Volume 20, Issue 3, August 2018

EditorialBy Dr. Edward Chow

The Newsletter of the Rapid Response Radiotherapy Programof the Odette Cancer Centre

In this issue of Hot Spot:Editorial

Applying the ethics “IDEA Framework” to an oncology case involving a request for a second medical opinion

Medicine, technology, and the siege mentality

Dihydropyrimidine dehydrogenase (DPD) deficiency

Continuing Medical Education

Inserts:ALK-positive non-small cell lung cancer—Next generation ALK inhibitors

Medical cannabis for inflammatory bowel disease

continued on page 2…

Drs. Angela Assal and Sally Bean discuss applying the ethics “IDEA Framework” to an oncology case involving a request for a second medical opinion. Dr. Philip C. Hébert correlates Medicine, technology, and the siege

mentality. Drs. Brooke Lipman and Mark Pasetka highlight Dihydropyrimidine dehydrogenase (DPD) deficiency. Continuing Medical Education is provided by Ms. Toby Rodin and Mr. Kiran Kaushik Dash. This newsletter

has two inserts: Medical cannabis for inflammatory bowel disease by Ms. S. O’Hearn et al., and ALK-positive non-small cell lung cancer—Next generation ALK inhibitors by Dr. Parneet K. Cheema. I hope you will enjoy the newsletter.

Applying the ethics “IDEA Framework” to an oncology case involving a request for a second medical opinionBy Angela Assal MD, MHSc & Sally Bean, JD, MA

Case A man* (case details have been

changed to de-identify the case) in his early 70s was admitted to the general internal medicine service with an upper gastrointestinal bleed. He was recently diagnosed with metastatic gastric cancer and still accepting the diagnosis. A few weeks prior to presentation he was independent and ambulating, but had a rapid deterioration in functionality and was now bedbound. He was a widower and had three adult children.

His acute gastric bleed was treated with a single dose of palliative radiation. The day after admission he was seen by oncology and told that given his disease extent and poor functional status, he was not a candidate for systemic

chemotherapy. However, he was told that if his acute decompensation and functional status improved then chemotherapy could be considered as an outpatient. Soon thereafter, he was seen by another Sunnybrook oncologist and told that the cancer was not curable and that goals should be focused on symptoms and maximizing length and quality of life. It was explained that chemotherapy would likely cause more harm from side effects than good. There were also concerns about his nutritional status, as he could not tolerate an oral diet due to persistent vomiting and a nasogastric tube was draining gastric fluids, which precluded feeds. He had ascites, which was a contraindication to a gastrostomy tube.

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At this point the patient and his family still wanted to pursue chemotherapy. The patient was very optimistic and interested in any treatment that could be curative. The family had firmly held beliefs that he was strong and could recover. The family requested a third opinion from an external oncologist and ethics was consulted.

IDEA ethics frameworkThe IDEA ethics framework adopted by Sunnybrook Health Sciences Centre (Sun-nybrook) provides a systematic approach for thinking through complex cases. IDEA is an acronym that stands for Identify the facts; Determine the ethical principles; Explore options; and Act. In this case, the patient is requesting a treatment, chemo-therapy, that the treating physician did not feel was clinically appropriate. The patient then requested an external third oncology opinion. The patient and his family felt strongly that ‘everything possi-ble be done.’ One key ethical issue that is raised in this case is a request for a second medical opinion (SMO).

Second medical opinions An SMO is sought to obtain alternate

treatment options, to seek additional information regarding a proposed controversial or risky procedure, or to seek expertise when a diagnosis or prognosis is uncertain.1 The Canadian Medical Association and Canadian Medical Protective Association both support a patient’s request for a second opinion.1,2 Bean et al. highlight three important principles when considering obtaining an SMO: 1) patient welfare (weigh risks and benefits of the SMO), 2) resource stewardship (reasonable limits on SMOs), and 3) transparency (process for obtaining an SMO should be clear).1

Sunnybrook guidelines recommend that relevant internal expertise is first sought before obtaining an external SMO.1 The healthcare team should help patients identify an appropriate consultant and inform them that the Sunnybrook treating physician will consider the recommendation, but does not mandate the physician to provide the recommended treatment.

Back to the case In terms of determining the ethics

principles, the patient and his family are valuing principles of beneficence (doing good) and autonomy (self-determination). They wish to pursue all possible treatments. The healthcare team is prioritizing non-maleficence (not causing harm) while promoting beneficence in terms of optimizing symptoms. Autonomy and beneficence must be weighed and balanced.

When applying the IDEA framework, we must consider and evaluate all possible options before deciding on a course of action. Potential options include the following: the team could refuse to provide chemotherapy or a second medical opinion, offer palliative options, offer chemotherapy without seeking an external SMO, or an SMO could be obtained with or without a plan to follow their recommendations.

In this case, the patient and his family were struggling with accepting the diagnosis and prognosis and were not ready to eliminate chemotherapy as an option. They needed time to accept and understand the situation, and to understand the risks of chemotherapy and why it was not a good choice for him. An external opinion was sought and they agreed that chemotherapy should not be offered. Transfer to the requested palliative care unit occurred.

Learning points • Cases where no treatment options are

available are tough for patients and healthcare professionals

• In the setting of a new diagnosis patients and families require time and ongoing discussions to process the information

• An external second medical opinion may provide reassurance to patients and families when they are disagreeing with the proposed treatment plan.

REFERENCES1. Bean S, Shin P, Henry B, Cuthbertson

B. External second medical opinions in critical care: an ethics-based approach. Healthcare Quarterly. 2017;20(2):23-26.

2. Canadian Medical Association. Code of ethics (Update 2004). [Reviewed March 2018]. Available from: https://www.cma.ca/Assets/assets-library/document/en/advocacy/policy-research/CMA_Policy_Code_of_ethics_of_the_Canadian_Medical_Association_Update_2004_PD04-06-e.pdf

3. CMPA 2014. Ottawa. When a patient seeks a second opinion. Originally published September 2014. Available from: https://www.cmpa-acpm.ca/en/advice-publications/browse-articles/2014/when-a-patient-seeks-a-second-opinion

4. Sunnybrook Health Sciences Centre Guideline for External Second Medical Opinions (Nov 2017)

Applying the ethics “IDEA Framework” to an oncology case involving a request for a second medical opinion

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Medicine, technology, and the siege mentality By Philip C. Hébert, MD, PhD, Professor Emeritus, University of Toronto

In 2016, Rosenthal and Verghese wrote Many healthcare professionals view by recognizing them as unique persons eloquently in the New England Journal their future, and their patients’ futures, with always fascinating stories, and by of Medicine that “the majority of what with dismay, feeling that theirs is a remembering the opportunities we have we define as [the physician’s] ‘work’ profession under siege.3 Indeed, attacks to make remarkable and unforgettable takes place away from the patient, in upon healthcare workers do seem to differences in their lives.8

workrooms and on computers… We’ve be escalating4 and drug addiction5 and Ethical sensitivity can help patients distanced ourselves from the personhood, mental despair are altogether too common and clinicians alike by enabling them to the embodied identity, of patients.”1 They among medical practitioners. Medicine recognize and strive for the best possible recommended that the healthcare system can be a demanding and dangerous outcomes not only in good times, but must be improved to make it a more enterprise. Politicians do not make it any also in hard times: when resources are humane environment for those who work easier and are wont to use healthcare as scarce, practices criticized, and outcomes there and, to that, in order to do so, we a political football with all the negative uncertain. Assiduous attention to need to spend “more time with each other consequences this can have for the professionalism and ethical concerns can and with our patients.” continuity and comprehensiveness of help those involved do their best to do

