Practice Update: Haematology & Oncology

COLON & RECTUM

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NEWS ESMO releases new consensus guidelines on the management of metastatic colorectal cancer ESMO, the leading European professional organisation for medical oncology, has released new consensus guidelines for the management of metastatic colorectal cancer that reflect an increasingly personalised approach to treatment, as published online in Annals of Oncology .

JOURNAL SCAN Clinical outcome after oxaliplatin treatment in stage II/III colon cancer subtypes JAMA Oncology Take-home message • The benefit of adding oxaliplatin to fluorouracil plus leucovorin was assessed in molecular subtypes of colon cancer through secondary analysis of the rand- omized NSABP C-07 trial. Recurrence-free survival was significantly improved with oxaliplatin in patients with stage III disease with an enterocyte subtype, but this was not validated in an independent cohort. Patients with the stem-like subtype did not benefit fromoxaliplatin treatment and shared poor prognosis with patients having colorectal cancer subtype 3 or consensus molecular subtype 4. • Clinical trials testing experimental therapies may be appropriate for colorectal cancer patients with stem-like subtype tumours because the subtype is as- sociated with poor prognosis regardless of stage or chemotherapy treatment.

“Management of metastatic colorectal cancer is be- coming more complex, requiring a strategic approach and evidence-based patient selection for the best treat- ment options,” said chair of the ESMO Consensus Conference Professor Eric Van Cutsem, from the University Hospitals Gasthuisberg/Leuven and KU Leuven, Belgium. In December 2014, ESMO convened an inter- national consensus panel of experts with subgroups focusing on molecular pathology and biomarkers, local and ablative treatment and treatment of metastatic disease. The subsequent recommendations are based on a significant new body of clinical trial evidence and an advanced understanding of the role and impact of molecular selection. One of the major innovations in the guidelines is the development of a detailed therapeutic algorithm that takes into account the patient’s condition and fitness; therapeutic goals such as tumour shrinkage or slowing disease progression; and molecular markers. The guidelines also address questions such as the use of chemoembolization and radioembolisation, imaging, and surgical resection. Recommendations made by the consensus panel include RAS and BRAF mutation testing at diagnosis for all patients with metastatic colorectal cancer. The guidelines also note that there is now growing evidence for more frequent testing for MSI. Testing emerging biomarkers such as EGFR or HER2 is not recom- mended as routine for patient management. “Colon cancer management is making progress,

leading patients who can be cured though multidisci- plinary management of metastases, and to prolonged survival – up from 6 months to 30 months – in many patients,” said Professor Van Cutsem. This progress is also attributed to the use of com- bination chemotherapy and the development of novel second line agents including angiogenesis inhibitors, EGFR antibodies and new agents for chemorefractory disease such as regorafenib and trifluridine/tipiracil. This second set of ESMO consensus guidelines for metastatic colorectal guidelines – the first were published in 2012 – integrates with the 2014 ESMO Clinical Practice Guidelines on metastatic colorectal cancer, which will be updated for publication in 2017. Commenting on the guidelines, Dr Fotios Loupakis from the Ospedale Civile – Istituto Toscano Tumori and member of the ESMO Faculty for Gastro-Intesti- nal Tumors, said, “With these long awaited guidelines, the management of metastatic colorectal cancer of- ficially enters the personalised era, addressing the role of existing and emerging biomarkers and their role in the clinic.” “The new guidelines move from the clinically- defined historical categories – which were focused on the resectability of metastases, to a less sharp but more realistic assessment that gives more importance to additional elements, such as patient, tumour and treatment characteristics.”

