Volume 20, Issue 4, November 2018

EditorialBy Dr. Edward Chow

In this issue of Hot Spot:Editorial

Who should recruit and obtain informed consent for research: Straddling the line between clinician and researcher

The incidence of febrile neutropenia in breast and lymphoma cancer patients receiving Grastofil® as primary prophylaxis: Early experience at the Sunnybrook Odette Cancer Centre (SOCC)

Different perspectives of the 2017 Canadian pain guidelines

How do functional status ratings by outpatients with advanced cancer correlate with physician-reported ratings and survival?

Continuing Medical Education

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

Insert:Tumour Lysis Syndrome (TLS)

continued on page 2…

In this issue, Ms. Julia Gill and Dr. Blair Henry discuss: Who should recruit and obtain informed consent for research: Straddling the line between clinician and researcher. Ms. Katie Wang and Dr. Carlo DeAngelis report on the incidence of febrile neutropenia in breast and lymphoma cancer patients receiving

Grastofil® as primary prophylaxis: Early experience at the Sunnybrook Odette Cancer Centre. Ms. Rashi Asthana and Dr. Carlo DeAngelis outline the different perspectives of the 2017 Canadian pain guidelines. Mr. Brian Li, Dr. Camilla Zimmermann and their group report how functional status ratings by outpatients

with advanced cancer correlate with physician-reported ratings and survival.

Ms. Toby Rodin and Mr. Kiran Dash update Continuing Medical Education. The insert on Tumour Lysis Syndrome (TLS) was provided by Drs. Steven Moore, Fiona Lim and Carlo DeAngelis. Hope you find this issue educational.

Who should recruit and obtain informed consent for research: Straddling the line between clinician and researcher By Julia Gill, JD, MHSc Bioethics, Ethics & Policy Fellow, and Blair Henry, D. Bioethics, Senior Ethicist at Sunnybrook Health Sciences Centre

IntroductionWhen research studies are designed

and clinical trials planned, recruitment and informed consent from participants are vital steps in this process. Figure 1 illustrates the seven components of an ethically sound recruitment and consent process. The ongoing debate in ethical research discourse has revolved around who should complete each of these steps in studies undertaken by clinician researchers. Ideally, participation in clinical trials calls for autonomous decision-making that is free from any agent that could affect or appear to affect the voluntariness. Power differentials between a patient and their researcher/healthcare provider can, under the guise of therapeutic misconception, undermine the participant’s perceived voluntary choice.

Recruitment activities are restricted to persons identified within the patient’s circle of care. Consent, on the other hand, can be delegated by the principle investigator (PI) to any member of the research team.

What does the Tri-Council Policy Statement on Ethical Conduct for Research Involving Humans, 2014 (TCPS2), say?

The TCPS2 gives some guidance on how best to avoid undue influence during the recruitment and informed consent process. The TCPS2 states that: “The approach to recruitment is an important

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Who should recruit and obtain informed consent for research: Straddling the line between clinician and researcher

element in assuring voluntariness. In particular, how, when and where participants are approached, and who recruits them are important elements in assuring (or undermining) voluntariness. In considering the voluntariness of consent, REBs and researchers should be cognizant of situations where undue influence, coercion or the offer of incentives may undermine the voluntariness of a participant’s consent to participate in research.”

The TCPS2 goes on to say that, “…researchers should also pay particular attention to elements of trust and dependency in relationships (e.g., between physician and patient or between professor and student). These relationships can impose undue influence on the individual in the position of dependence to participate in research projects. Any relationship of dependency, even a nurturing one, may give rise to undue influence even if it is not applied overtly. There may be a greater risk of undue influence in situations of ongoing or significant dependency.” [emphasis added]

It is worth noting that undue influence may occur in any dependent relationship, including when a researcher has a therapeutic relationship with the participant. The TCPS2 explicitly states that the “dual roles of researchers and their associated obligations (e.g., acting as both a researcher and a therapist, [or] health care provider…) may create conflicts, undue influences, power imbalances or coercion that could affect relationships with others and affect decision-making procedures (e.g., consent of participants).”