Certainly, this would be a step in the care. Patients and families, too, are restive what seems right and feel confident they right direction. Burnout by physicians and critical and know all is not right with have done so. This enriches us all. and other healthcare professionals—one healthcare.6

consequence of modern medicine’s poor Hard Times, Dickens’ 19th century This is an excerpt from the 4th edition organization—will have to be prevented book, seems apt for our times, as well: of Philip Hébert and Wayne Rosen, by ethically redesigning healthcare in hard times are here and also lie ahead. Doing Right: A Practical Guide to Ethics ways that can restore “meaning and Nonetheless, hard times can be catalysts for Physicians and Medical Trainees sanity” to what we do every day.2 for development and improvement. In (Oxford University Press, to be published:

The Internet has strengthened patients any times, an emphasis on the key ethical 2019).and families. They are less dependent principles and professional values, such as on professionals for information and altruism, humility, honesty, transparency, Referencesseem to have more choices than ever. trust, and mutual respect, can enhance the 1. Rosenthal DI, Verghese A. Meaning Transparency and access to information relationships between practitioner, patient, and the nature of physicians’ work. are recognized as key in making informed and other healthcare workers, and can NEJM, 2016. 375:1813-1815.decisions and increasingly put power make for a more satisfying practice. 2. Wright AA, Katz IT. Beyond burnout: in the hands of patients. The ship of The beginning of this lies in Redesigning care to restore meaning medicine, of which the doctor ostensibly conversing with our patients. In order to and sanity for physicians. NEJM, used to be captain, is swamped and must avoid the anomie and melancholy that 2018. 378: 309-311.give way to the notion of patients pairing can sometimes accompany the burdens 3. Zuger A. Dissatisfaction with medical with health professionals in designing, of practice, doctors, trainees and, indeed, practice. NEJM, 2004. 350(1): 69-75.co-operatively, better healthcare systems. all healthcare professionals, need to 4. http://www.who.int/emergencies/

This is not the end of professionalism. “devote time and resources to promoting attacks-on-health-care/en/.Healthcare is not a zero-sum game: we self-care.” 5. https://torontolife.com/city/crime/all gain when patients and professionals Studies suggest that healthcare doctor-perfect-life-got-hooked-work together in partnership to improve professionals experience less burnout and fentanyl/.and redesign healthcare. It’s a win-win cynicism if they remain in touch with the 6. Mokluk A. Hallway Health Care. proposition. Barring some worldwide meaning and significance of what they Toronto Life, 2018:44-48.conflagration and environmental or do.7 Medical trainees find benefit from 7. Horowitz CR, Suchman AL, Branch economic collapse (unfortunately, always ethics awareness and from self-reflection, WT, et al. What do doctors find possible, given the antidemocratic forces as well. The joys and challenges of meaningful about their work? Ann at work throughout the world), the process medical work can prevail over its Intern Med, 2003. 138: 772-775.of the moral renewal of healthcare and discouragements if practitioners can 8. Weinstein M. Out of the straitjacket. of the social world, more generally, will “re-moralize” their practice. They can do NEJM, 2018. 378:793-795.continue unabated. so by making connections with patients,

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Dihydropyrimidine dehydrogenase (DPD) deficiencyBy Brooke Lipman BSc, PharmD, RPh, and Mark Pasetka, BSc, BScPharm, PharmD, RPh

continued on page 5…

Figure 1: 5-FU Metabolism

IntroductionMany patients with cancer receive com-

bined chemotherapy and radiation as treat-ment for their disease. Fluoropyrimidines, including 5-Fluorouracil (5-FU) and capecitabine (Xeloda®), are commonly used in combination with radiotherapy for the treatment of gastrointestinal malignancies. The latter agent is a pro-drug of 5-FU (which is traditionally administered intrave-nously) that offers the convenience of oral administration while maintaining efficacy.1

In a general sense, capecitabine and 5-FU have similar side effect profiles, but the incidences and onset seem to vary depending on form (Table 1). These toxicities can be severe and may include hand-foot syndrome, neutropenia, nausea/vomiting, grade 3 or 4 diarrhea, stomatitis and oral mucositis.2

Table 1: Side effects of capecitabine and 5-fluorouracil3,4

Adverse effect Capecitabine onset

5-FU onset

Nausea & vomiting E I

Neutropenia E E

Diarrhea D E

Mucositis E E

Hand-foot syndrome E E

Cardiotoxicity E D

Neurological deficits E E, D

*Typical onset: I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months)

Role of dihydropyrimidine dehydrogenase (DPD) in fluoropyrimidine metabolism

The activity of capecitabine against cancer cells relies on the conversion to its active metabolite, 5-FU, at the tumour site. It then undergoes the same catabolic pathway as intravenously administered 5-FU, which relies on the rate-limiting enzyme dihydropyrimidine dehydroge-nase (DPD) primarily within the liver, to undergo conversion into its inactive form (Figure 1). Up to 80% of administered 5-FU is catabolized via this pathway. Deficiency of enzymes in this pathway can lead to accumulation of active metabolites resulting in severe and even fatal 5-FU tox-icities.5 DPD deficiency is detected in 39% to 61% of patients with severe side effects,

emphasizing its importance as a risk factor for fluoropyrimidine toxicity.6

What is a DPD deficiency?DPD enzyme deficiency occurs in

3% to 5% of the general population and is most often the result of deleterious polymorphisms within DPYD, the gene that encodes DPD.7-10 Although numerous DPYD genetic variants exist, only four have been shown to have a clinically meaningful impact on DPD enzymatic function and toxicity risk (see Table 2).2

Pharmacogenomic screening

Although the product monographs for both 5-FU and capecitabine provide warn-ings or contraindications for use in patients with DPD deficiencies, these genotypes are not always known at baseline. Despite evidence supporting the use of pre-treat-ment genotyping and dose-adjusting to improve patient safety,11 current guidelines do not recommend pre-screening for DPD deficiency as standard of care.3,4 Deenen et al. demonstrated that genotyping can be cost effective, although this study specif-ically looked at the DPYD*2A genotype and the analysis was based on genotyping costs in the Netherlands.11

Pharmacogenomic screening tests available

Currently, there is one commercially available genetic test for DPYD in Canada offered by CEN4GEN Institute for Genomics and Molecular Diagnostics in Edmonton, Alberta (cost = $1,070

CAD). Additional information about commercially available genetic testing options can be found at the Genetic Testing Registry website (http://www.ncbi.nlm.nih.gov/gtr/).

