergone complete resection of histologically-proven high-risk

stage II or stage III colon cancer • No prior chemotherapy or radiotherapy • Treatment started within 7 weeks of surgery

Size (N) • 12,834 patients Results • 3yr DFS was NOT non-inferior for the overall cohort. Overall, the

3 year DFS rate was 74.6% (3m) and 75.5% (6m). • However, non-inferiority of 3m vs 6m oxali-based adjuvant

therapy was supported in the XELOX group (HR 0.95). • For patients with T1-3N1 disease, 3 vs 6months had fairly

similar DFS (HR 1.01). • For patients with T4N2 disease, the difference between 3m v 6m

of chemo seemed greater (HR 1.12), suggesting that patients with T4N2 disease may benefit more from 6m of adjuvant chemo.

Toxicity • Grade 3 peripheral sensory neuropathy higher in the 6month group Conclusion • While NI was not established for the overall cohort, NI of 3m v 6m

oxali-based adjuv therapy was supported for XELOX. As each IDEA trial treated varying proportions of pts with XELOX (0 to 75%), the regimen interaction likely produced the differential outcomes observed between individual studies. Certain substages (T1-3 N1) also showed NI for 3m v 6m. These data provide a framework for discussions on risks and benefits of individualized adjuv therapy approaches.

Other Comments • (e.g. any criticisms about the study)

- Other Important Published Data: - Meta-analyses:

o Sargent DJ et al. Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20, 898 patients on 18 randomized trails. JCO 2005; 23:8664-70.

o Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Lancet. 1995;345(8955):939.

o Gill S et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol. 2004;22(10):1797.

§ Pooled data set of 3302 patients with stage II and III colon ca from seven randomized trails comparing FU + leucovorin or FU + levamisole to surgery alone

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§ Nodal status T stage and grade were the only prognostic factors independently significant for both DFS and OS. Age was significant only for OS.

§ Adjuvant therapy showed beneficial treatment effect across all subsets § A significant stage by treatment interaction was present, with treatment benefiting

stage III to greater degree than stage II o Sargent D et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in

elderly patients. NEJM 2001; 345(15):1091-7. o Sargent D et al. Evidence for cure by adjuvant therapy in colon cancer: Observations

based on individual patient data from 20,898 patients on 18 randomized trials. JCO 2009;27(6):872-7.

- Other Important Phase III clinical trials: o Yothers G et al. Oxaliplatin as adjuvant therapy for colon cancer: updated results of

NSABP C-07 trial, including survival and subset analyses. J Clin Oncol. 2011;29(28):3768.

o Haller DG et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011;29(11):1465.

§ XELOX vs bolus 5-FU and folinic acid for stage III § DFS 70.9% with XELOX vs. 66.5% with FUFA § HR OS 0.87 (NS)

LOCALIZED / ADJUVANT / LOCALLY ADVANCED – RECTAL CANCER - Bottom Line General Approach: Stage I: transabdominal resection (AR, LAR or APR), no role

for adjuvant therapy. - Stage II or III:

o For non-fixed tumours in the upper two-thirds of the rectum: neoadjuvant short-course radiation therapy (2500cGy in 5 fractions) à LAR or APR within 10 days of first radiation à 6 months of adjuvant chemotherapy with capecitabine (for stage II or III disease) or FOLFOX6 (for stage III disease). FOLFOX6 is considered over capecitabine for patients with node-positive disease. However, if the patient presented with advanced clinical stage (bulky T grade or high N stage), but achieved good downstaging, it is reasonable to consider either adjuvant capecitabine or FOLFOX6. Long-course chemoradiotherapy may also be used for stage III disease.

o For fixed rectal tumours approaching the mesorectal margin and for tumours in the distal one-third of the rectum: neoadjuvant long-course radiation therapy (4500cGy in 25 fractions with a possible boost of 540cGy in 3 fractions) with concurrent chemotherapy à LAR or APR within 6 to 10 weeks after completion of neoadjuvant therapy à 4 months of adjuvant chemotherapy with capecitabine (for stage II or III disease) or FOLFOX6 (for stage III disease). FOLFOX6 is considered over capecitabine for patients with node-positive disease. However, if the patient presented with advanced clinical stage (bulky T grade or high N stage), but achieved good downstaging, it is reasonable to consider either adjuvant capecitabine or FOLFOX6.

o Adjuvant chemotherapy should start within 4 weeks post-op. o If a patient with rectal cancer undergoes upfront resection, referral to a Cancer Centre is

recommended for consideration of adjuvant chemoradiotherapy.

Preoperative versus postoperative chemoradiotherapy for rectal cancer (The German Rectal Cancer Study)

N Engl J Med. 2004;351(17):1731.

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Regimen • Preop vs postop chemoradiotherapy • Chemoradiotherapy in both groups consisted of: 5040 cGy of

radiation therapy (RT) plus 5-FU 1000mg/m2 during weeks 1 and 5 of RT. A boost of 540cGy of RT was added to the postop group.

• One month after surgery, four 5-day cycles of 5-FU were given. Mechanism of Action of Experimental Drug

• 5-FU: Pyrimidine analog antimetabolite that inhibits thymidylate synthetase to deplete thymidine triphosphate and hence, inhibit DNA synthesis.

Primary Endpoint • OS Inclusion/Exclusion Criteria

• Resectable rectal cancer with the inferior margin within 16cm from the anal verge

• No prior chemo or radiotherapy • Age < 75

Size (N) • 823 patients Results • Survival: 5yr OS was NOT statistically significant (76% in preop

treatment group vs 74% in postop treatment group). • DFS/PFS/TTP: 5yr DFS was NOT statistically significant (68% in

preop treatment group vs 65% in postop treatment group). • Local Recurrence: The 5 yr incidence of local recurrence was 6%

in the preop treatment group and 13% in the postop treatment group. This was statistically significant.

• Quality of Life: not reported. Toxicity • More grade 3 or 4 acute toxic effects (diarrhea, heme or derm

toxicities) occurred with patients in the postop treatment group (40%) vs patients in the preop treatment group (27%).

