Fifteen years ago, the RRRP published the first issue of Hot Spot as a quarterly newsletter. Hot Spot has seen many changes over those years of continuous publication. We mail more than 2,000 copies of each issue to readers across the world who prefer the hardcopy to the digital version, which is available online at http://tinyurl.com/nusf3ap

The current issue contains two educa-tional inserts. One on New Updates in the Treatment of Advanced Gastric Cancer by Drs. Xiao Zhu and Yooj Ko, and the second on Latest Update in MASCC/ESMO Antiemetic Guidelines by Drs. Carlo DeAngelis and Edward Chow.

This newsletter also contains interest-ing articles on ethics, psychosocial and educational issues.

Karen Faith’s article highlights the ethical problem caused by cultural

differences and suggests that “moral imagination” may help us better under-stand and manage those conflicts within a multicultural society whose complex health systems are geared more towards cure than care.

Drs. Mary Vachon and Christopher Gittings refer to two books Remarkable Recovery and Radical Remission and pro-vide us with a fascinating case history to illustrate the variables contributing to lon-ger-than-expected survival with advanced stage 4 cancer.

The end of treatment is one which is “filled with mixed emotions ranging from happiness to anxiety” according to Tamara Harth, who highlights some timely, indi-vidualized teaching strategies and tools for coping with this transition phase.

Nathalie Pulenzas and Dr. Elizabeth Barnes provide a summary of their

research on “The Prevalence of Do-Not-Resuscitate Orders in the Rapid Response Radiotherapy Program”.

The article by Dr. Mark Pasetka pro-vides an excellent overview on Serotonin syndrome.

To help us with continuing educational activities Dr. Ewa Szumacher provides a list of upcoming meetings.

We hope that you find the content of this issue relevant, interesting, and educational.

Let us know what you think. We wel-come your suggestions for any topic you may want us to consider for future issues.

Conflicts that arise over treatment deci-sions for seriously ill patients are burden-some for all involved. It is my opinion that some conflicts cannot be avoided. Serious illness can raise significant ethical and clinical concerns within a multicultural society with complex systems for provid-ing care. Perhaps it is time for us to reach a more compassionate understanding of the challenges being faced today in both providing and receiving health care.

Canadians witnessed the plight of J.J., a young aboriginal child with a treatable form of leukemia. In efforts to resolve the conflict over treatment decisions, an

Ontario Court decision permitted J.J.’s mother to pursue traditional medicine for her child. First Nation’s treaty rights had bearing on the Court’s decision, which goes beyond the scope of this article. The Court’s decision, however, led opinion leaders like André Picard from the Globe and Mail (19/11/14) to conclude that the outcome was a “dereliction of duty” by both child protection and the Court. According to Picard, the hospital had failed to “adequately assuage the parents’ fears”. This is harsh judgement of a com-plex situation.

Volume 17, Issue 1, February 2015

EditorialBy Dr. Cyril Danjoux

Conflicts over care and the role of “moral imagination”By Karen Faith, BSW, MEd, MSc, Bioethics Consultant

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

InsertsNew updates in the treatment of advanced gastric cancer

Latest update in MASCC/ESMO Antiemetic Guidelines

In this issue of Hot Spot:Editorial

Conflicts over care and the role of “moral imagination”

Advanced cancer: The lived experience

Prevalence of Do-Not-Resuscitate Orders in the Rapid Response Radiotherapy Program

Learning about the end of treatment: Effective teaching strategies and tools for people finishing primary treatment for cancer

Serotonin syndrome: Part one

Continuing Medical Education 2015

continued on page 2…

B2

Conflicts over care and the role of “moral imagination”

Medical, legal and ethics experts ana-lyzing such a case will consider the values in conflict, values which pertain to achiev-ing the most good and doing the least harm. J.J.’s story reminds us that cultural beliefs, the way illness is envisioned, are deeply rooted in the life and experiences of the patient and her family. As members of the Six Nations of Grand River community, J.J. and her mother share values and beliefs shaped by a unique history and under-standing of health. How much did expert medical opinion mean in their culture? If perspectives about the right course of treatment greatly differ, then trust in the relationship between care providers, patient and family can be seriously compromised.

According to Andrew Lau, moral imagination is “an ability to imaginatively

discern various possibilities for acting in a given situation and to envision the potential help and harm that are likely to result from a given action”. Understanding conflict over treatment decisions requires moral imagina-tion. Imagination helps us to reason through how it is that dedicated health providers and devoted parents come to such irreconcilable notions about benefit and harm.