Fluoropyrimidine dosing based on genotype

The Clinical Pharmacogenetics Implementation Consortium (CPIC) pro-vides evidence-based recommendations for fluoropyrimidine dosing based on known DPYD genotype.12 Not all carriers of these polymorphs will develop severe toxicity at standard doses. Therefore, it is vital that the dose be titrated to avoid sub-therapeutic dosing and maintain effi-cacy of fluoropyrimidine therapy.2

Presentation and management of life-threatening 5-FU and capecitabine toxicity

Since genetic pre-screening is not currently a standard of practice with the use of fluoropyrimidines, the risk for tox-icity due to DPD deficiency remains. As such, it is critical that patients monitor for unusually early (before expected onset; refer to Table 1) and severe (grade 3 or greater) fluoropyrimidine-specific toxic-ities.13,14 Patients are encouraged to seek medical attention at first sign of toxicity, as symptoms may progress rapidly.15

In such cases, treatment with fluoropyrimidines should be held and supportive care should be provided.

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Vol. 20, Issue 3, August 2018Founders: Dr. L. Andersson, Dr. C. DanjouxEditor: Dr. E. ChowAssociate Editor: Dr. C. DanjouxConsultant: Dr. S. WongAdvisers: Dr. E. Barnes, Dr. R. Goldman, Ms. L. Holden, Dr. A. Husain, Dr. A. Sahgal, Dr. E. Szumacher, Dr. M. TsaoEditorial Manager: Ms. T. RodinOdette Cancer Centre, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5 Tel: 416-480-4974, Fax: 416-480-6002 E-mail: toby.rodin@sunnybrook.ca Hot Spot can be accessed on the RRRP website: http://sunnybrook.ca/content/?page=OCC_rrrp_aboutProduced by Pappin Communications, Pembroke, Ontario www.pappin.comThe opinions expressed here are those of the authors and do not necessarily reflect the views of Hot Spot or the RRRP/BMC. The contents of the newsletter and inserts cannot be reproduced or used for other purposes without the written permission of both the editor and the author.

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Table 2: Recommended dosing of fluoropyrimidines by DPD phenotypeAdapted from Tables 1 and 2 of the 2017 CPIC guidelines2

Likely phenotype(activity score)a

Genotypesb,c Implications Dosing recommendations

DPYD normal metabolizer (activity score = 2)

An individual carrying two normal function allelesc

Normal DPD activity and “normal” risk for fluoropyrimidine toxicity

Based on genotype, there is no indication to change dose or therapy; use label-recommended dosage and administration

DPYD intermediate metabolizer (activity score 1 or 1.5)

Activity score 1: an individual carrying one normal function allelec plus one no function alleled or an individual carrying two decreased functione alleles

Activity score 1.5: an individual carrying one normal function allelec plus one decreased function allelee

Decreased DPD activity

Increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugs

Reduce starting dose based on activity score; then titrate dose based on toxicity or therapeutic drug monitoring (if available)

Activity score 1.5: reduce dose by 25–50%

Activity score 1: reduce dose by 50%

DPYD poor metabolizer (activity score 0 or 0.5)

Activity score 0: an individual carrying two no function allelesd

Activity score 0.5: an individual carrying one no functiond plus one decreased function allelee

Complete DPD deficiency and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugs

Activity score 0.5: avoid fluoropyrimidines or administer 5-fluorouracil at a strongly reduced dosef with early therapeutic drug monitoringg

Activity score 0: avoid use fluoropyrimidines

a) Activity score is calculated as the sum of the two lowest individual variant activity scores – extent to which the variant alleles influence enzyme activity b) Allele definitions, assignment of allele function and references can be found using the DPYD Allele Functionality Table (https://www.pharmgkb.org/page/dpydRefMaterials)c) Normal function alleles (activity score 1) = wild-type; 85T>C (*9A); 1627A>G (*5)d) No function alleles (activity score 0) = 1905+1G>A (*2A); 1679T>G (*13)e) Decreased function alleles (activity score 0.5) = 2846A>T (rs67376798); 1129-5923C>G (HapB3). f ) If available, a phenotyping test should be considered to estimate the starting dose. In absence of phenotyping data, a dose of <25% of the normal starting dose is estimated assuming additive effects of alleles on 5-FU clearanceg) Therapeutic drug monitoring should be done at the earliest time point possible (e.g., minimum time point in steady state) in order to immediately discontinue the infusion if the drug level is too high

Additionally, genetic testing may be done to guide future therapy.3,4

Uridine triacetate (UTA) (brand name: Vistogard®) is an oral antidote to fluoro-pyrimidine overdose that acts by deliv-ering free uridine into the circulation to compete with toxic 5-FU metabolites for incorporation into RNA, thereby reduc-ing cellular damage and death.16 UTA is approved by the FDA for the emergency treatment of adult and pediatric patients:• following a fluorouracil or capecitabine

overdose regardless of the presence of symptoms, or

• those who exhibit early-onset, severe, or life-threatening toxicity affecting the cardiac or central nervous system, and/or early onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluoropyrimidine administration.17

UTA is not currently marketed in Canada. However, it is available via the Health Canada Special Access Program (SAP). The recommended adult dosing schedule for UTA is 10 grams orally every six hours for 20 doses.

FDA approval of UTA was based on two single-arm, open-label trials in which

it was administered to patients with a fluorouracil or capecitabine overdose or had exhibited severe or life-threatening toxicities. UTA achieved 96% survival at 30 days, compared to 16% survival in historical case reports of 5-FU overdoses prior to UTA availability. Common side effects of UTA include vomiting, nausea, and diarrhea.17,18

Summary1. DPD deficiency is a rare metabolic dis-

order that can result in severe and some-times life-threatening consequences to those taking fluoropyrimidines

2. Patients initiating fluoropyrimidine therapy should be advised to monitor for the development of rapid and severe known fluoropyrimidine side effects, and to access medical attention immediately

3. Although pre-treatment genotyping is not standard of care, genetic testing of DPYD can be ordered if necessary to guide fluoropyrimidine dosing

4. UTA is an oral antidote that can be used for fluoropyrimidine toxicity, and is available via the Health Canada SAP.

References can be provided on request

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Continuing Medical EducationBy Toby Rodin, Odette Cancer Centre, and Kiran Kaushik Dash, B Pharm, MBA

Continuing Medical Education (CME) can update healthcare professionals on the latest advances for modifications to their clinical practice. At the request of the CME organizers, Hot Spot will list the national and international activities in palliative medicine that are of interest to our readers. Please forward details of the CME activities to: toby.rodin@sunnybrook.ca

• September 7–8, 2018. American Society of Hematology (ASH) Meeting on Hematologic Malignancies, Chicago, Chicago, IL. http://www.hematology.org/Malignancies/

• Sept. 12–15, 2018. 2018 CARO-COMP-CAMRT Joint Scientific Meeting, Montreal Quebec. http://www.caro-acro.ca/annual-scientific-meeting/2018-caro-comp-camrt-joint-scientific-meeting/

• September 23–26, 2018. World Lung Cancer Conference. Toronto, Ontario Canada. https://camo-acom.ca/

• September 28, 2018. The Multi-disciplinary Gynecologic Oncology Annual Lecture Series. Toronto, Ontario, Canada. https://camo-acom.ca/

• September 29, 2018. Survivorship Care Post Treatment for Prostate and Breast Cancer. Vancouver, British Columbia. https://camo-acom.ca/

• October 2–5, 2018. 22nd International Congress on Palliative Care, Palais des Congrès, Montréal, Canada. http://www.palliativecare.ca/