Recruitment processSo, how does a conscientious PI

operationalize the principles of the TCPS2 to avoid undue influence? One way to do this is to more clearly separate the role of clinician and researcher. The PI is ultimately responsible for the entire study, but may delegate the role of recruitment. The PI or other coinvestigators are often straddling the line of both physician and researcher. This is a reality of research, and one to be encouraged to enrich the practice of medicine. However, a physician providing care has an important relationship of trust with their patients and

should avoid recruiting their own patients. Doing so may jeopardize this trust in a way that could negatively affect the patient/physician relationship in the future, as well as maybe unduly influencing patients to take part in research. This is not to say that a clinician, once they have confirmed eligibility, cannot have someone else recruit their patients for a study they are involved in. When possible, participant recruitment should be done by someone more neutral in the circle of care to whom a patient may feel more empowered to refuse participation. As noted in Figure 1, we recommend thinking of the recruitment process in two steps: Screening and Invitation. The first step undertaken by the physician and the second being undertaken by a clinical nurse or other staff member in the circle of care.

Obtaining informed consent

Once a patient has agreed to move forward to learn more about the study with the aim of potentially consenting to participate, the therapeutic relationship between the physician/patient may prevent some patients from probing and asking questions about their involvement in the study. This may be due to the implicit trust patients place in their physicians and that trust being extended to the study the physician appears to be endorsing. The patient may also feel discomfort associated with asking tough questions to a person with whom they have a prior relationship of dependence and trust. As with recruitment, a researcher obtaining informed consent should ideally not be in a therapeutic relationship with the patient, or a perceived position of authority over the patient.

This gets tricky when the PI, or persons most familiar with the study, wants or needs to recruit from their own patient pool. Some researchers would argue that it is best for the PI or those in similarly senior positions within the study to conduct the informed consent process; they are most knowledgeable about the research and best equipped to explain the study and answer any questions that arise. While this may be true in some cases, efforts should be made to familiarize research associates with the intricacies of the study and how best to obtain consent. If the prospective participant has any complex questions the research associate is unable to answer, the PI can make themselves available to address those issues.

ConclusionAllowing participants to make an

informed voluntary choice to participate in research is a preeminent ethical and legal requirement. In order to ensure that voluntariness and patient autonomy is maximized during recruitment and obtaining informed consent, both of these steps should be done by well informed, neutral researchers who are not in a therapeutic relationship with prospective participants.

REFERENCES1. Canadian Institutes of Health

Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council of Canada. Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans. December 2014.

Figure 1: Stages and process for recruiting and consenting patients into clinical trials

…continued from page 1

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The incidence of febrile neutropenia in breast and lymphoma cancer patients receiving Grastofil® as primary prophylaxis: Early experience at the Sunnybrook Odette Cancer Centre (SOCC)By Katie Wang, BSc, & Carlo DeAngelis, PharmD, Department of Pharmacy, Sunnybrook Odette Cancer Centre, Toronto, Ontario

Background Grastofil (filgrastim) is a biosimilar to

the reference biologic drug Neupogen®.1 Effective December 22, 2016, the Ontario Drug Benefit (ODB) Program began funding Grastofil for the prevention and treatment of neutropenia associated with chemotherapy.1 At our cancer centre, Grastofil replaced Neupogen for the primary prophylaxis (PPx) of febrile neutropenia (FN) for new cancer patients beginning in January 2017. By December 2017, more than 90% of all active cancer patients requiring PPx for FN were receiving Grastofil. The aim of our study was to determine the incidence of FN at the SOCC among breast and lymphoma cancer patients receiving Grastofil for the PPx of FN, during treatment with neoadjuvant/adjuvant chemotherapy in breast cancer patients or receiving chemotherapy with curative intent in lymphoma cancer patients. Secondary endpoints included the incidence of dose delays and dose reductions.