• More grade 3 or 4 long term toxic effects (GI toxicities, strictures, bladder problems) occurred in the postop treatment group (24%) vs preop treatment group (14%).

Conclusion • Preoperative chemoRT results in lower local recurrence rate, toxicity and a higher rate of sphincter preservation compared to postop chemoRT. No difference in OS.

Other Comments • (e.g. any criticisms about the study) Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial

Lancet Oncol. 2015 Aug;16(8):979-89.

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Regimen • Preop and postop chemoradiotherapy with 5FU + radiotherapy VS preop and postop chemoradiotherapy with 5FU + oxaliplatin + radiotherapy

• Chemoradiotherapy in the control group consisted of: 5040 cGy of radiation therapy (RT) plus 5-FU 1000mg/m2 during weeks 1 and 5 of RT. Postop chemo consisted of bolus 5-FU 500mg/m2 on days 1-5 and 29.

• Chemoradiotherapy in the experimental group consisted of: 5040 cGy of radiation therapy (RT) plus 5-FU 250mg/m2 on days 1-14 and 22-35 and oxaliplatin 50mg/m2 on days 1, 8, 22 and 29 preop. Postop chemo consisted of 8 cycles of oxaliplatin 100mg/m2 on days 1 and 15, leucovorin 400mg/m2 on days 1 and 15 and infusional fluorouracil 2400mg/m2 on days 1-2 and 15-16.


• 5-FU: Pyrimidine analog antimetabolite that inhibits thymidylate synthetase to deplete thymidine triphosphate and hence, inhibit DNA synthesis.


Primary Endpoint • DFS Inclusion/Exclusion Criteria

• cT3 or cT4 or cN1-2 rectal cancer with the inferior margin within 12cm from the anal verge

• ECOG </= 2 • No prior chemo or radiotherapy to the pelvis • Age > 18 • Patients with metastatic disease were excluded

Size (N) • 1265 patients Results • Survival: 3yr OS was NOT statistically significant (88.7% in

experimental group vs 88.0% in the control group). • DFS/PFS/TTP: 3yr DFS 76% vs 71% in experimental vs control

group (p = 0.03). • Locoregional Recurrence: The 3 yr incidence of local recurrence

was 2.9% in the experimental group and 4.6% in the control group. • Quality of Life: not reported.

Toxicity • Diarrhea, sensory neuropathy, fecal incontinence, anastomotic strictures

Conclusion • The addition of oxaliplatin to neoadjuvant and adjuvant chemoradiotherapy significantly improved DFS in cT3-4 or cN1-2 rectal cancers in comparison to the former 5-FU-based chemoradiotherapy regimen.

Other Comments • This is the only study that has shown a benefit of adding oxaliplatin to neoadjuvant chemoRT and this study used a different schedule of oxaliplatin administration. Consistent results from the Italian, French and US phase III trials found no benefit with increased toxicity, mainly diarrhea. Currently, oxaliplatin should NOT be recommended as part of the neoadjuvant chemoRT treatment for ecal cancer outside of clinical trials.

- Other Important Published Data: - Meta-analyses: - Breugom et al. Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for

patients with rectal cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol. 2015 Feb;16(2):200-7.

o This meta-analysis included trials that used 5-FU-based adjuvant chemotherapy administered according to outdated regimens that are no longer standards of care today.

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o Regardless, this meta-analysis showed no difference in distant relapse or OS with adjuvant chemo.

o However, these results should not change the standard of care, which is to offer adjuvant chemo to rectal cancer patients according to initial pre-neoadjuvant treatment stage.

- Maas et al. Adjuvant chemotherapy in rectal cancer: Defining subgroups who may benefit after neoadjuvant chemoradiation and resection. Int. J. Cancer: 137, 212-220 (2015).

- Other Phase III clinical trials: o Hong et al. Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as

adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2014 Oct;15(11):1245-53.

§ This trial (and 2 others) found a DFS advantage to adjuvant oxaliplatin-based treatment.

§ NCCN guidelines state that patients with rectal cancers should receive adjuvant therapy after resection, with treatment intensity based on initial (ie. pre-neoadjuvant treatment) stage.

o Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol 2012 Jun;13(6):579-588.

METASTATIC COLORECTAL CANCER

- Bottom Line General Approach:

A) Potentially resectable patients - In select patients, segmental resection of obstructing or bleeding colorectal primary lesions may

be considered. - Palliative radiotherapy or stereotactic body radiation therapy (SBRT) may be considered. - Liver-only metastasis or solitary/lobe-confined pulmonary mets may be considered for resection.

Potentially resectable patients may be treated with neoadjuvant chemotherapy until optimal resectability (please see “Unresectable patients” section for possible chemotherapy options in these patients). It is preferable to consider oxaliplatin-based chemotherapy prior to liver metastasectomy as irinotecan can cause steatohepatitis, which can interfere with surgery. However, irinotecan is NOT a contraindication to surgery and can be used if the patient is ineligible for oxaliplatin-based treatment. A limited number of cycles of chemotherapy should be delivered to minimize the consequences to the liver and adverse effects.

- The criteria for liver resection are: - at least 2 adjacent lobes (caudate lobe excluded) free of tumour, biliary drainage intact, arterial inflow, non-thrombosed portal vein, 20% or more liver functional reserve.

B) Unresectable patients - Upon diagnosis of metastatic disease, patients’ tumours should be tested for activating

mutations in Ras (Kras and Nras). Patients with known Ras mutations should NOT be treated with the EGFR inhibitors, Panitumumab or Cetuximab.

- Patients with RAS wild-type left-sided colorectal cancer should be treated with chemotherapy (FOLFOX or FOLFIRI) in combination with an EGFR inhibitor (cetuximab or panitumumab) in the first line setting.

- In patients with RAS wild-type right-sided colorectal cancer, first line EGFR inhibitors should NOT be used. The combination of a VEGF inhibitor with standard chemotherapy remains the standard for these patients.