• October 3–5, 2018. American Association for Cancer Education (AACE); International Cancer Education Conference (ICEC), American Association for Cancer Education AACE, Atlanta Georgia https://www.aaceonline.com/

• October 21–24, 2018. ASTRO Annual Meeting – American Society for Radiation Oncology, San Antonio, Texas. https://www.astro.org/annualmeeting/

• October 19–23, 2018. European Society for Medical Oncology (ESMO) 2017 Congress, Munich, Germany. https://www.esmo.org/Conferences/Past-Conferences/ESMO-2017-Congress/General-Information

• November 1, 2018. Canadian Immuno-Oncology Summit. Toronto, Ontario. https://www.oncologyeducation.com/events/upcoming-events/2018-canadian-immuno-oncology-summit/

• November 2, 2018. Best of Lung Cancer Summit. Toronto, Ontario. https://www.oncologyeducation.com/events/upcoming-events/best-of-lung-cancer-summit-2018/

• November 30, 2018. Best of Oncology East. Toronto, Ontario. https://www.oncologyeducation.com/events/upcoming-events/best-of-oncology-east-2018/

• November 25–30, 2018. Radiological Society of North America, RSNA, Annual Meeting, McCormick Place, Chicago, Illinois. https://www.rsna.org

• Dec. 1–4, 2018. 60th American Society of Hematology(ASH) Annual Meeting San Diego, California. http://www.hematology.org/Annual-Meeting/

• Dec 4–8, 2018. 41st Annual San Antonio Breast Cancer Symposium (SABCS) San Antonio, Texas, https://www.emedevents.com/c/medical-conferences-2018/41st-annual-san-antonio-breast-cancer-symposium-sabcs

CME ProgramsOncology Opinion Series In Lung Cancer: Dr. Ramalingam – Video Archive. OncologyEducation featured Dr. Suresh Ramalingam discussing evolving decisions and best practices in the management of EGFR-mutated NSCLC. This educational program was offered as a live event and interactive webinar. https://www.oncologyeducation.com/events/oncologyeducation-events-video-archives/oncology-opinions-series-in-lung-cancer-dr.-suresh-ramalingam/

Oncology Opinions Webinar in Merkel Cell Carcinoma – Video Archive. In this series Dr. David Hogg discussed new treatment options and advances in Merkel cell carcinoma. This educational program was offered as an interactive webinar. https://www.oncologyeducation.com/events/oncologyeducation-events-video-archives/oncology-opinions-in-merkel-cell-carcinoma/

12th Canadian Melanoma Conference – Video Archive. The Canadian Melanoma Conference is Canada’s international flagship meeting on the research and treatment of melanoma. This conference brought together medical oncologists, surgeons, dermatologists, radiotherapists, pathologists, molecular biologists, immunologists, and other

allied health professionals interested in the treatment of melanoma worldwide. https://www.oncologyeducation.com/events/oncologyeducation-events-video-archives/canadian-melanoma-conference-2018/

Best of GU & GI Cancers Summit Canada 2018- Video Archive. The focus of this meeting was to provide medical oncologists with a summary of the most significant treatment advances in Genitourinary and Gastrointestinal malignancies presented at major international events in 2017 and 2018. The Best of GU & GI Cancers Summit faculty was drawn from some of Canada’s most influential oncologists.

https://www.oncologyeducation.com/events/oncologyeducation-events-video-archives/best-of-gu-gi-cancers-summit-2018/

Oncology Opinions Series: Melanoma – Video Archive. In this series Dr. Caroline Robert discussed the Management of Melanoma Patients in the Metastatic Setting. This live educational program was offered in Toronto, ON and Montréal, QC (delivered in French). https://www.oncologyeducation.com/events/oncologyeducation-events-video-archives/oncology-opinions-series-in-melanoma-dr.-caroline-robert-(english)/

https://www.oncologyeducation.com/events/oncologyeducation-events-video-archives/oncology-opinion-series-in-melanoma-dr.-caroline-robert-(french)/

Best of ASCO® Series – Video Archives. The focus of this event was to provide medical oncologists and other healthcare practitioners with a summary of the most significant treatment advances presented at the ASCO 2018 Annual Meeting, with presentations focused on several key disease sites.

Best of ASCO® Montreal 2018. https://www.oncologyeducation.com/events/oncologyeducation-events-video-archives/best-of-asco-montreal-2018/

Best of ASCO® Toronto 2018. https://www.oncologyeducation.com/events/oncologyeducation-events-video-archives/best-of-asco-toronto-2018/

Supplement to Hot Spot, the newsletter of the Rapid Response Radiotherapy Program of the Odette Cancer Centre – August 2018

ALK-Positive Non-Small Cell Lung Cancer – Next Generation ALK inhibitors Dr. Parneet K. Cheema, HBSc, MD, MBiotech, FRCPC, Assistant Professor, Department of Medicine, University of Toronto, Medical Oncologist, William Osler Health System

Anaplastic lymphoma kinase (ALK)-rearrangements are oncogenic drivers that occur in ~4% of patients with non-small-cell lung cancer (NSCLC).1 Most patients with ALK-rearranged NSCLC are usually younger, are never smokers, have a more aggressive phenotype by stage, and initially present with central nervous system (CNS) metastases in 25% of patients with advanced stage disease.2

Crizotinib, the first ALK inhibitor approved for use in ALK+ NSCLC, has high initial activity; however, most patients eventually have disease progression within 1 year. The CNS is one of the most common sites of initial progression, likely because of poor CNS drug penetration.3 Mechanisms of acquired resistance to crizotinib include both “on-target” genomic alterations, includ-ing mutations in the ALK tyrosine kinase domain and amplification of the ALK fusion, as well as activation of bypass signaling pathways, including EGFR, IGF-1R, c-KIT, and SRC.4

Brigatinib, alectinib and ceritinib are next generation ALK inhibitors approved

by Health Canada after failure of crizotinib and more recently alectinib and ceritinib have been approved for patients with treat-ment naïve ALK+ NSCLC. Lorlatinib, and ensartinib are next generation ALK inhib-itors currently under development. This review will focus on the data of moving next generation ALK inhibitors to the first line setting and update data in pretreated ALK+ patients.

Part 1: Treatment naïve ALK+ NSCLC – Moving 2nd Generations ALK inhibitors to first-lineKey take away: Alectinib and ceritinib have replaced crizotinib as the preferred 1st line therapy due improved PFS and CNS activity. This is based on two pivotal trials, the ALEX trial with alectinib and ASCEND-4 with cer-itinib. Brigatinib may also replace crizotinib as it demonstrated a statistically significant improvement in PFS versus crizotinib in the ALTA-1L trial. Results will be presented at an upcoming congress.

ALEX trial5,6

Study design: • Phase III, randomized open label trial• Patients: 303 patients with treatment naïve,

metastatic ALK+ NSCLC• Intervention: Alectinib 600 mg po BID vs

crizotinib 250 mg po BID. No crossover.• CNS metastases: Patients with asymptom-

atic, treated or untreated CNS metastases were eligible. Brain metastases were pro-spectively studied with mandatory brain imaging at baseline and every 8 weeks on study.