Imagine how J.J. and her mother might perceive benefit and harm. First Nations communities have suffered from historic, systemic abuses (like those associated with residential schools). Many have lost trust in Western law and/or medicine. J.J.’s mother favoured traditional healing methods after witnessing her daughter’s struggle with chemotherapy. Was she negligent in her duties as a mother? Child protection services concluded that J.J.’s mother should

remain the legal guardian. Traditional heal-ing was pursued.

Imagine the perspective and experiences of J.J.’s health providers. They saw a sick child whose life they believed they could save, and a mother who was making an ill-advised decision, pursuing an option with no medical benefit. They parted with J.J. under less than medically optimal circumstances.

It is likely that J.J.’s family and health care providers shared a similar moral anguish, because they all cared so much for J.J.’s future and well-being. When substantive cultural differences exist, when consensus cannot be easily reached on such crucial decisions regarding care, judgement and blame needs to be tempered through a shared sense of compassion and moral imagination.

More people live with stage 4 cancer for longer periods of time with quality of life. Medical advances have obviously contributed, but are there other factors as well?

Remarkable Recovery1 documents the experience of people who either went into long-term remission, or were apparently cured of stage 4 cancer. Radical Remission2 expands on this topic. Both books investi-gate variables associated with longer-term survival, or cure, which will be high-lighted. Chris’s words, describing living with advanced disease, will be in italics.

Chris has lived with stage-four pancre-atic cancer with liver metastases for close to nine years. He attributes a large part of his survival to his long-term partner1 for 29 years, Julie Burnett, who took on the role of nutritionist, suggesting dietary changes1,2 and researcher (social sup-port1,2) of my rather strange form of the disease, glucagonoma.

Congruity between patient and phy-sician1—the chemotherapy and supports provided by my oncologist also played a major role in keeping me alive. Unlike many stage four cancer patients, the gift of longev-ity means that I’ve had the opportunity to develop a comfortable interpersonal relation-ship with my oncologist; we trust each other and can even have a laugh at the disease’s or hospital system’s expense. I actually enjoy my visits to the cancer centre. My oncologist has been in my position; Dr. Walter Kocha knows what it is to be diagnosed with cancer and, like me, to keep working through it. This isn’t to say we always agree on everything, but when my partner found data suggesting

that my extreme, life-threatening hypogly-cemia may not be caused by the tumour’s hormone production, but possibly by sando-statin, a drug that helps to keeps so many cancer patients going, including myself, my oncologist was, guardedly, open to exper-imentation that went against the grain of received knowledge where the overwhelming majority of patients were concerned (being treated as a unique individual1). That isn’t to say he didn’t interrogate this information with a healthy dose of skepticism. However, I was pretty insistent that my body was telling me it was the sandostatin (intuition2, taking control of your health2) that had to go. Most physicians would be wary of such a narrative being presented as strategy. With the support of both my oncologist and endocrinologist I stopped taking sandostatin and my blood sugars are no longer a threat; I no longer drop to 1.2, my blood sugars are 100% normal.

Spirituality1,2—at our very first encoun-ter, Dr. Mary Vachon took me on a guided meditation. I meditated regularly throughout and after treatment, envisioning animated scrub brushes, imported from a bathroom cleanser commercial, go to work ‘dissolving’ my tumours and metastases. I would then visualize a waterfall in a tropical environ-ment where I cleansed my body by shower-ing and drinking from its azure waters. When I went on a double blind oral chemo trial, my Uncle John, a researcher of placebo effect at Dalhousie, told me not to worry about whether or not I was on the actual drug; his research told him that if patients believe (intuition2) they are receiving benefit from

the med, there is a very good chance that they will improve. The staff was convinced I was on the drug and not the sugar pill, as I developed side effects associated with the pharmaceutical and the ‘material’ was stable. When it was revealed that I was on placebo, both the medical staff and I were surprised. Due to the success of the trial, I was put on the actual drug, Afinitor.

Having the opportunity to engage in meaningful work as a professor and chair of a university department (strong reasons for living2) has also made a huge differ-ence. I did not have to live the disease 24 hours a day. Thanks to meditation, regular palliative psychotherapy, my teaching and research interests, my colleagues and my students (social support 1,2, connected-ness1), I have had a very full life away from the disease. I won two teaching awards over those 9 years, went to bed most nights and woke up most mornings without any nagging thoughts about my illness. Of course, it intrudes at times when I’d rather not acknowledge it. Whenever I received bad news from imaging, was extremely fatigued or symptomatic, I felt more acutely the tensions inherent in ‘passing for healthy,’ which is what I try to do on most days. I never wanted my cancer to become a ground upon which my competence could be questioned. However, I also needed to be honest with myself and my colleagues and eventually, when I found myself particularly unwell, I would tell people, much as they would communicate having the flu or other