- Other standard first-line palliative chemotherapy options (eg. for patients who cannot receive combination chemo) are:

o Capecitabine o Irinotecan o 5-FU

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o CAPOX

- Patients who have progressed on all standard chemotherapy may receive fourth-line regorafenib or TAS-102.

C) Sequential vs Combination Chemotherapy Strategies - Sequential chemotherapy consists of a fluoropyrimidine monotherapy followed by either:

o Irinotecan monotherapy OR o Combination chemotherapy which consists of a doublet of a fluoropyrimidine with

irinotecan or oxaliplatin - There is a statistically significant difference in overall survival in favour of combination

chemotherapy over planned sequential chemotherapy. However, the magnitude of this difference may not be clinically significant. Additionally, sequential chemotherapy can minimize toxicities. Therefore, sequential chemotherapy and upfront combination chemotherapy are both acceptable standards of care and the choice should be made on a case-by-case basis.

D) Intermittent vs Continuous Chemotherapy Strategies - Intermittent strategies of delivering first-line chemotherapy to patients with unresectable mCRC

do not result in a clinically significant reduction in overall survival and improve or maintain quality of life in comparison to continuous chemotherapy. Therefore, consideration of intermittent chemotherapy strategies should be part of an informed discussion with patients.

- Prognosis: Data from the Surveillance, Epidemiology, and End Results (SEER) database report 5 year survivals of:

- Stage IV – 8 percent

- Important Phase III Clinical Trials:

i) First-line chemotherapy:

Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicenter randomized trial.

Douillard D et al. Lancet 2000; 355: 1041-47.

Regimen • Control: Fluorouracil + calcium folinate alone • Experimental: Irinotecan + fluorouracil + calcium folinate



• Irinotecan binds to topoisomerase to prevent religation of the cleaved DNA strand, resulting in DNA breaks and ultimately, termination of cellular replication.

Primary Endpoint • RR Inclusion/Exclusion Criteria

• Colorectal cancer • ECOG 2 or less, life expectancy > 3 months • No prior chemotherapy for metastatic disease • No CNS mets • Adequate organ function

Size (N) • 387 patients Results • Survival: mOS 17.4 months vs 14.1 months (p=0.031) in

experimental vs control groups. • PFS/TTP: mTTP was 6.7 months vs 4.4 months (p<0.001) in

experimental vs control groups. • Response Rate: 49 vs 31% (p<0.001) in experimental vs control

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group • Quality of Life: There was a significantly later deterioration in QOL

in the irinotecan group. Toxicity • Grade 3-4 diarrhea, asthenia, neutropenia and infection with

concomitant grade 3-4 neutropenia were significantly more frequent and severe in the irinotecan group than in the no-irinotecan group

Conclusion • First-line irinotecan combined with fluorouracil and calcium folinate increased RR, TTP, and OS in patients with metastatic CRC.

Other Comments • (e.g. criticisms about the study) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer.

de Gramont A et al. J Clin Oncol. 2000;18(16):2938. Regimen • FOLFOX4 vs 5-FU/LV alone Mechanism of Action of Experimental Drug



Primary Endpoint • PFS Inclusion/Exclusion Criteria

• Metastatic unresectable colorectal cancer • ECOG 2 or less • Age 18 to 75 • No prior chemotherapy for metastatic disease • Adequate organ function • No CNS mets or prior malignancies

Size (N) • 420 patients Results • Survival: mOS was numerically better in FOLFOX4 group (16.2

mos) vs 5-FU/LV alone group (14.7 mos) but this was NOT statistically signicant.

• PFS/TTP: mPFS was statistically better in FOLFOX4 group (9 mos) vs 5-FU/LV alone group (6.2 mos).

• Response Rate: Objective RR was statistically better in FOLFOX4 group (49.5%) vs 5-FU/LV alone group (28.6%).

• Quality of Life: median QOL scores were comparable for both groups.

Toxicity • Grade 3/4 neutropenia, diarrhea, mucositis, and neuropathy were more frequent with FOLFOX4.

• Other grade ¾ toxicities were typical 5-FU/LV and oxaliplatin toxicities.

Conclusion • FOLFOX4 is beneficial 1st-line therapy in mCRC with superior PFS and acceptable tolerability and QOL maintenance.

Other Comments • (e.g. criticisms about the study)

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Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer.

Cassidy J et al. JCO 2008;26(12)2006-12.

Regimen • Control arm: FOLFOX-4

• Experimental arm: XELOX • Later amended after bevacizumab data became available to a 2x2

factorial design: - FOLFOX-4 + placebo vs FOLFOX-4 + bevacizumab - XELOX + placebo vs XELOX + bevacizumab



• Capecitabine: an oral prodrug of fluorouracil. Capecitabine is absorbed intact through the intestinal wall and then converted to 5-FU through three enzymatic reactions that take place in the liver, the GI tract and the tumour cell. The final enzymes are present in much higher levels in tumour cells than in normal tissue allowing for enhanced tolerability. Fluorouracil inhibits thymidylate synthetase to inhibit DNA synthesis.



• Unresectable metastatic colorectal cancer • ECOG 1 or less, life expectancy more than 3 months • No prior chemo for metastatic disease • No CNS mets • No full-dose anticoagulation or thrombolytics or serious nonhealing

wound or severe proteinuria • Patients at least 18 years of age

Size (N) • 634 patients in original two-arm portion, an additional 1400 patients after the start of the amended 2 x 2 design.

Results • Survival: median OS 19.8 months with XELOX vs 19.6 months with FOLFOX-4 not significantly different

• PFS/TTP: median PFS 8.0 months with XELOX vs 8.5 months with FOLFOX not significantly different

• Response Rate: XELOX 47% vs FOLFOX 48% not significantly different

• Quality of Life: NR Toxicity • XELOX group experienced more grade 3 hand-foot syndrome and

diarrhea while the FOLFOX-4 group had more grade 3 or 4 neutropenia/granulocytopenia and febrile neutropenia/sepsis.