Generously supported by an educational grant from Takeda

Results:

Table 1: Endpoints of alectinib vs crizotinib in treatment naïve metastatic ALK+ NSCLC patients

Alectinib (n=152) Crizotinib (n=151)

HR; P value

Primary endpointPFS Inv assessed 34.8 mos. 10.9 mos HR: 0.43; p<0.001

Primary endpointPFS IRC

25.7 mos. 10.4 mos HR:0.50; p<0.001

PFS with CNS mets 27.7 mos 7.4 mos HR: 0.35

PFS without CNS mets 34.8 mos 14.7 mos HR: 0.47

Overall Survival NR NR HR: 0.76

ORR 83% 76%

CNS ORR 81% 50%

CNS duration of Response 17.3 mos. 5.5 mos.

Time to CNS progression HR 0.16; p<0.001

12 months Incidence of CNS progression

9.4% 41.4%

IRC, independent review committee; NR, not reached; CNS, central nervous system

Safety: • Despite significantly longer treatment

duration with alectinib (27 mos. vs 11 mos), proportion of patients with grade 3–5 AEs (44.7% vs 51.0%), AEs leading to dose reduction (16.4% vs 20.5%) or interruption (22.4% vs 25.2%) were lower with alectinib.

Supplement to Hot Spot, the newsletter of the Rapid Response Radiotherapy Program of the Odette Cancer Centre – August 2018

ASCEND-47

Study Design: • Phase III, randomized, open label trial • Patients: 376 patients with treatment naïve

metastatic ALK+ NSCLC• Intervention: Ceritinib 750mg po

OD fasted vs platinum-pemtrexed

pemetrexed maintenance. Cross over allowed.

• CNS metastases: Permitted if asymptom-atic, treated or untreated, and neurolog-ically stable >2 weeks. Baseline brain imaging was only required if patients had known brain metastases.

Results:

Table 2: Endpoints of ceritinib vs platinum/pemetrexed in treatment naïve metastatic ALK+ NSCLC patients

Ceritinib (n=189) Platinum/pemetrexed (n=187)

HR; p value

Primary endpointPFS BICR 16.6 mos 8.1 mos

HR 0.55; p<0.00001

PFS investigator assessed 16.8 mos 7.2 mos HR 0.49;p<0.00001

PFS with CNS mets 10.7 mos 6.7 mos HR 0.70

ORR 72.5% 26.7%

CNS ORR (n=44)* 73% (16/22) 27% (6/22)

OS NR (95% CI 29.3, NR) 26.2 mos (95% CI 22.8, NR) HR 0.73; p=0.06

BICR, blinded independent review committee; NR, not reached; CNS, central nervous system*CNS ORR in patients with measurable baseline brain metastases and at least one post-baseline assessment (BIRC neuroradiologist)

Safety:• 80% patients in the ceritinib group

required a dose interruption or reduction and were primarily due to GI toxicity or liver function abnormalities.

• GI-related AEs were considerably higher in the ceritinib 750 mg arm, although most were grade 1 or 2, manageable and led to treatment discontinuation in only 3 patients (2%).

ASCEND 88 • Randomized, randomized, open-label,

phase 1 study. • Part 1: investigated the steady-state phar-

macokinetics (PK) and safety of ceritinib 450 mg or 600 mg take with a low-fat meal, vs 750 mg fasted in patients with ALK+NSCLC who were either treatment naïve or pretreated with crizotinib and/or chemotherapy

• Part 2: was to assess efficacy and safety in patients that were treatment naïve.

• Enrolled: 267 patients, of which 121 were treatment naïve.

Results: • At steady state, 750 mg fasted and 450 mg

with food had comparable PK. 600 mg had higher PK.

• 450 mg with food had lower all grade GI toxicities, with no grade 3 or 4 events, study drug discontinuations or serious AES due to GI toxicities.

• Part 2: Treatment niave patients (450 mg po OD fed vs 750 mg po OD fasted)■■ ORR: 73% vs 70%■■ PFS: 17.6 mos vs 10.9 mos

Impact on treatmentBased on the ALEX and ASCEND-4

studies, 2nd generation ALK inhibitors have replaced crizotinib as standard of care for first-line therapy for metastatic ALK+ NSCLC. Although there is no head-to-head trial comparing alectinib and ceritinib, a recent network analysis found that alectinib significantly improved IRC assessed PFS compared to chemotherapy, crizotinib and ceritinib, both in the intent to treat group and in the subgroup of patients with baseline CNS metastases. Significantly fewer grade 3-4 AEs were experienced with alectinib compared with ceritinib.9 Results from the ALEX trial, based on updated PFS, safety profile, in addition to data supporting the prevention of CNS metastases, alectinib would be the preferred first-line treatment of patients with metastatic ALK+ NSCLC. Ceritinib is a reasonable alternative, with a dose of 750 mg po without food as per the ASCEND-4 study, although an option to reduce GI toxicity would be 450 mg po OD with a low fat meal. Also, brigatinib will potentially replace crizotinib as well as on July 25, 2018 Takeda announced the Phase 3 ALTA-1L (ALK in Lung Cancer Trial of AP26113 in 1st Line) trial met its primary endpoint at the first pre-specified interim

analysis, with brigatinib demonstrating a statistically significant improvement in PFS compared to crizotinib in patients with met-astatic treatment naïve ALK+ NSCLC. The data will be presented at an upcoming major congress.10

Upcoming Trials for Treatment Naïve Metastatic ALK+ NSCLC

ALTA-1L: A Phase 3 Study of Brigatinib Versus Crizotinib in ALK-positive Advanced Non-Small Cell Lung Cancer Patients (ALTA-1L). (NCT02737501). Met its primary endpoint – to be presented at an upcoming congress.

CROWN: A Study Of Lorlatinib Versus Crizotinib In First Line Treatment Of Patients With ALK-Positive NSCLC (NCT03052608)

eXalt3: Study Comparing X-396 (Ensartinib) to Crizotinib in ALK Positive Non-Small Cell Lung Cancer (NSCLC) Patients (NCT02767804)

Part 2: Next generation ALK TKIs following progression of crizotinibKey take away: Alectinib, ceritinib, briga-tinib, and lorlatinib are treatment options following crizotinib.

Brigatinib, alectinib and ceritinib are approved by Health Canada for the treatment of ALK+ NSCLC that have progressed fol-lowing crizotinib. Clinically, responses range from 49% to 58% of patients previously treated with crizotinib, including in patients with and without secondary ALK mutations and all three have shown activity in patients with CNS disease.11-13 Patients treated with alectinib and ceritinib tend to progress within 1 year when these agents are given following crizotinib (median PFS, 6.9–8.9 months) due to development of resistance, the PFS reported with brigatinib is 16.7 months.13

In vitro activity to 2nd/3rd generation ALK TKIs have demonstrated various sensitivities to ALK resistance mutations, with ceritinib, alectinib and crizotinib being resistant to the solvent front mutation G1202R.14 Exception

Supplement to Hot Spot, the newsletter of the Rapid Response Radiotherapy Program of the Odette Cancer Centre – August 2018

to this is in vitro data with brigatinib and in vitro and clinical data with lorlatinib having activity in tumours that harbor the G1202R mutation.13-15 Thus, there is a need for ALK inhibitors with activity against a broad range of ALK resistance mutations. Also, with the change in treatment algorithm of 2nd genera-tion ALK inhibitors moved into the first line setting, the development of next generation ALK inhibitors to overcome resistance to 2nd generation ALK inhibitors is warranted. Lorlatinib and ensartinib are currently in advanced development and will be discussed.