Study design A retrospective chart review of all

eligible breast and lymphoma cancer patients receiving PPx with Grastofil during January to December 2017 was conducted. Patient disease and treatment characteristics were collected along with Grastofil usage, incidence of FN, dose delays and dose reductions. We defined the incidence of FN as any reported

event of FN during treatment and up to four weeks post-treatment; dose delays as any delay in treatment that was six or more days; and dose reductions as any reduction in dosage in one or more chemotherapy agents of the regimen when compared to baseline dosage. The incidence of FN, dose delay and dose reduction were analyzed independently. The incidence of dose delays and dose reductions also includes patients who experienced an FN event.

Results Fifty-eight Grastofil patients met the

inclusion criteria and were analyzed, of whom 47 (81.0%) were breast cancer patients. Among the 58 patients, a total of 261 cycles of chemotherapy treatment was used for dose-delay and dose-reduction analyses. Overall, six (10.3%) patients experienced FN during chemotherapy treatment, six (10.3%) experienced a dose delay and 18 (31.0%) received a dose reduction.

DiscussionWe determined the incidence of FN

for breast and lymphoma cancer patients receiving PPx with Grastofil was 10.3%. This is comparable to reported real-world data from a European study that evaluated the incidence of FN (12.0%)2 in a similar patient population receiving Neupogen. Our study defines dose delay and dose reduction, as they are in clinical practice at the SOCC. Differences reported in

literature may be a reflection of practice preferences for dose delay and dose reduction, as there is currently no standard practice across cancer centres.

ConclusionOverall, our results show that the rate

of FN in breast cancer and lymphoma patients receiving PPx with Grastofil is consistent with data reported in the literature for PPx with Neupogen. Next, we have planned a case-matched cohort equivalency study comparing the rate of FN in breast cancer and lymphoma patients using Grastofil versus Neupogen as PPx for FN.

REFERENCES1. Ontario Ministry of Health and

Long-Term Care. Ontario Public Drug Programs: Grastofil (filgrastim) Frequently Asked Questions.

2. Pettengell R, Schwenkglenks M, Leonard R, Bosly A, Paridaens R, Constenla M, Szucs TD, Jackisch C; Impact of Neutropenia in Chemotherapy-European Study Group (INC-EU). Support Care Cancer. 2008;16(11):1299-1309. doi:10.1007/s00520-008-0430-4

This study is supported by an unrestricted educational grant from Apobiologix.

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Different perspectives of the 2017 Canadian pain guidelinesBy Rashi Asthana, MSc, PhD Student Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, and Dr. Carlo De Angelis, PharmD, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Sunnybrook Odette Cancer Centre, Toronto, Ontario

Opioids are invaluable for chronic pain management, and Canada has the second highest rate of opioid prescription per capita.1 The commonly prescribed opioids are codeine, oxycodone, hydromorphone, morphine, tramadol, and fentanyl.2 There are strong correlations between opioid prescriptions and opioid-related mortality, especially when opioid prescriptions are combined with other substances such as alcohol and/or benzodiazepines.2 In 2017, there were 3,987 apparent opioid-related deaths in Canada, 92% of these deaths were accidental, 68% involved fentanyl or fen-tanyl analogues, and 72% of these deaths also involved non-opioid substances.3 This is a 40% increase from opioid-related deaths in 2016.3 To address the opioid cri-sis, the 2017 Canadian pain guidelines rec-ommend low doses of opioids only when all other drugs (Tylenol and NSAIDs) and non-drug measures (exercise and cognitive behavioural therapy) have been exhausted and proven ineffective.1 Furthermore, the new guidelines discourage prescribing opioids to high-risk populations including patients with mental illness and history of substance use disorders.1

The risk factors for opioid-related deaths are patients who are prescribed strong opioids, or patients who are prescribed opioids for chronic pain, but the proportion of patients in these cate-gories has remained steady over the past five years.2 Opioid prescription increases with age, and seniors (age 65+) are at the greatest risk of opioid-related harms due to prescribed opioids.2 Age-related changes including drug absorption and metabolism, as well as neuro-cognitive changes such as forgetting if they took their pills or taking their pills twice can increase the risk of opioid overdose.2 Therefore, seniors have high hospitalization rates due to toxicities from prescribed opioids, but only 7% of their deaths were opioid related in 2017.2,3

