Colorectal Cancer A Multidisciplinary Approach to Individualized Patient Care 1st Lebanese Oncology Forum Mount Lebanon Hospital Gharios Medical Center

Professor of Medical Oncology Session 2: Enhancing Colorectal Cancer Care - How does a tumor’s location impact the surgical treatment and long- term outcomes for patients with colorectal cancer - Colorectal Cancer A Multidisciplinary Approach to Individualized Patient Care Fadi Farhat, MD, MHHM Professor of Medical Oncology

1. Introduction Because treatment options for cancer care have increased rapidly in recent decades, establishing an multidisciplinary team - MDT is crucial to fulfilling the requirement of multimodal treatments in current practice in cancer treatment Establishing MDTs for treating various cancers is encouraged in some countries and is considered a standard of quality control in cancer care Here, we present a review that focuses on the influence of MDTs in colorectal cancer treatment through the literatue review

Group of people of different healthcare disciplines MDT is Pathologist & Radiologist Group of people of different healthcare disciplines The first set of ESMO consensus guidelines for metastatic colorectal guidelines was published in 2012. In 2014, an international panel of experts in the management of patients with CRC was convened to update the existing ESMO Consensus Guidelines for the management of patients with CRC A set of pre-formulated topics was prepared and three working groups convened in the areas of:

Radiologist & Radio-Oncologist MDT is Radiologist & Radio-Oncologist Pathologist & Radiologist Which meets together at a given time “whether physically in one place, or by video or teleconferencing”

ESMO consensus guidelines to discuss a given case Radio-Oncologist & Palliative Sp Pathologist & Radiologist Set of pre-formulated topics; 3 working groups convened in areas: Molecular pathology and biomarkers [1-9] Local and ablative treatment (LAT) (including surgery and the management of patients with oligometastatic disease) [10-17] The treatment of metastatic disease [18-…]

ESMO consensus guidelines Oncological Surgeon Medical Oncologist ESMO consensus guidelines Radio-Oncologist & Palliative Sp Pathologist & Radiologist Set of pre-formulated topics; 3 working groups convened in areas: Molecular pathology and biomarkers [1-9] Local and ablative treatment (LAT) (including surgery and the management of patients with oligometastatic disease) [10-17] The treatment of metastatic disease [18-…] who are each able to contribute independently to the diagnostic and treatment decisions about the case”.1

2. Definition of MDTs In general, the composition of an MDT for cancer care includes specialists from Medical, surgical Oncology

2. Definition of MDTs In general, the composition of an MDT for cancer care includes specialists from Medical, surgical Oncology Radiologist & Radiation oncology

2. Definition of MDTs In general, the composition of an MDT for cancer care includes specialists from Medical, surgical Oncology Radiologist & Radiation oncology Pathology, & palliative care, nursing professionals, & nutritionists2

2. Definition of MDTs In general, the composition of an MDT for cancer care includes specialists from Medical, surgical Oncology Radiologist & Radiation oncology Pathology, & palliative care, nursing professionals, & nutritionists2 Through regular meetings and discussions within MDTs, healthcare professionals can improve communication, cooperation, and decision-making regarding cancer treatment The composition of an MDT may vary depending on the cancer type*

The composition of an MDT may vary depending on the cancer type At Taipei Veterans General Hospital, Taipei, Taiwan an MDT for CRC was established in October 2008 The core members are surgeons, medical oncologists, radiation oncologists, pathologists, diagnostic and interventional radiologists, nurse specialists, and coordinators Initially, the group included colorectal & hepatobiliary surgeons as team members, and because of an increase in treatment demands for pulmonary metastatic lesions, thoracic surgeons have been included since October 2011

3. MDTs in cancer care 1996: UK issued National standards & guidance for cancer care; establishment of MDTs - consistent recommendation 2-5 MDTs - now widely accepted as a model of various approaches to cancer care in many other countries USA,6,- 8 Canada,9 Australia,10-11, some in Europe12-13 & Asia.14 Effect of MDTs on more favorable patient selection & improved patient survival - demonstrated in patients with esophageal,15-16 gastric,16 pancreatic,17 lung,13-18 breast,7 & gynecological cancers.14, 19-20