Brigatinib• Phase I/II trial of the oral ALK inhibitor

brigatinib in metastatic ALK+ NSCLC, treatment naïve or post crizotinib resulted in ORR of 62% and median PFS of 12.9 months.16

• PFS was 16.3 mos in patients that had 90 mg po OD of brigatinib x 7 days lead up to brigatinib 180 mg po OD which is the dose recommended for further development.

• There was a unique toxicity seen with bri-gatinib at the 180 mg dose showing early onset pulmonary toxicity (median time to onset, 2 days [range, 1 to 9 days]) in about 5.8% of patients, which was reduced with a lead in of 90 mg x 7 days (Brig-90/180).

• Early onset pulmonary toxicity presented as dyspnea, cough, pneumonia or pneumo-nitis and can be managed early recognition with dose interruption then dose reduction.

• Older age, shorter interval (<7 days) between last crizotinib dose and the first dose of brigantib were significantly associ-ated with an increased rate.

ALTA13

Study design: • Randomized, phase 2 trial• Patients: 222 patients with crizotinib-re-

fractory metastatic ALK+ NSCLC. Patients could not have an ALK TKI other than crizotinib. Any number of prior che-motherapy regimens were allowed.

• Intervention: Brigatinib 90 mg po OD (Brig-90) vs Brigatinib 90 mg po OD x 7 days then 180 mg po OD (Brig-90/180)

• CNS metastases: Patients with asymp-tomatic or treated stable CNS metastases were eligible. Brain MRI was required at baseline and post baseline in patients with CNS metastases. 71% of patients and 67% of patients had brain metastases at baseline in Brig-90/180 and Brig-90 arms.

• Primary endpoint: Investigator assessed confirmed ORR

Table 3: Endpoints of brigatinib in patients with crizotinib refractory ALK+ NSCLC

Brig-90/180(n=110)

Brig-90(n=112)

Primary endpointORR Investigator assessed 56% 46%

ORR by IRC 56% 51%

PFS investigator assessed 15.6 mos 9.2 mos

PFS IRC 16.7 mos 9.2 mos

Intracranial ORR(pts with measurable baseline CNS mets)

67% (12/18) 50% (13/26)

Intracranial PFS (pts with any brain mets) 18.4 mos 12.8 mos

Median OS 34.1 mos 29.5 mos

IRC, independent review committee; CNS, central nervous system

Safety:• Early onset pulmonary AEs occurred

in 14/219 patients (6.4%) with an onset median of 2 days

• No events occurred following escalation to 180 mg in the Brig-90/180 arm

• Most frequent TRAEs in the Brig 90/180 were increased, nausea (33%), diarrhea (35%), elevated CPK (32%), vomiting (19%), fatigue (18%), increased lipase (17%), muscle spasms (17%), increased aspartate aminotransferase (16%) hyper-tension (17%), rash (17%), elevated amy-lase (15%). Grade 3/4 pneumonitis was 4%

• Dose reductions: 29% of patients, with 11% discontinuing due to an AE

Lorlatinib• Lorlatinib is an oral inhibitor of ALK and

ROS1, specifically designed to penetrate the blood brain barrier

• Phase 1 trial of lorlatinib in metastatic ALK+ NSCLC patients results in ORR 46%, median duration of response 12.4 months17

Phase 1/2 trial18 Study design:• Open-label, single arm phase 1/2 trial• 5 ALK+ arms: EXP1: Treatment naïve;

EXP2: Prior crizotinib only; EXP3: Prior crizotinib only + chemotherapy OR 1 other ALK TKI +/- chemotherapy; EXP 4: 2 prior ALK TKIS +/- chemotherapy; EXP5: 3 prior ALK TKIs

• Patients: ALK+ NSCLC treated with > to 1 ALK TKI

• Intervention: Lorlatinib 100 mg po OD• CNS metastases: Patients eligible with

or without, untreated or treated CNS metastases

• Primary endpoint: ORR and intracranial ORR

Results:• Treatment naïve ALK+ (n=30)

■■ ORR 90%■■ 8 patients had CNS metastases at base-line, the IC ORR: 75%

Table 4: Efficacy of lorlatinib for metastatic ALK+ NSCLC pts with > 1 ALK TKI

Prior crizotinib only +/- chemotherapy

Prior Non-crizotinib ALK TKI +/- chemotherapy

> 2 Prior ALK TKIs +/- chemotherapy

Overall (n) 59 28 111

ORR 73% 43% 40%

PFS NR 5.6 mos 9.9 mos

Intracranial – overall (n) 37 13 81

IC ORR 70% 46% 48%

Duration of IC response NR (19.5-NR) NR (4.1- NR) 14.5 (11.1- NR)

IC ORR with > 1 measurable brain metastases at baseline (n)

24 9 48

IC ORR 88% 67% 52%

Duration of IC response NR (15.2-NR) NR (4.1-NR) 12.4 mos (6.0-NR)

NR, not reached

Supplement to Hot Spot, the newsletter of the Rapid Response Radiotherapy Program of the Odette Cancer Centre – August 2018

Table 5: Efficacy of lorlatinib in ALK+ NSCLC pts by last prior 2nd generation ALK TKI received

Alectinib Ceritinib Brigatinib

Overall (n) 62 47 8

ORR 40% 43% 38%

PFS 5.6 mos 6.9 mos NC

Intracranial – Overall (n) 37 35 5

IC ORR 41% 54% 40%

Duration of IC response 11.6 mos NR (6.0-NR) NC

NR, not reached; NC, not calculated

• Translational: 190 patients with pretreated ALK+ patients, 24% had > to 1 detectable ALK kinase domain mutation. 27 unique mutations were found, and G1202R/del was the most frequently observed (25%) mutation.

• Among the 139 patients without a detect-able ALK mutation in cfDNA, 63 patients (45%) responded to lorlatinib.

• Safety• Most common TRAEs were hypercholes-

terolemia (84%) and hypertriglyceridemia (67%), edema (44%), peripheral neurop-athy (34%), cognitive effects (23%) and weight gain (23%)

• TRAEs leading to dose reductions was 25% and treatment discontinuation 3.3%

• Unique side effect seen with lorlatinib is cognitive effects, 23% all grades, 1.1% grade 3/4.

Ensartinib• Ensartinib (X-396) is a small molecule

tyrosine kinase inhibitor (TKI) that has activity against ALK but also targets MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK.19

Study design• Phase 1/2 in patients with ALK+ NSCLC

to evaluate safety and determine the rec-ommended phase II dose (RP2D).

• Patients: Prior therapy with crizotinib without a limit on prior therapies

• CNS metastases: MRI brain required at baseline for patients with known brain metastases or suspected. Enrolled patients with stable or asymptomatic CNS metasta-ses at baseline

• Primary endpoint: Safety

Results:

Table 6: Efficacy endpoints of ensartinib in ALK+ NSCLC pts in patients that received > 200 mg and had one post-baseline response assessment

Evaluable patients(n=60)

ALK TKI naïve80% (n=15)

Prior crizotinib only ORR (n=29)

Crizotinib and > 1 2nd generation ALK TKI (n=16)

ORR 60% (36/60) 80% 69% 25%

PFS 9.2 mos 26.2 mos 9.0 mos 1.9 mos

IC ORR (baseline target CNS lesions)

64% (9/14)

Safety:• Thirty-seven patients enrolled in dose

escalation, and 60 enrolled in dose expan-sion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experi-enced a treatment-related grade 3 to 4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity.