Conclusion • XELOX is noninferior to FOLFOX as first-line treatment for mCRC and should be considered in the appropriate patients.

Other Comments • (e.g. criticisms about the study) ii) Chemotherapy sequencing FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a

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randomized GERCOR study.

Tournigand C et al. J Clin Oncol. 2004;22(2):229. (Please also see the companion trial: Colucci JCO 2005; 23(22):4866-75). Regimen • Arm A: FOLFIRI

• Arm B: FOLFOX6 • At progression, irinotecan was replaced by oxaliplatin (arm A) or

oxaliplatin was replaced by irinotecan (arm B). Mechanism of Action of Experimental Drug




Primary Endpoint • PFS, OS Inclusion/Exclusion Criteria

• Unresectable metastatic CRC • ECOG 2 or less • No prior chemo for metastatic disease • No CNS mets • Adequate organ function

Size (N) • 226 patients Results • Survival: mOS was 21.5 mos for arm A vs 20.5 mos for arm B (NOT

statistically significant). • PFS/TTP: median second PFS was 14.2 mos for arm A vs 10.9 mos

for arm B (NOT statistically significant). • Response Rate: In 1st-line therapy, FOLFIRI achieved 56% RR and

FOLFOX 54% RR. • Quality of Life: not reported.

Toxicity • FOLFIRI: more grade 3 or 4 mucositis, N/V and alopecia • FOLFOX: more grade 3 or 4 neutropenia, and neurosensory toxicity

Conclusion • Both regimens and sequences achieved similar efficacy with different toxicity profiles.

Other Comments • (e.g. criticisms about the study) iii) FOLFOXIRI Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. Falcone A et al. J Clin Oncol. 2007 May 1;25(13):1670-6.

14

Regimen • Arm A: FOLFOXIRI • Arm B: FOLFIRI





Primary Endpoint • RR Inclusion/Exclusion Criteria

• Unresectable metastatic CRC • No prior chemo for metastatic disease • ECOG 2 or less • Adequate organ function

Size (N) • 244 patients Results • Survival: mOS was 22.6 months v 16.7 months FOLFOXIRI v

FOLFIRI, p = 0.032 • PFS/TTP: median PFS 9.8 months in FOLFOXIRI group vs 6.9

months in FOLFIRI group, p = 0.0006 • Response Rate: 66% v 41% FOLFOXIRI v FOLFIRI, p = 0.0002 • Quality of Life: not significant difference between the two arms.

Toxicity • Increased grade 2 to 3 peripheral neurotoxicity and grade 3 to 4 neutropenia in the FOLFOXIRI arm.

Conclusion • Both regimens and sequences achieved similar efficacy with different toxicity profiles.

Other Comments • (e.g. criticisms about the study) iv) Surgical candidates Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial

Nordlinger B et al. Lancet 2008 Mar 22;371(9617):1007-1016.

Regimen • surgery alone vs 6 cycles of FOLFOX4 à surgery à 6 cycles of FOLFOX4




Primary Endpoint • PFS (HR 0.71 or less) Inclusion/Exclusion Criteria

• Age 18 to 80 years, ECOG 2 or less • Histologically-proven colorectal cancer with one to four liver mets

that were potentially resectable and no detectable extrahepatic tumour

• Primary tumour had to either be already resected (R0 resection) or judged to be resectable by the hospital multidisciplinary team

• No prior oxaliplatin-based chemotherapy

15

• No prior major liver disease, significant peripheral neuropathy or other significant major organ dysfunction (detailed in original paper).

Size (N) • 364 patients Results • Survival: not reported

• PFS/TTP: median PFS 18.7mos for periop chemo group vs 11.7 mos for surgery alone group

• Response Rate: not reported • Quality of Life: not reported

Toxicity • Reversible postop complications occurred significantly more frequently in the periop chemo group than in the surgery alone group.

• In the periop chemo group, typical FOLFOX chemo adverse effects were seen: grade 3 diarrhea, grade 3 stomatitis, grade 3 or 4 neutropenia, grade 3 sensory neuropathy

Conclusion • Periop chemotherapy with FOLFOX4 is compatible with liver tumour resection and improves PFS in eligible and resected patients.

Other Comments • (e.g. criticisms about the study) v) Biologic therapy

- Anti-VEGF Inhibitors: Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer

Hurwitz H et al. N Engl J Med. 2004;350(23):2335.

Regimen • Irinotecan/bolus 5-FU/LV plus bevacizumab vs irinotecan/bolus 5-

FU/LV plus placebo Mechanism of Action of Experimental Drug


• Bevacizumab: Recombinant humanized monoclonal antibody which binds to and inhibits VEGF effectively inhibiting angiogenesis and retarding cell growth in all tissue.

• Primary Endpoint • OS Inclusion/Exclusion Criteria

• metastatic CRC • ECOG 0 or 1 • Age >/= 18 • No prior chemo or biologic therapy for metastatic disease • Adequate organ function

Size (N) • 813 patients Results • Survival: mOS 20.3 mos with bevacizumab vs 15.6 mos without

• PFS/TTP: mPFS 10.6mos with bevacizumab vs 6.2 without • Response Rate: Overall RR 44.8% with bev vs 34.8% without • Quality of Life: not reported

Toxicity • Grade 3 or 4 toxicities were higher in the bev group because of HTN, diarrhea and leukopenia.

• The other well-known bevacizumab adverse effects (such as proteinuria, GI perforation, arterial-venous thrombosis and poor wound healing) occurred at similar rates in both groups.

Conclusion • Bevacizumab added to 5-FU-based combination chemo results in improved OS in patients with mCRC.


16

Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in

metastatic colorectal cancer: a randomized phase III study. Saltz et al. J Clin Oncol. 2008 Apr 20;26(12):2013-9.