Primary care physician 3. MDTs in cancer care The cancer-specific outcome is considered more favorable when patients are managed under MDT care MRC Patient Journey MDTs Improve Patient Outcomes by Combining Specialist Knowledge to Identify Individual Diagnostic & Treatment Options Primary care physician Gastro-enterologist Radiologist Meical Oncologist Pathologist Surgeon Patient Cedars-Sinai: : http://www.cedars-sinai.edu/Patients/Programs-and-Services/Endocrinology/Treatment/Carcinoid-and-Neuroendocrine-Tumor-Program/ accessed 1 October 2010

3. MDTs in cancer care The cancer-specific outcome is considered more favorable when patients are managed under MDT care. MDTs can improve clinical decision-making, outcomes & experiences of patients with various cancers.6, 15,21 Retrospective study of Australian patients NET m+ (n = 49) Median Survival for pts managed at medical oncology unit- longer than elsewhere (112 vs.53 mos) Treatment differed between oncology unit compared to other sites 120 100 80 60 Median Survival (months) 40 20 Specialty Multidisciplinary Center Community Care Townsend A, et al. J Clin Gastroenterol 2009.

3. MDTs in cancer care The cancer-specific outcome is considered more favorable when patients are managed under MDT care. MDTs can improve clinical decision-making, outcomes & experiences of patients with various cancers.6, 15,21 Validating the specific effects of MDTs on patient outcomes is challenging because most studies on MDTs are observational or retrospective2 and 22 Initiate RCT trial validating effects of MDTs- impossible.

Before The Era of Chemotherapy 4. MDTs in CRC treatment Diagnosis & treatment of CRC - rapidly developed in the past decade. 1980 1985 Before The Era of Chemotherapy 35 30 25 20 15 10 5 Months Best supportive care 1980 1985 1990 1995 2000 2005+ 17

Chemotherapy Has Improved Survival 4. MDTs in CRC treatment Diagnosis & treatment of CRC - rapidly developed in the past decade. Managing through a single treatment is difficult. 1980 1985 1990 1995 Chemotherapy Has Improved Survival 35 30 25 20 15 10 5 Months 5-FU 1980 1985 1990 1995 2000 2005+ 18

Improved CRC Survival But More To Be Done 1980 1985 1990 1995 2000 2005 - Drug development & Multidiscplinary approach 35 30 25 20 15 10 5 Irinotecan Capecitabine Oxaliplatin Months 1980 1985 1990 1995 2000 2005+ mCRC = metastatic colorectal cancer; 5-FU = 5-fluorouracil; MoAbs = monoclonal antibodies; OS = overall survival 19

Targeted Therapy Improved CRC Survival Bevacizumab, Cetuximab, Panitumumab, Aflibercept, etc… 1980 1985 1990 1995 2000 2005 2015 MDT Chemotherapy MoAb 35 30 25 20 15 10 5 Months 1980 1985 1990 1995 2000 2015+ 20

4. MDTs in CRC treatment Although some limitations regarding MDTs are emphasized in the literature,24, 25 and 26 such as debates On decision-making within MDTs On the costs of MDTs (extra hours & workload for members attending MDT meetings, unnecessary discussion in routine cases) On the limitation of discussion regarding elective cancer patients MDTs have been incorporated into government policies and guidelines.

4. MDTs in CRC treatment USA- the American College of Surgeons Commission on Cancer has included MDTs as a key program requirement for CRC care German Cancer Society- has provided certification for oncological care institutions since 2003 and the numbers of pre and postoperative case presentations at MDT conferences are evaluation indicators for CRC care28 Taiwan- certification program on the quality of cancer care in hospitals initiated by the National Health Research Institutes in 200829 Establishing MDTs for cancer care is required for certification30 Results of certification - available on a website for public access & influence national health insurance payments by the government

4.1. Decision-making Ryan and Faragher25 Prospectively assessed 197 consecutive cases presented to a CRC MDT Compared plans made using routine care pathways vs. made at MDT meetings Routine cases of colon cancer: authors demonstrated that discussing rarely changed management (3.4%) Complex cases: conversely, management changed in 50%

4.1. Decision-making Topics that commonly generated useful discussion: Preoperative management of rectal cancer Metastatic or recurrent disease’s management Malignant polyps management Deviation from the proposed treatment Only 4% of all cases Because of complex patient factors Poor prognostic features Patient age Medical comorbidity.25