In 2017, 78% of the opioid-related deaths occurred in males, and 28% of these males were between the age of 30–39.3 Youths (age 15–24) have the lowest opioid prescription rates, yet have a steadily increasing hospitalization rate.2 Youths are more likely to steal prescribed opioids from friends and family.2 Thus, toxicities in youths are more likely to occur due to ille-gally produced and obtained opioids rather than prescribed opioids.2 Furthermore, street drugs are often tainted with fentanyl, which contributes to a significant number of

accidental opioid-related deaths in youths.3To bridge the gap between patient lived

experiences and healthcare professionals, Dr. Seema Marwaha initiated “The Opioid Chapters”, which is a collaborative effort between the Ontario Drug Policy Research Network (ODPRN) and healthy debate.4 The healthcare profession is focused on practical knowledge such as data and policies when making decisions, but the decision-makers are often distanced from the people who are prescribed opioids and the frontline workers who work with people with substance use disorders.4 Policy decisions should be a discussion between healthcare professionals and people who require opioids for chronic pain without stigmatization.4 Chronic pain is often debilitating and requires continual low-dose opioids for effective pain management.4 Many people taper opioids once it starts alleviating pain, but opioids also help with ongoing mental health issues as well.4

Teva Harrison, a patient who speaks about her opioid experience in the “Opioid Chapters”, had pain due to metastatic breast cancer bone metastases, which was so severe she could not think clearly or function in her daily life.5 She tried muscle relaxers and Tylenol 3, but nothing worked.5 She was prescribed hydromor-phone and then the fentanyl patch.5 She claims her pain was well-managed with the trans-dermal fentanyl patch, as it is effective for two to three days, and there are no “crashes” in her pain management; meaning the drug levels are maintained at an efficacious level.5 She emphasizes that pain is not completely gone, as opioids are not “pain killers” but rather pain suppres-sors that make the pain more tolerable.5 She states that she did not experience opioid-in-duced constipation through the fentanyl transdermal patch.5 She expresses concern about the benefits of opioids for terminal cancer patients, how many people are afraid to talk about the pain relief, and how it improved their quality of life because of the stigma associated with the opioid crisis. She wants to break the stigma and openly discusses the importance of opioids in improving quality of life for terminal patients. She asks, “What is the shame in getting your life back?”

The Canadian pain guidelines are potentially stigmatizing people who require chronic opioid use or higher opioid doses to manage their pain by creating an “us versus them”, but the opioid crisis is incredibly

complex.4,5 Many people are afraid to openly talk about the positive impact that opioids have had on their quality of life because of a fear of being stigmatized for requiring opioids to remain functional.5 Healthcare professionals often put people in boxes, to determine what their opioid dose should be based on their medical history.4 For example, people with emotional trauma require opioids to deal with angst, not just pain, so they are often put in boxes that define them as addicts.4 Hence, they don’t get the help they need. The whole idea of putting people in boxes based on what we think we know about them creates a negative relationship between healthcare professionals and patients.4

The 2017 Canadian pain guidelines recommend restricting opioid prescrip-tion, which can increase the risk of poor pain control in cancer patients who require higher opioid doses for pain management. The resolution to the opioid crisis is to change how society views opioid addiction, but the opioid crisis cannot exclusively be solved by limiting opioid prescriptions. Rather than stigma-tizing those who require opioids for pain management, doctors and patients should strategize pain management, not just with pills, but also non-drug therapies.1

REFERENCES 1. Galloway M. Opioid Guidelines.

https://www.cbc.ca/listen/shows/metro-morning/segment/12555482

2. Pan-Canadian Trends in the Prescribing of Opioids, 2012 to 2016: Canadian Institute for Health Information. 2017. https://secure.cihi.ca/free_products/pan-canadian-trends-opioid-prescribing-2017-en-web.pdf

3. National Report: Apparent Opioid-Related Deaths in Canada (Released June 2018): Special Advisory Committee on the Epidemic of Opioid Overdoses.; 2018. https://www.canada.ca/en/public-health/services/publications/healthy-living/national-report-apparent-opioid-related-deaths-released-june-2018.html.