IMPORTANCE Oxaliplatin added to fluo- rouracil plus leucovorin therapy for patients with colon cancer has been shown to provide significant but mod- est absolute benefit for disease-free survival. However, acute and chronic neurotoxic effects from this regimen underscore the need for markers that predict oxaliplatin benefit. OBJECTIVE To test our hypothesis that mo- lecular subtypes of colon cancer would be associated with differential prognosis and benefit from oxaliplatin added to fluorouracil plus leucovorin therapy. DESIGN, SETTING, AND PARTICIPANTS Par- ticipants in the NSABP C-07 trial were divided into discovery (n = 848) and validation (n=881) cohorts based on the order of tissue block submission. A re- estimated centroid using 72 genes was used to determine Colorectal Cancer Assigner subtypes and their association with oxaliplatin benefit in the discovery cohort. The validation cohort was ex- amined with a locked-down algorithm for subtype classification and statistical analysis plan. Post hoc analysis included examination of the entire cohort with Colorectal Cancer Assigner, Colorectal Cancer Subtype (CCS), and Consensus Molecular Subtype (CMS) methods. INTERVENTIONS Fluorouracil plus leucov- orin with or without oxaliplatin. MAIN OUTCOMES AND MEASURES Percent recurrence-free survival. RESULTS Among 1729 patients, 744 (43%)

were female and mean (SD) age was 58 (11) years. Although C-07 participants with stage III disease with an enterocyte subtype showed a statistically significant benefit from oxaliplatin in the discov- ery cohort (hazard ratio, 0.22 [95% CI, 0.09–0.56]; P=0.001 [n=65]), no statisti- cally significant benefit was observed in the validation cohort (hazard ratio, 0.53 [95% CI, 0.22–1.24]; P=0.14 [n=70]). The stemlike subtype was associated with poor prognosis and lack of benefit from oxaliplatin treatment (HR, 0.99 [95% CI, 0.73–1.34]; P=0.96 [n=367]). Examination of the different subtyping methods shows that all 3 methods robustly identified patients with poor prognosis (stemlike, CCS-3, and CMS-4) in both stage II and III. CONCLUSIONS AND RELEVANCE Patients with stemlike tumours may be appropri- ate for clinical trials testing experimental therapies because stemlike tumours were robustly identified and associated with a poor prognosis regardless of stage or chemotherapy regimen. The clinical utility of using subtyping for the identification of patients for treatment with oxaliplatin requires validation in independent clinical trial cohorts. Clinical outcome from oxaliplatin treatment in stage II/III colon cancer according to intrinsic subtypes: sec- ondary analysis of NSABP C-07/NRG oncology randomised clinical trial. JAMA Oncol 2016 Jun 06;[EPub Ahead of Print], N Song, KL Pogue-Geile, PG Gavin, et al.

ESMO Press Commentary

JOURNAL SCAN Recommendations on controversial issues in the primary treatment of rectal cancer European Journal of Cancer Take-home message • Controversial issues related to the treatment of rectal cancer were discussed and voted on by a multidisciplinary international panel in the context of the second St. Gallen EORTC Gastrointestinal Cancer Conference. MRI or MRI plus endoscopic ultrasonography was recommended by the panel for staging modalities as mandatory, except for early T1 cancers with an option for local excision. In early tumours with low risk of recurrence, primary surgery with total mesorectal excision was recommended. For tumours of other stages, multimodal treatment was recommended. In cases where neoadjuvant therapy is indicated, long-course radiochemotherapy (RCT) was recommended over short-course radiotherapy except for T3a/b N0 tumours. Preoperative short-course radiotherapy with combination chemotherapy or a liver-first resection was recommended for potentially resect- able tumours with coincident liver metastases instead of beginning with fluoropyrimidine-based RCT. • Treatment decisions for rectal cancer rely on critical pretreatment staging and range from local excision to radiochemotherapy in combination with more extensive resection.

JOURNAL SCAN Outcome according to KRAS-, NRAS-, BRAF-, and KRAS variant mutations inmetastatic colorectal cancer Annals of Oncology Take-home message • This study sought to analyse the outcomes of KRAS, NRAS, BRAF, and KRAS variant mutations in 1239 patients with metastatic colorectal cancer. Mutations in KRAS and BRAF were associated with shorter progression-free survival (PFS) and overall survival (OS) compared with non-mutated tumours. Further- more, KRAS G12C and G13D variants were associated with shorter survival. • In patients with metastatic colorectal cancer, mutations in KRAS and BRAF are associated with shorter PFS and OS.