4.1. Decision-making These findings highlight the need of information on the general health status of patients and their preference for treatment, which should be available at MDT meetings. Typically, MDT decisions are made by physician members according to biomedical information and patient choice is seldom considered in the decision-making process.31 Nurses should attend MDT meetings because they can offer the views of patients and the psychosocial aspects of care to the meetings. When nurses are actively involved, the performance of an MDT is apparently higher.3

4.2. Preoperative workup under the care of MDT Evidence has shown that implementing an MDT approach for managing CRC can result in more complete preop evaluations as well as higher rates of access to multimodal therapies33-34 When the preop tests prescribed by the NCCN guidelines were considered, the proportion of patients with colon cancer who underwent complete preoperative tests was significantly higher under MDT care (91.7% vs. 27.5%, p < 0.001) Trend observed in patients with rectal cancer (84.0% vs. 15.3%, p < 0.001). Differences - observed in the rates of Chest CT (95.0% vs. 37.1%, p < 0.001) CEA (100% vs. 63.8%, p < 0.001) Transrectal US for rectal cancer (88.0% vs. 37.7%, p < 0.001). 34 carcinoembryonic antigen testing

4.2. Preoperative workup under the care of MDT Another study - significantly more patients underwent CT TNM staging (81.3% vs. 41.1%, p < 0.001). 35 Population-based study in The Netherlands MRI more used (p = 0.001) TNM staging - more complete (p < 0.001)36 Staging accuracy improves after MDT approach Radiological TNM staging according to CT scans was compared with the final pathological stage between the periods before and after the establishment of an MDT approach CT TNM staging more accurate in MDT group 64.0% vs. 45.9%, p = 0.04435

ESMO 2014 : Patient groups and treatment strategy Not R0-resectable liver Lung metastases only may become resectable after induction CT Maximum tumor shrinkage Upfront most active combination Multiple metastases,sites Rapid progression Tumor-related symptoms Clinically relevant tumor shrinkage ASAP Control progression Upfront active combination: at least doublet Multiple metastases/sites with no option for resection and/or initially asymptomatic, less aggressive disease Prevent further progression, low toxicity Watchful waiting or sequential approach (triplet regimens only in selected patients) Clinical presentation Treatment goal Treatment strategy Van Custem E. et al. Ann Oncol 2014;25(Supplement 3):iii1–iii9

ESMO 2014 : Patient groups and treatment strategy Decreasing treatment intensity Not R0-resectable liver Lung metastases only May become resectable after induction CT Maximum tumor shrinkage Upfront most active combination Multiple metastases & sites Rapid progression Tumor-related symptoms Clinically relevant tumor shrinkage ASAP Control progression Upfront active combination: at least doublet Multiple metastases/sites No option for resection Initially asymptomatic Less aggressive disease Prevent further progression, low toxicity Watchful waiting or sequential approach (triplet regimens only in selected patients) Group 1 Group 2 Group 3 Van Custem E. et al. Ann Oncol 2014;25(Supplement 3):iii1–iii9

The main components of rectal cancer treatment include 4.3. Access to multimodal therapy for rectal cancer MDTs are crucial for treating patients with rectal Ca The main components of rectal cancer treatment include Total mesorectal excision Assessment of the quality of surgery by pathologists Identification of patients at a high risk of local recurrence through imaging techniques Use of effective neoadjuvant and adjuvant therapies, including radiotherapy and chemotherapy MDT approach that identifies, coordinates, delivers, and monitors the ideal treatment on an individual basis27

4.3. Access to multimodal therapy for rectal cancer MDTs are crucial for treating patients with rectal Ca According to an international survey, regular MDT meetings significantly influence decisions on the choice of staging modality neoadjuvant treatment several other critical factors in the preop planning of rectal cancer treatment33 MDT approach enables distinguishing between patients who should first be treated surgically and those who should be offered neoadjuvant therapy.37

4.3. Access to multimodal therapy for rectal cancer MDTs are crucial for treating patients with rectal Ca Are more often discussed by MDTs.36 Advanced disease (cT3 or N+) Distal tumors Preoperative chemo-radiotherapy International survey involving 123 colorectal cancer centers North America, Europe, and Asia, departments with regular MDT More likely to use MRI to determine local staging More likely to encourage patients with threatened circumferential resection margins to undergo neoadjuvant treatment.33