4. Galloway M. New first-person stories from the opioid crisis. https://www.cbc.ca/listen/shows/metro-morning/segment/15593095

5. Galloway M. How Teva Harrison is using fentanyl to handle her cancer pain. https://www.cbc.ca/listen/shows/metro-morning/segment/15594879

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Vol. 20, Issue 4, November 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.

The newsletter of the Rapid Response Radiotherapy Program of the Odette Cancer Centre is published through the support of:

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Scan the QR code with your smartphone to read past issues of Hot Spot

How do functional status ratings by outpatients with advanced cancer correlate with physician-reported ratings and survival?By Brian Li, MSc, Ashley Pope, BSc, Gordana Popovic, MD, and Camilla Zimmermann, MD, PhD

Performance status measures can be used in oncology settings to assess clinical prognosis,1-3 but there is conflicting evi-dence on who should best complete these measures. Studies have presented data suggesting that patient-reported perfor-mance status is significantly associated with survival,4-6 though some have found physicians’ ratings to be more accurate.5,6 While performance status has traditionally been assessed by physicians, there has been a shift towards having patients com-plete these measures themselves,7-9 since physician-completed measures are already largely based on patients’ interpretation of their own level of function.

Since 2008, every oncology outpatient visit in Ontario includes the completion of the patient-reported performance status (PRFS). This assessment was derived from the clinically validated Patient-Generated Subjective Global Assessment (PG-SGA),10 and is a lay language version of the physician-reported Eastern Cooperative Oncology Group (ECOG) measure. The ECOG is a clinically validated, widely used assessment11 that captures patients’ functional activity such as self-care and physical ability on a six-point scale where: 0 is “fully active, able to carry on all pre-disease performance without restriction”, 1 is “restricted in physically strenuous activity, but ambula-tory and able to carry out work of a light or sedentary nature,” 2 is “ambulatory and capable of all self-care but unable to carry out any work activities; up and able more than 50% of waking hours,” 3 is “capa-ble of only limited self-care; confined to bed or chair more than 50% of waking hours,” 4 is “completely disabled; cannot carry on any self-care; totally confined to bed or chair,” and 5 is “dead.” The PRFS instructs patients to rate their activities and functions on a five-point scale where: 0 is “normal with no limitations,” 1 is “not my normal self, but able to be up and about with fairly normal activities,” 2 is “not feeling up to most things, but in bed or chair less than half of the day,” 3 is “able to do little activity and spend most of the day in bed or chair,” and 4 is “pretty much bedridden, rarely out of bed.”

We conducted a study in the outpa-tient oncology palliative care clinic at the Princess Margaret Cancer Centre, a

member of the University Health Network, to investigate how often the PRFS cor-responded with the physician-completed ECOG and also how well the scores predicted survival. Complete results were recently published in the Journal of Pain and Symptom Management.12 PRFS and ECOG assessments for 949 patients with advanced cancer were completed and collected separately so that both patients and physicians were blind to each other’s ratings. We first assessed the level of agreement between the PRFS and ECOG, as well as potential factors that may con-tribute to discrepancies in agreement. We then evaluated how closely each score was able to predict patients’ survival.

Physicians mostly rated patients as ECOG 1 (41%) or 2 (41%) while patients most commonly provided a PRFS rating of either 1 (32%), 2 (24%), or 3 (34%). Agreement between the PRFS and ECOG was found in 42% of assessments, a fair to moderate correlation. Our results showed that overall patients tended to rate their performance status worse than physicians; this was especially the case for younger patients and those with greater symp-tom burden. These results may indicate physicians’ tendency to underestimate the decline in performance status in younger patients and those who are more symptom-atic. On the other hand, these results may represent a tendency for younger or more symptomatic patients to overestimate the decline of their performance statuses.

Both patient- and physician-reported performance status scores were reasonably associated with patient survival. The ECOG scores demonstrated a slightly better pre-dictive capacity compared to PRFS scores, although the results were not statistically sig-nificant. Interestingly, predictive capability showed improvement after using the average of the patient- and physician-reported scores when compared to each score individually.