Advanced cancer: The lived experienceBy Mary L.S. Vachon, PhD, RN, and Chris E. Gittings, PhD, Chair, Film Studies, Associate Professor, Western University

…continued from page 1

continued on page 3…

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Advanced cancer: The lived experience

Prevalence of Do-Not-Resuscitate Orders in the Rapid Response Radiotherapy ProgramBy Natalie Pulenzas, BSc(C), and Elizabeth Barnes, MD, FRCPC, Sunnybrook Odette Cancer Centre

Success rates of cardiopulmonary resuscitation (CPR) of cancer patients are in the order of 8-10%. For those with metastatic disease, CPR is thought to be of minimal effectiveness.1 The Rapid Response Radiotherapy Program (RRRP) is an outpatient radiotherapy clinic for palliative cancer patients. Patients referred to the RRRP are of varying stages of advanced disease, prognosis, and location as either inpatients or outpatients. In 2004, Bradley et al.2 conducted a study to determine the incidence of do-not-resuscitate (DNR) orders in the RRRP. Medical documentation such as physician progress notes or ambulance transfer forms were assessed for documentation of DNR status for patients seen between May and August of 2004. There were 209 patients who were included in this study, eight of which had DNR status (3.8% of patients).

In 2013, a similar study was conducted for a four-month period between January and April.3 The study methodology was very similar to the comparison study mentioned above. Basic demographic data including primary cancer, age, and gender were noted. Among this information collected was the location of the patient at the time of clinic visit. As the RRRP

is an outpatient clinic, the physicians are not the point of primary care for patients, making determination of code status more difficult. Code status was recorded as either “DNR” or “full code” at the time of arrival to clinic. If patients returned for a follow-up appointment, they were only recorded once in the database, but changes in code status were noted, if applicable.

There were a total of 145 patients included in the 2013 study. The median age was 71 years old and most common primary cancer sites were as follows: breast (28%), lung (23%), and prostate (20%). More than half of patients came from home (63.5%), and 34.5% were inpatients at various hospitals. The remaining three patients (2%) were in supportive housing or a nursing home. Twenty-four patients had documented DNR status (16.5%). Of these 24, four patients were full code at first visit, but returned with DNR status at a subsequent visit. Of the 50 who were inpatients, 19 had DNR status (38%), versus only five of 92 outpatients (5%). Therefore, inpatients were much more likely to have a DNR code status (p<0.0001). Those who were inpatients were also significantly of older age compared to outpatients, median age

of 75 versus 68 years for outpatients, p=0.04. Table 1 summarizes the results from each study.

The incidence of DNR status has certainly increased over the past nine years from 3.8% in 2004, to 16.5%. Due to the limitations in our study design, these rates may even be underestimated. The patient group seen in the RRRP does not capture those who are deemed too sick to benefit from palliative radiation treatment. There is also a possibility of misplaced or missing information from the patients’ travel between locations, as many patients come from other hospitals via ambulance transfer. To avoid unnecessarily upsetting patients, code status discussions were not initiated by the RRRP physicians for the sole reason of determining incidence for this study. This may also be a contributing factor to the lower awareness of outpatients’ code status, since the majority did not bring written orders with them to clinic. In conclusion, DNR code status has risen in prevalence and may even represent a conservative evaluation.

REFERENCES1. Reisfield GM. Survival in cancer

ailments. The only time I actually missed a class or a meeting was due to cold or flu. As far as I know, there was only one attempt in nine years to use cancer to ques-tion my competency; thankfully it wasn’t taken seriously and I bolstered myself with the knowledge that I had support from 99% of those I worked with, reduc-ing the 1% to a toxic, negligible stat, and negotiating it as such. Unfortunately, we all have toxic relationships and when you

become terminally ill, the toxicity doesn’t just disappear; so, it is up to you, to the best of your ability, to remove yourself from the toxic flow; your energies are required elsewhere.

Discovering who my friends are through illness has also been instruc-tive and enriching (social support1,2). Following and genuinely engaging with someone through this journey can, I imagine, be a harrowing experience, and the friends who continue to stay in touch,

offer support and ‘be there’ make huge contributions to my well-being that they may be quite unaware of.

REFERENCES1. Hirshberg C, Barasch MI. Remarkable

recovery. New York: Riverhead Books; 1994.

2. Turner KA. (2014). Radical remission: The nine key factors that can make a real difference. HarperOne; 2014.

…continued from page 2

Table 1: Demographics and results from each comparison study

patients undergoing in-hospital cardiopulmonary resuscitation: A meta-analysis. Resuscitation. 2006;71:152-160.