• The unique toxicity of rash was managed with topical medications and for are severe holding the dose until improvement and resuming at a reduced dose. The mecha-nism of rash is unclear.

Upcoming trials in pre-treated ALK+ NSCLC

eXALT 2: Phase 2 study of ensarti-nib following progression on alectinib or crizotinib.

Impact on treatmentThere are now multiple ALK TKIs

available for patients with metastatic ALK+ NSCLC that have progressed on crizotinib. Cross trial comparison should be done with caution as each trial had slightly different patient populations. Ceritinib and alectinib are approved by Health Canada but unfortu-nately patients do progress within one year. Next generation ALK inhibitors with briga-tinib and lorlatinib have encouraging data, and with brigatinib also recently approved by Health Canada reporting an IRC PFS of 16.7 months. Lorlatinib and brigatinib have broad activity for ALK resistance mutations including the G1202 resistance mutation and thus would be options after failure of the 2nd generation ALK inhibitors ceritinib and alectinib. The next generation ALK inhibi-tors have unique side effect profiles and thus patient tolerability and preference may also determine best therapy; clinically this offers a variety of options for patients should they not tolerate one therapy.

We await the first-line data of brigatinib, lorlatinib and ensartinib to further inform the sequencing algorithm for ALK+ NSCLC patients.

References available upon request

Supplement to Hot Spot, the newsletter of the Rapid Response Radiotherapy Program of the Odette Cancer Centre – August 2018

Medical cannabis for inflammatory bowel diseaseBy E. Mckenzie, P. Zaki, H. Lam, A. Fefekos, C. DeAngelis, S. O’Hearn

Inflammatory bowel disease (IBD) is a chronic condition that causes significant mor-bidity and decreased quality of life (QOL) in those affected. Cannabis and its derivatives, cannabidiol (CBD) and tetrahydrocannabi-nol (THC), have been investigated for their therapeutic potential in several prevalent IBD disorders, namely Crohn’s disease (CD) and ulcerative colitis (UC). Benefits of these ther-apies are attributable to the known anti-in-flammatory properties of cannabis-derived compounds and the role of the endocanna-binoid system in human gut motility. Some clinical trials have shown that cannabinoids have the potential to produce symptomatic and clinical benefits for patients with IBD.

Low-dose cannabidiol is safe, but not effective in the treatment for Crohn’s disease, a randomized controlled trialNaftali, T. et al. Digestive diseases and sciences. 2017;62(6):1615-20.

Nineteen patients aged 20–75 years with a Crohn’s disease activity index (CDAI) between 200 and 450 points were randomized to receive oral CBD or placebo twice daily. All patients had previously received at least one intervention for Crohn’s disease with no effect, including steroids (n=11), thiopurines (n=14), and/or TNF antagonists (n=11).

Study design• A double-blind study was conducted at the

Meir Medical Centre in Israel, in which

patients were randomized to receive CBD oil (5 mg/mL) (n=10) or a placebo (n=9) con-taining pure olive oil. Patients were ordered to take 2 mL of oil sublingually twice a day for the total eight-week study duration.

• Patients were evaluated at weeks 0, 2, 8 and 10 (two weeks post-treatment) for disease activity using the CDAI, medical interview, physical examination and blood tests (com-plete blood count, liver and kidney function and levels of C-Reactive Protein [CRP]).

• QOL and side effect questionnaires (graded by severity from 1 to 7, where 1 = no symptoms and 7 = very severe symp-toms) were filled on weeks 0 and 8.

• Concomitant medications were kept constant throughout the study (except corticosteroids, which were tapered).

Results• No statistically significant differences in

blood test results, side effects, or average change in CDAI between the study (n=10, CDAI: 117±130) and placebo group (n=9, CDAI: 91±81) (p=0.6).

• Side effects graded on a severity scale of 1 to 7 included: headache (1.2 CBD versus 1.4 placebo), sleepiness (3.8 CBD versus 3.6 placebo), nausea (2.8 CBD versus 3.5 placebo) and dizziness (1.7 CBD versus 2 placebo).

• Four and three patients in the study and placebo group achieved full remission (CDAI < 150), respectively.

• One patient in the study group and one patient in the placebo group required rescue intervention during the eight-week period.

ConclusionDespite reduction in the CDAI scores and the excellent tolerability and safety of CBD, there was no significant difference between study and placebo groups, indicating low-dose CBD may not generate significant benefits for Crohn’s disease.

Cannabis induces a clinical response in patients with Crohn’s disease: A prospective placebo-controlled studyNaftali, T. et al. Clinical Gastroenterology and Hepatology. 2013;11(10):1276-80.

22 patients with a Crohn’s disease activity index (CDAI) score of 200-450 points and who had failed at least one form of treatment including mesalamine (n=21), corticosteroids (n=20), thiopurines (n=20), methotrexate (n=4), or TNF antagonists (n=17) were enrolled in the study. Patients received either medical cannabis or placebo in the form of cigarettes for inhalational administration.

Study design• Patients were randomized to a treatment

(n=11) or placebo (n=10) group. The treat-ment group received a cigarette containing 0.5 mg of dried cannabis flowers with 115 mg of THC and the placebo group received a cigarette of cannabis flowers from which the THC had been extracted. The study period was eight weeks.

• Patients were evaluated at weeks 0, 2, 8 and 10 (two weeks post-treatment) for disease activity using the CDAI, medical interview, physical examination and blood tests (complete blood count, liver and kidney function and levels of CRP).

• QOL (SF-36) and side effect question-naires (items graded on a severity scale of 1-7) were completed at weeks 0 and 8.

• Concomitant medications were kept constant throughout the study (except corticosteroids, which were tapered).

Results• No statistically significant differences in

blood test results, side effects, or rates of full remission (CDAI < 150) between the study group (remission rate: 45%, n=11) and the placebo group (10%, n=10) (p=0.43).

• Five patients in the study group (n=11, 45%) and one patient in the placebo group (n=10, 10%) achieved full remission of CDAI < 150 although statistical signifi-cance was not demonstrated (p=0.43).

• CDAI scores were reduced by 177 ± 80 in the study group and 66 ± 98 in the placebo group (p=0.05).

• The response rate (CDAI reduction >100) was 90% in the study group and 40% in the placebo group.

• Four patients in the placebo group and no patients in the study group required rescue intervention during the eight-week period.

• Significant improvement in QOL was observed in the cannabis group (SF-36, +28; p=0.04) and minimal change was observed in the placebo group (SF-36, +5; p=0.04).

• The cannabis group reported significantly decreased pain (p=0.001), improved appetite (p=0.008) and higher treatment satisfaction (p=0.002) compared to the placebo group.

ConclusionCannabis was ineffective in significantly

inducing remission compared to placebo, but did exhibit higher rates of response, as shown in CDAI scores.