Our study demonstrates that physicians’ and patients’ ratings of performance status may differ, with younger patients and those with greater symptom burden tending to rate their performance status as worse. There may be value in obtaining assessments from both patients and physicians in outpatient oncology settings to better predict survival in patients with advanced cancer.

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

• November25–30,2018. Radiological Society of North America, RSNA, Annual Meeting, McCormick Place, Chicago, Illinois. https://www.rsna.org

• November30,2018.Best of Oncology East. Toronto, Ontario.https://www.oncologyeducation.com/events/upcoming-events/best-of-oncology-east-2018/

• December1–4,2018.60th American Society of Hematology(ASH) Annual Meeting San Diego, California. http://www.hematology.org/Annual-Meeting/

• December4–8,2018. 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

• January10–12,2019.Canadian Uro-Oncology Summit. Urological Association, CUOS Toronto, ON http://www.cuameeting.org/en

• January18,2019.Best of SABCS. Toronto, Ontario.https://www.oncologyeducation.com/events/upcoming-events/best-of-sabcs-2019/

• January25,2019.Best of Oncology West. Vancouver, British Columbia.https://www.oncologyeducation.com/events/upcoming-events/best-of-oncology-west-2019/

• February7–8,2019.Canadian Lung Cancer Conference. Vancouver, Canada.http://clcco.ca

• February21–23,2019. 13th Canadian Melanoma Conference. Banff, Alberta.https://www.oncologyeducation.com/events/upcoming-events/13th-canadian-melanoma-conference/

• February25–26,2019.World Congress on Breast Cancer. London, United Kingdom. https://breastcancer.pulsusconference.com

• February28–March2,2019.American Psychosocial Oncology Society Annual Conference (APOS) 16th Annual Conference. Sheraton, Atlanta. https://apos-society.org/annual-conference/apos-annual-conference/

• March14–16,2019.7th ICHNO, International Congress on innovative approaches in Head & Neck Oncology, Barcelona, Spain. https://www.estro.org/congresses-meetings/next-event

• April22–23,2019.Global Summit on Radiation Therapy & Targeted Tumours. Vancouver, Canada. https://radiationtherapy.conferenceseries.com

• April25–28,2019.Canadian Association of Pharmacy in Oncology (CAPhO) Association canadienne de pharmacieen oncologie. Halifax, Nova Scotia. http://www.capho.org/capho-conference

CME ProgramsOncologyOpinionSeriesinBreastCancer:Dr.SunilVerma–VideoArchive.OncologyEducation featured Dr. Sunil Vermadiscussing current and emerging roles of PARP inhibitors in breast cancer. This educational program was offered as a live event and interactive webinar.https://www.oncologyeducation.com/information/breast/breast-videos/current-and-emerging-roles-of-parp-inhibitors-in-breast-cancer/OncologyOpinionSeriesinLungCancer:Dr.ParneetCheema–VideoArchive.OncologyEducation featured Dr. Parneet Cheema discussing – Practice Update: Locally Advanced Non-Small Lung Cancer. This educational program was offered as a live event and interactive webinar. https://www.oncologyeducation.com/information/lung/lung-cancer-videos/practice-update-locally-advanced-non-small-lung-cancer/

OncologyOpinionSeriesinGynecologicalCancer:Dr.AmitOzaandDr.StephanieLheureux–VideoArchive.Oncology Education featured Dr. Amit Oza and Dr. Stephanie Lheureux discussing – Switching from Olaparib capsules to tablets. This educational program was offered as a live event and interactive webinar in both English and French. https://www.oncologyeducation.com/information/gynecology-information/gynecology-videos/o/OncologyOpinionSeriesinLungCancer:Dr.Ramalingam–VideoArchive.Oncology Education 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/OncologyOpinionsWebinarinMerkelCellCarcinoma–VideoArchive.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/BestofASCO®Series–VideoArchive.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.