Regimen • 2x2 factorial design: • Arm A: XELOX + placebo • Arm B: XELOX + bevacizumab • Arm C: FOLFOX4 + placebo • Arm D: FOLFOX4 + bevacizumab






• metastatic unresectable CRC • ECOG 0 or 1, life expectancy > 3 months • Age >/= 18 • No prior systemic therapy for mCRC or prior oxaliplatin or

bevacizumab • Adequate organ function • No CNS mets • No serious nonhealing wound, significant proteinuria or use of full-

dose anticoagulants/thrombolytics Size (N) • 1401 patients Results • Survival: mOS 21.3 mos in the bevacizumab group vs 19.9 mos in

the placebo group, p=0.077 • PFS/TTP: mPFS 9.4 in bevacizumab group vs 8.0 months in the

placebo group, p=0.0023 • Response Rate: 47% vs 49% in the bevacizumab + chemo group

vs placebo + chemo groups, respectively, p=0.31. • Quality of Life: not reported

Toxicity • Grade 3 or 4 toxicities were similar in both arms. Bevacizumab toxicities were higher in the bevacizumab arms (16% and 8%).

Conclusion • Bevacizumab added to oxaliplatin-based chemo results in improved PFS in the first-line setting in patients with mCRC.


- EGFR-inhibitors Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal

cancer. Amado RG et al. J Clin Oncol. 2008;26(10):1626.

17

Regimen • Panitumumab (P-mab) 6mg/kg plus best supportive care (BSC) q 2 weeks vs BSC


• Panitumumab: recombinant human IgG2 monoclonal antibody that binds to EGFR competitively inhibiting the binding of EGF to other ligands. This results in inhibition of cell growth, proliferation and survival. KRAS is a G-protein downstream of EGFR and cells with RAS mutations are unaffected by EGFR inhibition.


• metastatic CRC • ECOG 2 or less • Age >/= 18 • Two or three prior chemotherapy regimens for metastatic CRC • 1% or more EGFR-positive membrane staining in evaluated tumour

cells • No prior CNS mets • Adequate organ function

Size (N) • 427 patients included in KRAS analysis Results • Survival: No statistically significant difference was seen among

treatment arms (HR 0.97). With the treatment arms combined, wildtype KRAS patients had longer OS (HR 0.67).

• PFS/TTP: mPFS in the wildtype KRAS group was 12.3 weeks for P-mab vs 7.3 weeks for BSC.

• Response Rate: RR to P-mab was 17% in the wildtype KRAS group vs 0% in the mutant KRAS group.

• Quality of Life: not reported. Toxicity • More grade III diarrhea and rash were seen in P-mab group Conclusion • Panitumumab monotherapy efficacy in mCRC is restricted to

patients with wildtype KRAS tumours. Patients should undergo KRAS tumour testing prior to considering P-mab therapy.


K-ras Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer Karapetis et al. NEJM 2008;359:1757-65.

Regimen • Arm A: Cetuximab + best supportive care (BSC)

• Arm B: BSC alone Mechanism of Action of Experimental Drug

• Cetuximab: recombinant IgG1 human/mouse chimeric monoclonal antibody that binds to EGFR competitively inhibiting the binding of EGF to other ligands. This results in inhibition of cell growth, proliferation and survival. KRAS is a G-protein downstream of EGFR and cells with RAS mutations are unaffected by EGFR inhibition.


• metastatic CRC expressing EGFR • ECOG 2 or less • Age >/= 18 • Prior chemotherapy with a fluoropyrimidine, irinotecan, and

oxaliplatin with no response to treatment or had contraindications to treatment with these drugs

• No prior EGFR inhibitor • No prior CNS mets • Adequate organ function

Size (N) • 572 randomized Results • Survival: In patients with wild-type K-ras tumours, median OS was

9.5 months in the cetuximab group vs 4.8 months in the BSC alone

18

group, p<0.001). • PFS/TTP: mPFS in the wildtype KRAS group was 3.7 months vs 1.9

months, p<0.001. • Response Rate: In the cetuximab group, RR was 12.8% among

patients with wild-type K-ras tumours vs 1.2% in patients with mutated K-ras tumours.

• Quality of Life: Patients with wild-type K-ras tumours who received cetuximab had improvement in global health status in comparison to BSC alone group. There was no difference in QOL between the cetuximab and BSC alone groups in the mutated K-ras patients.

Toxicity • More rash was seen in cetuximab group Conclusion • Patients with a colorectal tumour bearing wild-type K-ras had

improved survival with cetuximab therapy while patients with a K-ras mutated colorectal tumour did not benefit from cetuximab. The mutation status of the K-ras gene did not impact survival in patients treated with BSC alone.

Other Comments • (e.g. criticisms about the study) Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomized, multicenter, open-label, non-inferiority

phase 3 study Price TJ et al. Lancet Oncol 2014;15:569-79.

Regimen • Panitumumab (P-mab) 6mg/kg vs Cetuximab 400mg/m2; 250mg/m2

once a week thereafter. Mechanism of Action of Experimental Drug

• Panitumumab: recombinant human IgG2 monoclonal antibody that binds to EGFR competitively inhibiting the binding of EGF to other ligands. This results in inhibition of cell growth, proliferation and survival. KRAS is a G-protein downstream of EGFR and cells with RAS mutations are unaffected by EGFR inhibition.


Primary Endpoint • OS for non-inferiority Inclusion/Exclusion Criteria

• Chemotherapy-refractory metastatic CRC • ECOG 2 or less • Age >/= 18 • Wild-type KRAS exon 2 status • Adequate organ function

Size (N) • 1010 patients Results • Survival: 10.4 months for P-mab vs 10.0 months for cetuximab. P-

mab was non-inferior to cetuximab. • PFS/TTP: mPFS 4.1 months for P-mab vs 4.4 months for cetuximab. • Response Rate: RR to P-mab was 22% vs 19.8% in the cetuximab

group. • Quality of Life: QOL was similar for both groups.

Toxicity • More grade III rash and hypomagnesemia were seen in P-mab group (62% vs 48%). Lower infusion reactions in the P-mab group.

Conclusion • Panitumumab is noninferior to cetuximab and these therapies provide similar overall survival benefit.