2. Bradley NME. The do-not-resuscitate order: Incidence of documentation in the medical records of cancer patients referred for palliative radiotherapy. Curr Oncol. 2006;13(2):47-54.

3. Pulenzas N. The incidence of DNR documentation in patients referred for palliative radiotherapy in Rapid Response Radiotherapy Program. Journal of Palliative Medicine. 2014;17(12):1296-1297.

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Learning about the end of treatment: Effective teaching strategies and tools for people finishing primary treatment for cancerBy Tamara Harth, BA Hons, M.L.I.S., Program Manager, Patient Education/Regional Lead Patient Education, Toronto Central North LHIN

The end of treatment on the cancer care pathway can be one that provides people with a sense of relief and with a number of lingering questions about what care and life might look like going forward. People who have gone through an experience with cancer have described the end of treatment as a period of transition and one that is filled with mixed emotions ranging from happiness to anxiety. Many describe being glad that it is over, but also wondering about what comes next. A number of people indicate they were able to get lots of information and support during the time they had a diagnosis and were receiving treatment for cancer, but not as much once treatment ended. Research shows that people at the end of treatment for cancer often have new questions with different learning needs that are not always responded to before they leave the treatment centre. These issues include follow-up care, lifestyle after cancer, body changes, intimacy, latent effects of treatment, return to work, and emotional support.

Patient education is an excellent way to provide answers to questions on these topics and is widely available, but is not always provided at the time of need. Many people leave the treatment phase of their cancer experience not knowing where to turn or how to access these resources. Patient education plays a major role in empowering patients and families with cancer. Educating patients about all aspects of the cancer experience including disease, treatment, symptom management and quality of life can decrease patient anxiety, support coping mechanisms, promote patient autonomy and improve the experience for patients and families.

There are a few helpful strategies for teaching people about the end of treatment that are important to follow to be effective in decreasing anxiety and helping individuals prepare for this new phase in the cancer experience. Where

possible, introduce education about the end of treatment some time before the individual is leaving the treatment centre. This helps to decrease some of the anxiety associated with the end of treatment. A number of cancer programs incorporate some teaching about the end of treatment all the way through the cancer trajectory, as a means of managing expectations and preparing people about what to expect. Tailoring the resources and teaching to the needs of the person is essential. To do this effectively, ask specific questions about what concerns they may have related to the end of treatment. Is the focus on latent effects, sexuality, or lifestyle changes? Try to tailor the teaching and education tools on the topics articulated as priority ones by the person rather than attempting to cover all potential issues that may arise in the care required after cancer. Focusing on the person’s needs, as they have articulated them, will allow for increased retention of information and likelihood of higher satisfaction.

Make sure that if you are providing print resources the quality of print materials meets the patients’ reading abilities, knowledge base and are culturally relevant. Involving family and caregivers in the learning process, where possible, is advised, as this group of people often hear information in a different way and, additionally, may have their own specific questions to help support their loved one in this phase of care. Knowing about and making referrals to appropriate agencies for support and reinforcement of learning, where necessary, can be a critical part of empowering patients. There are a number of great places to start in terms of tools that can help people with a variety of issues related to the end of treatment.

Below is a list of tools and programs people can be referred to for helping with the end of treatment that offer support and education in print, virtually, and face to face.

Life after cancer treatment. Canadian Cancer Society (pamphlet) Facing forward: Life after cancer treat-ment. National Cancer InstituteFacing forward: When someone you love has completed cancer treatment. National Cancer InstituteCancerChat Canada – www.cancerchat-canada.caCanadian Cancer Survivor Network – http://survivornet.ca/en/CANCERCare podcasts – www.cancer-care.org• Managing post-treatment neuropathy• Changing roles and responsibilities for

caregivers• Recapturing joy and finding meaning• Using mind/body techniques to cope

with the stress of survivorship• Fear of recurrence and late effects:

Living with uncertainty• Chemobrain: The impact of cancer

treatments on memory, thinking and attention

• Survivors too: Communicating with and among family, friends and loved ones

• Survivorship and workplace transitions• Communicating with your health care

team after treatment: Making the most of your visit

• Trouble sleeping? Sleep better to feel better: Tips you can use

• The importance of nutrition and physical activity

• Managing the stress of survivorship• Rediscovering intimacy in your

relationships following treatment• The importance of communicating with

your doctor about follow-up care• Finding hope and meaning after

treatment• My treatment is over: Why do I feel so

alone and sad?• Neuropathy and joint aches: New post

treatment challenges• Stress management tips for survivors

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Serotonin syndrome: Part oneBy Mark Pasetka, BSc, BScPharm, PharmD, RPh