4.3. Access to multimodal therapy for rectal cancer Neoadjuvant treatment, MDT meetings, reduced positive circumferential resection margin rate, lowered rate of local recurrence, and more favorable OS38 Burton 38- higher positive rate (26%) of the circumferential resection margin observed in 62 patients surgery alone without MRI-based MDT discussion vs. surgery with MRI-based MDT discussion (1%) Positive circumferential resection margin rate decreased to 7% overall at 1 year of follow-up after compulsory MDT discussion in 96% of patients with rectal cancer.38

4.4. Quality of pathology reports MDTs significantly affected the quality of pathology reports (RR = 4.85, 95% CI = 1.34–17.46, p = 0.01) in one study, 33 (circumferential resection margin in millimeters) # LN examined in an MDT group - significantly higher than that in a pre-MDT group (8.5 vs. 13.7, p < 0.001)35 MSI analysis - more likely to be performed under care of MDT (29.6% vs. 10.6%, p < 0.001)34 ***

MSI analysis - more likely to be performed under care of MDT (29.6% vs. 10.6%, p < 0.001)34 The past: One size fits all The future: Individualized treatment MMR/MSI RAS BRAF Better identification of patient subgroups Dynamic monitoring of therapeutic effect and resistance

Stage II Colon Cancer - MSI Status is Prognostic Correlation with Adjuvant Chemotherapy (5 FU-based) MSS/MSI-L MSI-H 36

4.4. Quality of pathology reports MDTs significantly affected the quality of pathology reports (RR = 4.85, 95% CI = 1.34–17.46, p = 0.01) in one study, 33 (circumferential resection margin in millimeters) # LN examined in an MDT group - significantly higher than that in a pre-MDT group (8.5 vs. 13.7, p < 0.001)35 MSI analysis - more likely to be performed under care of MDT (29.6% vs. 10.6%, p < 0.001)34 Suggest that MDT meetings & discussions encourage pathologists to improve their reports to fulfill guidelines & provide more information for diagnosis and decision-making regarding treatment planning

4.5. Adjuvant chemotherapy MDTs - suitable recommendations for adjuvant chemo for CRC MacDermid40 significantly > patients adjuvant chemotherapy after the implementation of MDT approach (31.3% vs. 13.0%, p < 0.001; Dukes' B, p = 0.002; Dukes' C, p = 0.004) Survey in Netherlands: Stage III colon cancer in MDT meetings > adjuvant chemotherapy (OR = 1.33, 95% CI = 1.15–1.55, p < 0.05)23 Ye et al35 revealed that significantly fewer patients with Stages I & IIA disease - adjuvant chemotherapy after the implementation of MDT approach (64% vs. 0%, p < 0.001; 82% vs. 12%, p < 0.001) No significant differences in the prescription of adjuvant chemotherapy to Stages IIB & III between pre-MDT & MDT groups

MOSAIC: OS - stage II & III patients 1.0 0.8 0.6 0.4 0.2 p=0.996 0.1% p=0.029 4.4% Probability FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III HR (95% CI) Stage II 1.00 (0.71–1.42) Stage III 0.80 (0.66–0.98) 0 12 24 36 48 60 72 84 96 Overall survival (months) De Gramont A, et al. J Clin Oncol 2007;25 (Suppl. 18)165s (Abstract 4007) Data cut-off: January 2007

4.5. Adjuvant chemotherapy MDTs - suitable recommendations for adjuvant chemo for CRC MacDermid40 significantly > patients adjuvant chemotherapy after the implementation of MDT approach (31.3% vs. 13.0%, p < 0.001; Dukes' B, p = 0.002; Dukes' C, p = 0.004) Survey in Netherlands: Stage III colon cancer in MDT meetings > adjuvant chemotherapy (OR = 1.33, 95% CI = 1.15–1.55, p < 0.05)23 Ye et al35 revealed that significantly fewer patients with Stages I & IIA disease - adjuvant chemotherapy after the implementation of MDT approach (64% vs. 0%, p < 0.001; 82% vs. 12%, p < 0.001) No significant differences in the prescription of adjuvant chemotherapy to Stages IIB & III between pre-MDT & MDT groups