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FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial.

Lancet Oncol. 2014 Sep;15(10):1065-75.

Regimen • Arm A: FOLFIRI + cetuximab • Arm B: FOLFIRI + bevacizumab




Primary Endpoint • Objective response Inclusion/Exclusion Criteria

• metastatic CRC • ECOG 2 or less, life expectancy > 3 months • Age >/= 18 • Wild-type KRAS exon 2 status • No prior chemotherapy for colorectal cancer except for adjuvant

therapy • No prior EGFR-targeting agent or bevacizumab • No CNS mets • Adequate organ function • No serious nonhealing wound, significant proteinuria or use of full-

dose anticoagulants/thrombolytics Size (N) • 592 patients Results • Survival: mOS 28.7 months in the cetuximab group vs 25.0 months

in the bevacizumab group, p=0.017. • PFS/TTP: mPFS 10.0 months in the cetuximab group vs 10.3

months in the bevacizumab group, p=0.55. • Response Rate: objective RR was 62% in cetuximab group vs 58%

in bevacizumab group, p=0.18. • Quality of Life: QOL was similar for both groups.

Toxicity • Most common grade 3 or worse adverse event were hematotoxicity, skin reactions and diarrhea.

Conclusion • Despite similar objective response rates, mOS was higher in the cetuximab group suggesting that this may be the preferred first-line regimen in patients with KRAS exon 2 wild-type mCRC.

Other Comments • (e.g. criticisms about the study) CALGB/SWOG 80405 abstract: Phase III trial of FOLFIRI or FOLFOX with Bevacizumab or Cetuximab for patients with KRAS wild type untreated metastatic adenocarcinoma of the colon or rectum Venook A et al. Presented at ASCO 2014.

20

Regimen • Arm A: FOLFOX/FOLFIRI + Bevacizumab • Arm B: FOLFOX/FOLFIR + Cetuximab





• Untreated metastatic CRC • Tumour KRAS wild-type codons 12 & 13 • ECOG 1 or less • Age >/= 18 • Adequate organ function

Size (N) • 1137 patients Results • Survival: Interim analysis - mOS 29.9 months for cetuximab group

vs 29.0 months for bevacizumab group, p=0.34. • PFS/TTP: Interim analysis - mPFS 10.4 months for cetuximab vs

10.8 months for bevacizumab, p=0.55. • Response Rate: Interim analysis – ORR 66% for cetuximab group

vs 57% for bevacizumab group. • Quality of Life: Higher skin-related QOL scores in bevacizumab

group, p < 0.0001. Toxicity • More grade III rash and diarrhea were seen in cetuximab group.

More HTN and VTE in bevacizumab group. Conclusion • OS is similar in chemo/cetuximab and chemo/bevacizumab groups

in first-line treatment for patients with KRAS wild-type (codons 12&13) mCRC.

Other Comments • (e.g. criticisms about the study) Impact of primary tumour location on overall survival and progression-free survival in patients with metastatic colorectal cancer: Analysis of CALGB/SWOG 80405. Venook et al. Presented at ASCO 2016.

Regimen • This was a chart review analysis of the 80405 study to assess the

impact of primary side (Right vs Left) and Cetuximab and Bevacizumab treatment on overall survival and PFS in 80405 patients. Please see original CALGB 80405 trial results above.

Methods • Primary location was determined by chart review • All 1137 patients with KRAS wt (codons 12 and 13) were included • R-sided = cecum to hepatic flexure • L-sided = splenic flexure to rectum • Transverse = hepatic to splenic flexure

Results • OS and PFS differed by side (statistically significant): • For cetuximab-treated patients, L-sided primary OS was 37.5

months vs. 16.4 months for R-sided primary. 12.0 vs 7.7 months for PFS.

• For bevacizumab-treated patients, L-sided primary OS was 24.5 vs 32.1 months. 11.1 vs 9.5 months for PFS.

Conclusion • Patients with L-sided primary mCRC have superior OS and PFS compared to patients with R-sided primary tumours. OS and PFS were prolonged with cetuximab in L and with Bevacizumab in R but poorer with Cetuximab in R. These data support Bev in 1st line

21

treatment for mCRC patients with R-sided primary tumour regardless of KRAS status.

Other Comments • Not a pre-planned analysis vi) Treatment-resistant mCRC

Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.

Grothey A, et al. Lancet. 2013;381(9863):303-12.

Regimen • Regorafenib 160mg po od plus best supportive care (BSC) vs BSC plus placebo


• Regorafenib: a multikinase inhibitor that targets kinases involved in angiogenesis and oncogenesis. The kinases regorafenib targets are: EGF receptors 1-3, KIT, PDGFR-alpha, PDGFR-beta, RET, FGFR1 and 2, TIE2, DDR2, TrkA, Eph2A, RAF-1. BRAF, BRAFV600E, SAPK2, PTK5, and Abl.


• metastatic CRC • ECOG 0 or 1 • Age >/= 18 • Patients had to have received standard chemotherapy for mCRC

and progressed within 3 months of receiving standard therapy, or have stopped therapy secondary to toxicity.

• Adequate organ function Size (N) • 760 patients Results • Survival: mOS 6.4mos in regorafenib group vs 5.0 mos in placebo

group. • PFS/TTP: mPFS was 1.9 mos in regorafenib group vs 1.7mos in

placebo group. • Response Rate: objective RR 1.0% in regorafenib group vs 0.4% in

placebo group • Quality of Life: Both groups demonstrated a deterioration in QOL.

Toxicity • Common grade 3 or more adverse effects in the regorafenib group were: rash, fatigue, diarrhea, hand-foot syndrome, and HTN.

Conclusion • Regorafenib shows survival benefit in patients with mCRC who have progressed on all standard therapies.


Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer. Mayer RJ et al. N Engl J Med. 2015 May 14;372(20):1909-19.