unmutated tumours (multivariate HR 2.26 (1.25–4.1), P = 0.001). A similar trend for OS was seen in the KRAS G13D-variant (n=71, multivariate HR 1.46 (0.96–2.22), P = 0.10). More frequent KRAS exon 2 variants like G12D (n = 152, multivariate HR 1.17 (0.86– 1.6), P = 0.81) and G12V (n = 92, multivariate HR 1.27 (0.87–1.86), P =0.57) did not have significant impact on OS. CONCLUSION Mutations in KRAS, and BRAF were associated with inferior PFS and OS of mCRC patients compared to patients with non-mutated tumours. KRAS exon 2 mutation variants were as- sociated with heterogeneous outcome compared to unmutated tumours with KRAS G12C and G13D (trend) being as- sociated with rather poor survival. Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants – pooled analysis of five randomised trials in metastatic colorectal cancer by the AIO Colorec- tal Cancer Study Group. Ann Oncol 2016 Jun 29;[EPub ahead of print], Modest DP, Ricard I, Heinemann V, et al.

BACKGROUND To explore the impact of KRAS, NRAS and BRAF mutations as well as KRAS mutation variants in patients with mCRC receiving first-line therapy. PATIENTS AND METHODS 1239 pts. from five randomised trials (FIRE-1, FIRE-3, AIOKRK0207, AIOKRK0604, RO91) were included into the analysis. Outcome was evaluated by Kaplan-Meier method, log rank tests and Cox models. RESULTS In 664 tumours no mutation was detected, 462 tumours were diagnosed with KRAS-, 39 patients with NRAS- and 74 patients with BRAF-mutation. Mutations in KRAS were associated with inferior progression-free (PFS) and overall survival (OS) (multivariate hazard ratio (HR) for PFS: 1.20 (1.02–1.42), P = 0.03; multivariate HR for OS: 1.41 (1.17–1.70), P<0.001). BRAFmuta- tion was also associated with inferior PFS (multivariateHR: 2.19 (1.59–3.02), P < 0.001) and OS (multivariate HR: 2.99 (2.10–4.25), P < 0.001). Among specific KRAS mutation variants, the KRAS G12C-variant (n = 28) correlated with inferior OS compared to

N0 with clear mesorectal fascia on MRI and clearly above the levator muscles), whereas all other stages were considered for multimodal treatment. The consensus panel recom- mended long-course RCT over short-course radiotherapy for most clinical situations where neoadjuvant treatment is indicated, with the exception of T3a/b N0 tumours where short-course radiotherapy or even no neoadjuvant therapy were regarded to be an option. In patients with potentially resectable tumours and synchronous liver metastases, most panel members did not see an indication to start with classi- cal fluoropyrimidine-based RCT but rather favoured preop- erative short-course radiotherapy with systemic combination chemotherapy or alternatively a liver-first resection approach in resectable metastases, which both allow optimal systemic therapy for the metastatic disease. In general, proper patient selection and discussion in an experienced multidisciplinary team was considered as crucial component of care. Second St. Gallen European Organisation for Research and Treatment of Cancer Gastrointestinal Cancer Conference: Consensus recommendations on contro- versial issues in the primary treatment of rectal cancer. Eur J Cancer 2016 Aug 01;63(xx)11-24, Lutz MP, Zalcberg JR, Glynne-Jones R, et al.

Primary treatment of rectal cancer was the focus of the second St. Gallen European Organisation for Research and Treatment of Cancer (EORTC) Gastrointestinal Cancer Conference. In the context of the conference, a multidisci- plinary international expert panel discussed and voted on controversial issues which could not be easily answered using published evidence. Main topics included optimal pretherapeutic imaging, indication and type of neoadjuvant treatment, and the treatment strategies in advanced tumours. Here we report the key recommendations and summarise the related evidence. The treatment strategy for localised rectal cancer varies from local excision in early tumours to neoadjuvant radiochemotherapy (RCT) in combination with extended surgery in locally advanced disease. Optimal pretherapeutic staging is a key to any treatment decision. The panel recommendedmagnetic resonance imaging (MRI) or MRI + endoscopic ultrasonography (EUS) as mandatory staging modalities, except for early T1 cancers with an op- tion for local excision, where EUS in addition to MRI was considered to be most important because of its superior near-field resolution. Primary surgery with total mesorectal excision was recommended by most panellists for some early tumours with limited risk of recurrence (i.e. cT1-2 or cT3a

VOL. 1 • No. 2 • 2016