4.6. Chemotherapy for metastatic disease For patients with metastatic disease, MDTs Significantly influenced the use of new chemotherapy regimens if liver metastases were present (relative risk = 6.41, CI = 1.34–30.64, p = 0.02)33 However, no difference was observed in the number of patients who were prescribed palliative chemotherapy before and after the implementation of an MDT approach (p = 0.750 and p = 0.431, respectively) 35-40

Many patients present with metastatic CRC All patients with CRC1 ~25% of patients present with mCRC1 ~50% of patients will develop metastases1 The liver is the most common organ site for CRC metastases2 1. Van Cutsem E, et al. Ann Oncol 2010; 21 (Suppl. 5): v93–v97. 2. DiSibio G, French SW. Arch Pathol Lab Med 2008; 132: 931–939

mCRC: Liver Metastases Resectability Profile 80% non-resectable 20% resectable Active therapy 80% remain non-resectable/20% might shift Resection Potential for cure! The liver is the most common organ site for CRC metastases2 1. Van Cutsem E, et al. Ann Oncol 2010; 21 (Suppl. 5): v93–v97. 2. DiSibio G, French SW. Arch Pathol Lab Med 2008; 132: 931–939

Resection for CRC Liver Metastases MSKCC p<0.01 N=563 (1999-2006) Probability N=1036 (1980-1998) Disease-specific survival (months) Improvements in survival over time Better chemotherapy Better imaging Better patient selection

Variance in Multidisciplinary Consultation Setting: In untreated patients with liver-only colorectal cancer, I generally; Always consult with my surgeon to determine resectability Only consult with my surgeon if there are fewer than 3 lesions that appear resectable to me Key points: The extent to which multidisciplinary consultation is a reality varies considerably across different care settings in the US In a 2006 NMCR Challenging Casessm survey, medical oncologists were asked whether they habitually consulted with a surgeon upon seeing a previously untreated patient with liver-only colorectal metastases More academics than community oncologists consulted with a surgeon as a matter of course regarding such patients Community oncologists were more likely than academics to decline to refer patients with 3 or more lesions for a surgical consultation Data on file, sanofi-aventis. ©2006-2007 Network for Medical Communication and Research, LLC. Generally do not consult with my surgeon as these patients are best treated with systemic chemotherapy alone Network for Medical Communication and Research (NMCR), Challenging Casessm 2006 is a nationwide forum for peer-to-peer market research for oncology practitioners. Data on file, sanofi-aventis. Network for Medical Communication and Research (NMCR), Challenging Casessm 2006.

4.6. Chemotherapy for metastatic disease For patients with metastatic disease, MDTs Significantly influenced the use of new chemotherapy regimens if liver metastases were present (relative risk = 6.41, CI = 1.34–30.64, p = 0.02)33 However, no difference was observed in the number of patients who were prescribed palliative chemotherapy before and after the implementation of an MDT approach (p = 0.750 and p = 0.431, respectively) 35-40

4.7. Patient survival Most studies have confirmed + effect of MDTs on survival Observational or retrospective MDTs - effects of multiple concurrent changes in cancer treatment & care should always be considered when study results are interpreted (+MDTs) Morris4 - population-based retrospective survey - 25% 3% reduction risk of death all CRC [HR = 0.97, 95% p = 0.01] Survey Netherlands: mortality < in MDT group (HR = 0.97, 95% p < 0.05), not rectal cancer (HR = 0.96, 95% CI = 0.92–1.01) 23 MacDermid40 single institution- independent predictor of survival (HR = 0.73, 95% CI = 0.54–0.98, p = 0.044)

Summary : mCRC is an interesting disease Every patient is different ! Summary – Every Patient is different, every disease is different Don’t put all mCRC patients into one bag Biological presentation - Molecular profile Clinical presentation - Burden of the disease Choice of the treatment Goal Resectable disease or not? Sequence of Treatment Explore different strategies to prolong survival

5. Conclusion Establishing MDTs for CRC care can lead to more complete preoperative evaluation higher rates of access to multimodal therapies Moreover, MDTs can improve the quality of pathology reports provide suitable recommendations for adjuvant chemotherapy increase overall survival in patients with CRC To enhance the quality of cancer care, hospitals should encourage establishing MDTs