Regimen • Arm A: TAS-102 35mg/m2 bid q4wks + BSC

• Arm B: Placebo + BSC Mechanism of Action of Experimental Drug

• TAS-102: Composed of trifluridine and tipiracil. Trifluridine is the active cytotoxic component and is a thymidine-based nucleic acid analogue that is incorporated into DNA to interfere with DNA synthesis and inhibit cell proliferation. Tipiracil is a thymidine phosphorylase inhibitor that prevents the rapid degradation of trifluridine, allowing for greater trifluridine exposure in the cell.


• metastatic CRC • ECOG 2 or less • Age >/= 18 • 2 or more prior regimens. Refractory/intolerant of: fluoropyrimidine,

22

irinotecan or oxaliplatin • Adequate organ function

Size (N) • 800 patients Results • Survival: mOS 7.1 months in TAS-102 arm vs 5.3 months in

placebo arm, p<0.0001 • PFS/TTP: mPFS was 2.0 mos in TAS-102 group vs 1.7mos in

placebo group, p<0.0001. • Response Rate: • Quality of Life:

Toxicity • Nausea, vomiting, decreased appetite, fatigue, diarrhea, cytopenias, elevated liver enzymes

Conclusion • TAS-102 significantly improves overall survival in comparison to placebo in patients with refractory mCRC.

Other Comments • (e.g. criticisms about the study) vii) Immunotherapy

- Other Important Published Data: (e.g. meta-analysis, retrospective analyses, phase II) o Meta-analysis studying the sequence of therapies in mCRC - Asmis T et al. Strategies of

sequential therapies in unresectable mCRC: a meta-analysis. Curr Oncol, Vol 21, pp. 318-328.

o Phase II trial studying immunotherapy in mCRC - Le et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. NEJM 2015;372:2509-20.

o Awaiting the results of KEYNOTE-164, a Phase II study of Pembrolizumab as monotherapy in patients with refractory mCRC that is mismatch repair deficient or microsatellite instability-high.

- Other important Phase III studies in mCRC: o Another trial comparing capecitabine to 5-FU/LV in mCRC - Hoff PM et al.

Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001;19(8):2282.

o Cunningham D et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Irinotecan as a single agent - Lancet. 1998;352(9138):1413.

1) Other first line chemotherapy trials: • Trials establishing FOLFIRI in 1st-line mCRC:

• Saltz LB et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000;343(13):905.

• Köhne CH et al. Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol. 2005;23(22):4856.

o N = 430 with mCRC randomized to 5-FU (FA500mg/m2 as 2h infusion and FU 2.6mg/m2 as 24h infusion weekly = AIO) +/- IRI 80mg/m2

o mPFS 8.5 mos vs 6.4 mos (ss) o mOS 20.1 vs. 16.9 mos (ns) o ORR: 62.2 vs. 34.4% (ss)

• Trials establishing FOLFOX in 1st-line mCRC: - Goldberg RM et al. A randomized controlled trial of fluorouracil plus

leucovorin, irinotecan, and oxaliplatin combinations in patients with

23

previously untreated metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):23-30.

• Companion trial to the Tournigand trial establishing FOLFIRI/FOLFOX in the 1st line setting:

- Colucci G et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. JCO 2005;23(22)4866-75.

2) Other capecitabine combination trials: • Fuchs CS et al. Randomized, controlled trial of irinotecan plus infusional, bolus,

or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25(30):4779.

• Porschen et al. Capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxalitain: a randomized comparison in mCRC-a final report of the AIO Colorectal Study Group. JCO 2007;25:4217-23.

• Diaz-Rubio E et al. Phase III study of capecitabine plus oxaliplatin versus continuous infusion fluorouracil plus oxaliplatin as first-line therapy in mCRC: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumours trial. JCO 2007;25:4224-30.

• Comella P et al. Randomised trial comparing biweekly oxaliplatin plus oral capecitabine versus oxaliplatin plus i.v. bolus fluorouracil/leucovorin in mCRC patients: results of the Southern Italy Cooperative Oncology study 0401. J Cancer Res Clin Oncol 2009;135:217-26.

• Rothenberg et al. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplain (FOLFOX-4) as second-line therapy in mCRC: a randomized phase III noninferiority study. Ann Oncol 2008;19:1720-6.

3) Other FOLFOXIRI trial • Souglakos J et al. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and

irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer 2006; 94(6) 798-805.

4) Continuous vs Intermittent chemotherapy: This table shows the important clinical trials studying continuous vs intermittent chemotherapy strategies in mCRC patients (courtesy of Dr. Scott Berry):

n Induction/Continuous Tx

Maintenance Tx

Primary Outcome

OS HR (95% CI)

Maughan BMJ 2003 354 5FU

None

OS 0.87 (0.69-1.09( p=NS

Labianca Ann Oncol

2011 337 FOLFIRI OS 0.91 (0.72-

1.15) p=NR

Alexopoulos ASCO 2006 39 FOLFIRI NR Not available

Chibaudel (“OPTIMOX2”)

JCO 2009 216 FOLFOX DDC 1.14 (0.83-

1.57) p=NS

Adams (“COIN”)

Lancet 2011 1630 Cape/FOLFOX OS 1.08 (0.97-

1.21) p=NR

Koopman (“CAIRO3”) ASCO 2014

558 CapeOx+Bev PFS2 1.12 (0.93-1.36) p=NS

Tournigand 620 FOLFOX 5FU DDC 0.93 (0.75-

24

(“OPTIMOX1”) JCO 2006

1.15) p=NS

Grothey (“CONCEPT”) ASCO 2008

180 FOLFOX + Bev TTF Not available

Diaz-Rubio (“MACRO”) Oncologist

2012

480 FOLFOX + Bev Bev PFS 1.05 (0.85-1.30) p=NS

Tveit (“NORDIC VII”)

JCO 2012 372 Nordic FLOX +

Cetuximab Cetuximab PFS 1.03 (0.81-1.32) p=NS

Yalcin ASCO 2012 123 CapeOx + Bev 5FU + Bev PFS Not available

5) Sequential vs Combination chemotherapy:

• Seymour MT 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.

• Koopman M et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-42.

