Biomarkers to optimize treatment selection in colorectal cancer Edwin Pun HUI, MBChB, MD, FRCP (Lond & Edin)

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1 Recent advances in the management of CRC II 2017/12/17 (Sun.) 10:10-11:00 Biomarkers to optimize treatment selection in colorectal cancer Edwin Pun HUI, MBChB, MD, FRCP (Lond & Edin) Department of Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong The available evidence supports initial combination of chemotherapy with molecular targeted therapy for most patients with metastatic colorectal cancer (CRC), particularly for those whose metastases might be potentially resectable after an initial response. However, the best way to combine and sequence currently available active agents is not well established, nor is the optimal duration of treatment. Biomarker testing is increasingly driving therapeutic decision-making to improve patient outcomes for targeted and conventional therapies in colorectal cancers. The 2017 update from American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology has recommended testing for RAS and BRAF mutation. There is emerging evidence supporting testing for DNA mismatch repair (MMR) deficiency / microsatellite instability (MSI). Benefit from monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) is restricted to patients whose tumors do not contain mutated RAS genes. Therefore colorectal carcinoma patients being considered for anti-egfr therapy must receive RAS mutational testing which should include KRAS exons 2, 3, and 4 and NRAS exons 2, 3, and 4 in the tumor tissue of patients with mcrc ( expanded or extended RAS). BRAF V600E mutational analysis should be performed in colorectal cancer tissue in patients with colorectal carcinoma for prognostic stratification, which may also provide new therapeutic options. Emerging data suggested that primary tumor location (left versus right-side of colon) or sidedness, a surrogate for biomarkers, could potentially impact on treatment choice. Mutations in one of several DNA mismatch repair (MMR) genes are found in Lynch syndrome (hereditary nonpolyposis CRC [HNPCC]) as germ line mutation and in 15-20% of sporadic colon cancers. Among patients with localized CRCs, tumors that are MMR deficient (dmmr) or microsatellite instability high (MSI-H) are associated

2 with better survival, but less benefit from adjuvant fluorouracil based chemotherapy. The prognostic influence of MSI is less clear in patients with metastatic CRC, a population in which the prevalence of MSI-H disease is low (~ 3.5%). However, immune checkpoint inhibitors has demonstrated remarkable activity in patients of mcrc with dmmr or MSI-H tumors.

3 Recent advances in the management of CRC II 2017/12/17 (Sun.) 11:00-11:40 New Strategies for Locally Advanced Rectal Cancer Gong Chen, MD, PhD Dept. of Colorectal Cancer, Sun Yat-sen University Cancer Center Preoperative concurrent chemoradiation therapy (CRT) or short radiotherapy (SCPRT) followed by TME surgery and postoperative adjuvant chemotherapy is the current standard treatment model for locally advanced rectal cancer (LARC). Total neoadjuvant therapy (TNT) is the research focus for treatment of locally advanced rectal cancer patients recently. Neoadjuvant therapy, especially concurrent chemoradiotherapy could allow a portion of patients to achieve complete clinical response, making it possible to preserve anal sphincter by "watch and wait" non-surgical treatment strategy. Replacing some or all adjuvant chemotherapy with neoadjuvant therapy may further increase sphincter preservation opportunity. More data are expected to reveal whether TNT strategy could really reduce distant metastasis risk and increase long-term survival rate for locally advanced rectal cancer patients. This is the principle concept of TNT strategy. Choosing appropriate patients to recommend TNT treatment model or to carry out TNT clinical study, as well as how to tailor individualized TNT strategy, need further exploration.