BestofASCO®Montreal2018.https://www.oncologyeducation.com/events/oncologyeducation-events-video-archives/best-of-asco-montreal-2018/BestofASCO®Toronto2018.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 – November 2018

Tumour Lysis Syndrome (TLS)By Steven Moore, PhD, Fiona Lim, MBBS, and Carlo DeAngelis, PharmD

This education grant provided by Sanofi Genzyme is

gratefully acknowledged

Three key categories of risk factors1:1. Co-morbidities (e.g. dehydration, pre-ex-

isting renal impairment, hyperuricaemia)2. Disease-related factors (e.g. tumours

with high prolifertative rate, bulky solid tumour, especially with liver metastasis, high-grade lymphomas), and

3. Treatment-related factors (e.g. cytore-ductive chemotherapy in hematologic malignancies).

Based on these risk factors, patients are categorized into low, intermediate, or high risk for developing TLS, each with recom-mendations for prevention and treatment.•A model was developed to assess low-,

intermediate- and high-risk TLS classi-ficationandassociatedTLSprophylaxisrecommendations, see Figure 1 for part of this model.2

For patients at low risk3

•Adequate hydration is usually effective •Allopurinol can be considered an option •Monitoring with daily labs for changes in

potassium, phosphate, uric acid, calcium, and serum creatinine levels.

For patients at intermediate risk3

• Increased hydration plus allopurinol•Monitoring with labs performed every 8 to

12 hours initially, less frequently after 48 hours of chemotherapy.

For patients at high risk3

• Increased hydration unless evidence of renalinsufficiencyandoliguria

•Single prophylactic dose of rasburicase, repeated if uric acid levels are elevated

•Monitoring with labs performed every 4to6hoursduringthefirst48hoursofchemotherapy.

For patients with intermediate- or high-risk, recommended at least twice-daily before andduringthefirstsevendaysofanticancertherapy.4 Patients who develop laboratory TLS or hyperuricaemia, regardless of their initial risk, should initiate treatment.4

Update on Prevention and treatment of TLS andefficacyandroleofrasburicase.3

Relevant study updates1. FLORENCE Study5

•Febuxostatsignificantlysuperiorincontrolling sUA level (P < 0.0001) and sUA reduction compared with allo-purinol in intermediate and high risk patients (Figure 2)

•Both able to prevent creatinine increase over time.

2. Urate oxidase for the prevention and treatment of TLS in children with cancer6

•Based on a Cochrane review, it is unclear whether urate oxidase reduces clinical TLS, renal failure, or mortality in children.

•Clinicians should weigh the poten-tialbenefitsofreducinguricacidanduncertainbenefitsofpreventingmortal-ity or renal failure from TLS against the potential risk of adverse effects.

Table 1: Recommendations for prevention and treatment of tumour lysis syndrome

Low-risk disease

Intermediate-risk disease High-risk disease

Diagnostic measures

No specific measures

• Daily monitoring of laboratory abnormalities before and during the first 7 days of anticancer therapy

• At least twice daily monitoring of laboratory abnormalities before and during the first 7 days of anticancer therapy

Preventative measures

Moderate hydration is recommended

• Vigorous hydration• Keep urinary output 100mL/hr• Treatment with allopurinol or

febuxostat should be started at least 24 hours before initiation of anticancer therapy and should be continued till normalization of uric acid levels and signs of large tumour burden are absent

• Vigorous hydration• Keep urinary output

100mL/hr• Single dose 6 mg of

rasburicase. Repeat doses as necessary. In case of contraindication treatment with febuxostat

Treatment of established tumour lysis syndrome

• Admission to intensive care unit with continuous cardiac monitoring and monitoring of laboratory abnormalities every 4–6 hours

• Early nephrology consultation to estimate the indications for renal replacement therapy• Correction of electrolyte abnormalities• Vigorous hydration, keep urinary output 100mL/hr• Single dose 6 mg of rasburicase. Repeat doses as necessary. In case of

contraindication, treatment with febuxostat.

Modified from Oncology Nurse Advisor. 2013(January/February):5.

Figure 1: TLS risk assessment of solid tumours, myelomas and chronic leukemia.