Impact of cannabis treatment on the quality of life, weight and clinical disease activity in inflammatory bowel disease patients: A pilot prospective studyLahat, A. et al. Digestion. 2011;85(1):1-8.

Study design• Israeli patients treated at the Sheba

Medical Centre with a diagnosis of CD or UC for at least a year were prescribed medical cannabis by their gastroenterolo-gist independently of the study.

This education grant provided by MedReleaf Corp. is

gratefully acknowledged

Supplement to Hot Spot, the newsletter of the Rapid Response Radiotherapy Program of the Odette Cancer Centre – August 2018

• 50 g of dry processed plant was given per month in prepared cigarettes with instruction to take up to three inhalations for pain flares.

• Concomitant medications were unchanged for 16 weeks prior to and during the study period.

• QOL questionnaires (EQ-5D and SF-36v2), body weight, the Harvey Bradshaw Index (for CD patients only) and the partial Mayo score index for disease activity assessment (for UC patients only) were completed and measured at baseline and three months following treatment.

Results• 13 patients with IBD diagnoses (CD, n=11;

UC, n=2) were prescribed cannabis and enrolled in the study (9 male, 4 female).

• No adverse events were reported.• On the SF-36, statistically significant

improvement in pain severity (p=0.0002), general health perception at the present compared to one year ago (p=0.001), ability to work (p=0.0005) and ability to engage in social activities (p=0.0002) was reported.

• On the EQ-5D, significant improvement in pain (p=0.004), depression (p=0.007), and schematic scale items (p=0.0002) was reported.

• On the Harvey Bradshaw Index for CD patients, significant improvement in general well-being (p=0.001), abdominal pain (p=0.0039) and reduction in number of liq-uid stools per day (p=0.0039) was reported.

• The small sample size limited significant conclusions for UC patients based on the partial Mayo score.

• Average weight gain was 4.3 ± 2 kg during treatment (p=0.0002) and average rise in BMI was 1.4 ± 0.61(p=0.002).

• Inflammatory markers showed elevated CRP levels in five out of six evaluable CD patients (1.21 ± 0.4) at baseline, which returned to normal range (< 0.5) during treat-ment; the sixth patient had maintained nor-mal CRP levels before and after treatment.

ConclusionInhaled cannabis improves QOL, pro-

motes healthy weight gain and improves clinical disease activity in CD patients after

three months of treatment. There was an insufficient number of UC patients enrolled to form conclusions on medical cannabis use for this condition.

Cannabis use provides symptom relief in patients with inflammatory bowel disease, but is associated with worse disease prognosis in patients with Crohn’s diseaseStorr, M. et al. Inflammatory Bowel Diseases. 2014;20(3):472-80.

Study design• Adult patients (18 years or older) seen

at the University of Calgary with IBD completed an anonymous questionnaire comprised of 53 questions for patients who used cannabis for treatment of IBD and 23 questions for those who did not use canna-bis for treatment of IBD.

• Questions addressed demographics, clinical characteristics of the disease, years with IBD, number of flares, main symptoms, previous hospital stays and surgeries, med-ication use, severity of disease and type of cannabis use (medicinal or recreational).

• For medicinal use, frequency, mode, patterns of use, symptomatic benefits, possible side effects, personal motives, how the patient obtained cannabis-related information and the cost of cannabis were explored.

Results• A total of 319 surveys (out of 461 distrib-

uted) were returned. Current or past use of cannabis for IBD was reported by 17.6% (n=56), and 82.5% (n=263) reported that they had never used cannabis for their condition.

• Amongst non-users, 27.4% of responders were male (n=72) and 72.6% were female (n=191) and amongst cannabis users, 50% were male (n=28) and 50% were female (n=28).

• After correcting for demographics, smok-ing history, years with IBD and biological cannabis use, prolonged cannabis use was found to be associated with a history of previous surgery (OR=5.03, 95% CI= 1.92 – 16.98).

• Of the patients that use cannabis for their IBD (n=56):■■ 75% (n=42) had CD, 17.9% (n=10) had UC and 7.1% (n=4) had indeterminate colitis

■■ Most users (n=46, 82.1%) plan to continue cannabis use for their IBD, would recom-mend cannabis to others with IBD (n=49, 87.5%), did not report cannabis use to their physician (n=34, 60.7%), and use cannabis chronically (>12 months) (n=32, 57.1%) and to reduce symptoms (n=50, 89.3%)

■■ Most patients that use cannabis found it was beneficial for their IBD (n=51, 91.1%), namely for abdominal pain (n=47, 83.9%), abdominal cramps (n=43, 76.8%), joint pain (n=27, 48.2%), and diarrhea (n=16, 28.6%)

■■ On a graded scale (1 = worse, 3 = no effect, 5 = better) describing change in symptoms, patients rated cannabis 4.2 ± 0.6 on aver-age, indicating a beneficial effect.

• Most users experienced mild side effects including anxiety, increased appetite, dry mouth, drowsiness and a ‘high’ feeling (reported by ≥75%).

ConclusionA significant number of patients self-ad-

minister cannabis to treat IBD symptoms with reported benefits. Physicians should be aware of this and inform their patients of the potential benefits and risks of medical cannabis use.

Treatment of Crohn’s disease with cannabis: An observational studyNaftali, T. et al. Israel Medical Association Journal. 2011;13(8):455-8.

Study design• Patients with CD at the Meir Medical

Centre in Israel who had received per-mission from the Ministry of Health to receive cannabis for their symptoms were interviewed about disease details, previous treatments, and motivation for cannabis usage. The dose and form of cannabis administration was documented.

• Patients self-assessed their general well-be-ing after cannabis treatment using a Visual Analog Scale ranging from 0 (very poor well-being) to 10 (excellent well-being).

• Medical records were reviewed for objec-tive measures of disease severity, hospital admission history, and use of other drugs, particularly steroids.

• Disease activity before and after canna-bis use was obtained using the Harvey Bradshaw index.

Results• 30 patients aged 21 to 65 with CD currently

using cannabis for their IBD were inter-viewed for the study (4 male, 26 female).

• 50% of patients had previous surgery (n=15) and 13% of those (n=2) required another surgery within an average of two years of the initial procedure.

• Reasons for cannabis use included lack of response to traditional treatment (n=21, 70%), chronic pain (n=6, 20%) and recre-ational purposes (n=4, 13%).

• Most patients smoked cannabis and con-sumed one to three joints/day, equating to an average dosage of 0.5-1.5 mg/day of THC.

• All patients stated that cannabis had a positive effect on their disease activity, as evidenced by: Visual Analog Scale increas-ing from 3.1 to 7.3, Harvey Bradshaw Index decreasing from 14 ± 6.7 to 7 ± 4.7 (p<0.001), mean number of bowel movements decreasing from eight to five, and the number of patients using steroids decreasing from 26 to four.

• Cannabis did not induce significant improvement in nine patients, indicated by less than a four-point reduction in the Harvey Bradshaw index.

ConclusionThe safety profile for the use of cannabis

independent of concurrent alcohol and other drug consumption was excellent. Due to the observed symptomatic relief and clinical benefit, cannabis could be reasonably con-sidered as an adjuvant treatment for Crohn’s disease with the establishment of a greater body of evidence.