4 Total Cancer Care in CRC patients- focus on Quality of Life 2017/12/17 (Sun.)14:00-14:30 Quality of Life on CRC patients- the clinical significances for the patients and healthcare professional Johnson Lin, B.M., MPH Mackay Memorial Hospital Colorectal cancer (CRC) serves as the most frequently diagnosed cancer in Taiwan. Fortunately, with the earlier diagnosis of tumors and the advance in therapeutic intervention, the survival rate for patients with CRC has increased in decades. According to an earlier report in Taiwan, the mortality rate is 3.6 % lower in 2015 than that of in Meanwhile, these life-lengthening medical actions often concomitantly bring many unpleasant side effects, such as pain, fatigue, psychological and physical problems, which drastically disturb patients quality of life (QoL). Furthermore, the QoL assessments of CRC survivors have been shown to be inferior than that of the age-matched individuals without cancer. However, based on evident-based medical reports, QoL has been demonstrated as a critical factor for the incurrence prevention and the increase of survival rate. Therefore, it is time to reconsider QoL control as an equivalently essential part during the course of the therapy. In this speech, we will first talk about 1) the unique challenges of QoL for colorectal cancer survivorship from the angle of patients and health care professionals. Later, we will discuss about 2) the QoL caused by treatment at different stages of CRC. Palliative care is an approach to improve the QoL for CRC survivorship. Among all the QoL, pain control is still under-treatment for late stage of CRC survivorship. Many studies also demonstrated that the improvement of pain control for late stage cancer survivorship will significantly increase QoL which is also beneficial for not only health care giver but also health care professionals. Long-term follow-up, health maintenance, and lifestyle modifications remain important components of the care of CRC survivors. Furthermore, early palliative care is appropriate at any age and any stage in a serious illness, and can be provided together with curative treatment according to a field-tested definition developed by the Center to Advance Palliative Care and the American Cancer Society. Take the pain control for example, pain management is

5 one of the quantifiable QoL which have been proved that the patient with early palliative care including pain management have higher survival rate and better QoL compared to those patient under standard care processes. To sum up, early provision of specialty palliative care improves quality of life, lowers spending, and helps clarify treatment preferences and goals of care for patients with advanced cancer. However, widespread integration of palliative care with standard medical treatment remains unrealized, and more evidence is needed to demostrate the potential gains of early palliative care in CRC populations. Key word: CRC, QoL, CRC survivorship, early palliative care, and cancer pain

6 Total Cancer Care in CRC patients- focus on Quality of Life 2017/12/17 (Sun.) 14:30-15:00 The effectiveness of colorectal cancer pain control and impact of quality of life by the right approach of pain management strategy Lu Chien-Chang, M.D. Division of Colon Rectal Surgery, Kaohsiung Chang Gung Memorial Hospital Late stage colorectal cancer is almost incurable, and can only have limited extension on progression free survival, disease control rate, and a few months of life expectancy. Palliative care has appropriately been receiving increased attention in recent years. From the surgeon s standpoint, therapy is considered palliative when resection of all known tumor sites is no longer possible or advisable. The goal of treatment is eventually judged by the control of symptoms and alleviation of suffering, finally reflect on quality of life improvements. Palliative care in colorectal cancer patients includes pain management, side effect and symptom management, psychological function support, social function support, and hospice/bereavement care. Pain is a common complication of advanced cancer and is prevalent in all stages of disease. Uncontrolled pain is a source of significant distress, morbidity and disability treatment, with inadequate pain control reported in over 80% of patients in some series. Several retrospective studies indicated that severity of pain in cancer patients can directly correlated to their status on quality of life, especially physical condition and psychological condition if the pain becomes long-term burden to patients. Based on updated NCCN guideline for adult cancer pain, a good pain management strategy should include right approach on analgesics prescription, which means management with long-acting opioid analgesics with adequate dose, combined with short-acting opioid analgesics for breakthrough pain for patients with cancer. With the good management of background pain under acceptable level, frequency of breakthrough pain should also be decreased, and reduce the use of PRN opioid analgesia and non-opioid adjuvants. The whole pain management process should be regularly monitored and assessed, with side effect management strategy, to achieve adequate pain control.

7 Here we demonstrate 19 cases of good pain management approach in CGMH-KS with advanced colorectal cancer for 12 weeks. Long-acting oxycodone was used for background pain control, and short-acting oxycodone for breakthrough pain management. Pain assessment results includes NRS pain score, quality of analgesia, frequency of breakthrough pain, EQ-5D VAS score, and COWS score in the hospitalization period. The results indicated that around the clock principle of using long-acting strong opioids for background pain management is a good strategy. Combining with a good managed background pain, frequency of breakthrough pain will also reduced. The result indicated that with long-acting oxycodone (daily total dose mg) and PRN short-acting oxycodone, quality of analgesia increase significantly while patients reached adequate pain control (NRS>3) at week 4, and the frequency of breakthrough pain was limited to less than 3 times daily. With the implementation of good pain management strategy, we believe it can direct benefit to end-stage cancer patients suffering from moderate to severe cancer pain by improvement on quality of life, which lead to effectively reduction of their physical and psychological burdens. It can also reflect on the reduction of comorbidity on pain with other QoL dimensions (ex: depression, social function, and self-recognition) which will directly link to the impact on quality of life. Furthermore, we hope the right approach of pain management strategy, can be early implemented with other palliative cares in late-stage colorectal cancer patients.