Modified from Cairo et al., 2010

LRD: Low-risk disease, IRD: Intermediate-risk disease

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

Figure 2: FLORENCE study; Mean sUA time course for both treatment arms

Mean sUA time course. Error bars indicate the standard deviation (SD) of the mean.

3. Efficacyandsafetyoffebuxostatforprevention of TLS in patients with malig-nant tumours receiving chemotherapy; comparing febuxostat and allopurinol7

• Febuxostatdemonstratedefficacyandsafety similar to allopurinol in patients with malignant tumors receiving chemotherapy.

4. Incidence of TLS in patients with hematological malignancies treated with rasburicase8

•Results■■ 52 patients with hematological malig-nancies received rasburicase 19 patients had high risk (37%), 23 had intermediate risk (44%) and 10 had low risk (19%) 5 patients (9.6%) had spontaneous TLS

■■ Overall, 24 patients (46.2%) devel-oped LTLS No patients developed renal events requiring dialysis or emergence of clinical TLS 2 of the patients (3.8%) developed CTLS (only increased serum creati-nine level)

•Conclusions■■ Nosignificantassociationbetweenrasburicase daily dose, duration, or post-administration laboratory data and TLSriskclassification

■■ Rasburicase; highly effective for the pre-vention/management of hyperuricemia, even at a low dose (7.5 mg/day) and with a short duration (3 days)

■■ Nosignificantdifferenceamonghigh,intermediate and low risk groups

5. Impact of dialysis requirement on out-comes in TLS.9

•Results■■ An estimated 12% of all hospitaliza-tions develop AKI-D (acute kidney injury requiring dialysis).

■■ After adjustment for confounders, AKI-D was associated with greater odds of mortality (OR 1.98; (95% CI 1.60–2.45)), adverse discharge (OR 1.63 (95% CI 1.19–2.24)) and longer LOS (19 vs 14.6 days; P < 0.01) com-pared with those without AKI-D.

General updatesUrine alkalinisation •No longer recommended• Lowefficacyandanincreasedriskofcal-

cium phosphate precipitation and reduced xanthine solubility.10,11

Hyperkalaemia•Treatment of life-threatening hyperkalae-

mia (particularly those patients with ECG changes)12

•Renal replacement therapy should be considered

•Reduce potassium12

Hyperphosphatemia3

• If accompanied by acute kidney injury (AKI),treatmentisdifficult.

•Oral phosphate binders have limited effectiveness

• Significanthyperphosphatemiaistreatedbest with renal replacement therapy.

Dialysis•TLS can result in AKI, in some cases,

severe enough to require dialysis (AKI-D).

Future treatments New treatments that target Xanthine

oxidoreductase (XOR) are being looked at to hopefully offer less or no toxicity.13

Study design•Millet- (fast-growing cereal plant) derived

compounds interactions with target, human XOR through molecular docking and dynamic simulation studies.

Results•The millet-derived compounds reported a

binding energy of -9.7kcal/mol•Febuxostat and Allopurinol showed bind-

ing energy -8.0kcal/mol and -5.5kcal/mol respectively.

DiscussionWith treatment for cancer becoming more

effective, TLS is a common and life-threat-ening condition of which healthcare profes-sionals and patients need to be increasingly aware. Risks for developing TLS are associated with tumour characteristics, as well as patient co-morbidities and the type of treatment the patients receive. Guidance to manage low-, intermediate- or high-risk patients include prophylaxis, treatment, and monitoring.

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February):5.5. Ann Oncol. 2015;26(10):2155-61.6. Cochrane Database Syst Rev.

2017;3:CD006945.7. Int J Clin Oncol. 2016;21(5):996-1003.8. Mol Clin Oncol. 2017;6(6):955-9.9. Nephrology (Carlton). 2017;22(1):85-8.10. Haematologica. 2008;93(12):1877-85.11. Br J Haematol. 2015;169(5):661-71.12. J R Coll Physicians Edinb.

2013;43(3):246-51.13. Comput Biol Chem. 2018;76:32-41.