• Ducreux M et al. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial. Lancet Oncol 2011;12(11):1032-44.

6) Chemotherapy +/- Bevacizumab This table shows the important clinical trials studying chemotherapy +/- Bevacizumab in mCRC patients (courtesy of Dr. Scott Berry): Statistically significant results are bolded and underlined.

RR (%) Median

PFS/TTP (mos)

Median OS (mos)

Combination infusional

chemo

CapeOx/FOLFOX +/- Bev

(Saltz, JCO 2008) 38 vs 38 9.4 vs 8.0

HR=0.83 21.3 vs 19.8

HR=0.89

FOLFIRI/FOLFOX +/- Bev

(Passardi, ASCO 2013)

49 vs 48 9.6 vs 8.4 HR=0.87

Results pending

Combination bolus chemo

IFL +/- Bev (Hurwitz, NEJM

2004) 45 vs 35 10.6 vs 6.2

HR=0.54 20.3 vs 15.6

HR=0.66

Iri/5FU bolus q 3 weeks +/- Bev (Stathopolous,

Oncology, 2010)

37 vs 35 NR 22.0 vs 25.0 HR=NR

mIFL +/- Bev (Guan, Chinese

Journal of Cancer, 2011)

35 vs 17 8.3 vs 4.2 HR=0.44

18.7 vs 13.4 HR=0.62

Fluoropyrimidine monotherapy

5FU/LV +/- Bev (pooled analysis)

(Kabbinavar, JCO, 2005)

34 vs 24 8.8 vs 5.6 HR=0.63

17.9 vs 14.6 HR=0.74

25

Cape +/- Bev (Tebutt, JCO,

2010) 38 vs 30 8.5 vs 5.7

HR=0.63 18.9 vs 16.4

HR=0.88

Cape +/- Bev (Cunningham, Lancet Onc,

2013)

19 vs 10 9.1 vs 5.1 HR=0.53

20.7 vs 16.8 HR=0.79

7) Chemotherapy +/- EGFR Inhibitors

This table shows the important clinical trials studying chemotherapy +/- EGFR inhibitors in mCRC patients (courtesy of Dr. Scott Berry): Statistically significant results are bolded and underlined.

First Line Trials: KRAS WT RR % Median PFS/TTP

(months) Median OS (months)

CRYSTAL (FOLFIRI +/- Cetux) Van Cutsem, JCO

2011

59 vs 43 9.9 vs 8.7 (HR=0.68)

(primary outcome) 23.5 vs 20 (HR=0.80)

PRIME (FOLFOX +/- Pmab) Douillard, JCO 2009

55 vs 48 9.6 vs 8.0 (HR=0.80)

(primary outcome) 23.9 vs 19.7 (HR=0.80)

OPUS (FOLFOX +/- Cetux)

Bokemeyer, JCO 2009 57 vs 34 8.3 vs 7.2

(HR=0.57) 22.8 vs 18.5 (HR=0.86)

COIN (CapeOx/FOLFOX +/-

Cetux) Maughan, Lancet

2011

64 vs 57 8.6 vs 8.6 (HR=0.96)

17.0 vs 17.9 (HR=1.04)

Nordic VII (NORDIC FLOX +/-

Cetux) Tveit JCO 2012

46 vs 47 7.9 vs 8.7 (HR=1.07)

20.1 vs 22.0 (HR=1.14)

• Companion trial to the Karapetis NEJM 2007 trail (Cetuximab trial pre-KRAS

analysis) - Jonker DJ et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357(20):2040.

- N = 572, IHC detectable EGFR previously treated with FOLFIRI/FOLFOX randomized to cetuximab vs. BSC

- mOS 6.1 vs. 4.6 mos (HR death 0.77; ss) - PFS (HR 0.68; ss) - Partial response in 8 vs. 0%; stable disease in 31.4% vs. 10.9% (ss) - QOL better in cetuximab group, less deterioration in physical function

and global health scores - Grade 2+ rash associated with improved survival (HR death 0.33 ss)

• Panitumumab trial pre-KRAS analysis - Van Cutsem E et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25(13):1658.

- N = 463 with 1%+EGR staining; PMab vs. BSC; primary EP PFS - mPFS: 8weeks vs. 7.3 weeks (ss) - Mean PFS 13.8 weeks vs. 8.5 weeks - ORR: 10% vs. 0% after minimum 12-month FU - No difference OS

• PEAK trial – Schwartzberg LS et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin

26

(mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014 Jul 20;32(21):2240-7.

• Ye et al. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. JCO 2015; 33(32).

8) 2nd line Anti-VEGF Trials

This table shows the important clinical trials studying 2nd line VEGF inhibitors in mCRC patients (courtesy of Dr. Scott Berry): Statistically significant results are bolded and underlined.

% Receiving Prior

Bevacizumab N RR (%) Median OS

(months)

0

FOLFOX +/- Bevacizumab

(Giantonio, JCO, 2007)

829 23 vs 9 12.9 vs 10.8

30

FOLFIRI +/- Aflibercept (Van Cutsem, JCO,

2012)

1226 20 vs 11 13.5 vs 12.1

100

Chemo +/- Bevacizumab (Bennouna, Lancet Onc,

2013)

820 5 vs 4 11.2 vs 9.8

100

Chemo +/- Bevacizumab

(Masi, Ann Oncol, 2015)

184 21 vs 18 NR

100

FOLFIRI +/- Ramicirumab (Tabernero, Lancet Onc,

2015)

1072 13 vs 12 13.3 vs 11.7

REFERENCES (e.g. Alberta Health Services/Cancer Care Ontario/BC Cancer Agency Clinical Practice Guidelines, ASCO Guidelines, Canadian Cancer Statistics 2015, UpToDate) 1. Canadian Cancer Statistics 2015 2. BC Cancer Agency Guidelines 3. Alberta Cancer Guidelines 4. Cancer Care Ontario Guidelines 5. UpToDate

colorectal cancer updated august 2017 by dr. doreen...

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