IntroductionConcern has arisen regarding the use of

5-hydroxytryptamine3 receptor antagonists

(5-HT3 RAs) and their implication in

causing serotonin syndrome. Recently, Health Canada published a warning pertaining to an increased risk for the development of serotonin syndrome that was based on two local case reports.1 These reactions were associated with the use of 5-HT

3 RAs and subsequent

alterations were made to the product monographs for ondansetron (Zofran®), granisetron (Kytril®), and palonosetron (Aloxi®). The manufacturer of the fourth agent in this class, dolasetron (Anzemet®), has withdrawn this product from the Canadian market.

A recent meta-analysis demonstrated the benefit of 5-HT

3 RAs in the setting

of radiation-induced nausea and vomiting (RINV), and they are currently recommended as prophylaxis for certain types of radiation treatments.2-4 As such, concern has recently been raised regarding the use of these agents in this setting.

Serotonin syndromeSerotonin syndrome (SS) is an

uncommon, but potentially life-threatening medication-induced reaction that can occur when an excess of serotonin (5-hydroxytryptamine – 5-HT) is present in the central and peripheral nervous systems (CNS, PNS).5,6 This excess of 5-HT may occur due to an intentional medication overdose, with normal therapeutic use, or via a medication interaction; all situations require inclusion of one or more serotonin affecting medications.6

The incidence of SS based on reports of selective serotonin reuptake inhibitor (SSRI) ingestions at American Poison Control Centres in 2003 and 2005 suggests moderate to major effects occur in 16–18% of patients and death, as a result of this reaction, in 0.2% of patients.7

An understanding of some basic concepts is essential in the diagnosis and management of serotonin syndrome. First, SS is not an idiopathic reaction, meaning it is a predictable consequence of excessive amounts of serotonergic agonism in the central and peripheral nervous systems; second, a spectrum of clinical manifestations is produced from the presence of excess 5-HT; and third, these signs and symptoms may range from

being barely perceptible to highly overt and, ultimately, lethal.5,6,9

PathophysiologySerotonin is a neurotransmitter created

from the metabolic processing of dietary L-Tryptophan and falls under stringent regulation with respect to its effects on, and presence in the body.6,8 In addition, several families of 5-HT receptors (5-HT

1-7) reside within both the central and

peripheral nervous systems and through their stimulation a variety of functions are managed, some of which include sleep, mood, pain, and the emetic reflex.5,8 The body controls 5-HT activity and quantity by utilizing a combination of enzymatic degradation (via monoamine oxidase - MAO), synaptic reuptake, and feedback mechanisms.6 Medications affecting these regulatory processes may ultimately lead to an imbalance in the serotonergic environment and, subsequently, the development of serotonin syndrome.

Although many medications can affect serotonin in one capacity or another, severe or lethal effects seem only to be seen when specific serotonin receptors are agonised; in particular, those of the 5-HT

2 class, which would be responsible

for the manifestations of hyperthermia, incoordination, and neuromuscular excitation.5,8 There is also thought that agonism of 5-HT

1A receptors is involved,

which could explain the symptoms of hyperactivity, hyperreflexia, and anxiety.6,8 The antagonism of other 5-HT receptors (5-HT

1A,1D, and 3), on the other

hand, are not felt to carry a significant risk of developing SS (e.g., ondansetron, granisetron, palonosetron).5 Interestingly, genetic polymorphisms of serotonin receptors and certain cytochrome P450 enzymes, as well as pharmacokinetic abnormalities may also play a part in the pathophysiology of this condition.9

At least four different medication-inducing mechanisms for increasing the risk of SS through overstimulation at 5-HT receptors have been proposed and include reduction in 5-HT breakdown, reduction in serotonin reuptake, elevation in 5-HT precursors or agonists, and increased release of serotonin (Table 1).8-10 Interactions between pro-serotonergic medications can also be responsible for inducing toxicity for which several have been documented, often involving monoamine oxidase inhibitors (MAOIs) and/or SSRIs.6,9,11 These interactions

may be in the form of pharmacodynamic (additive serotonergic effects) or through pharmacokinetic mechanisms (inhibition or induction of metabolic pathways) involving these agents.

Table 1: Medications that have been associated with SS by way of mechanism (NOTE: This is not a complete list)adapted from 6-9

Mechanism of Serotonin Increase

Medications Associated

Reduction in serotonin breakdown

MAO InhibitorsTranylcypromine, Phenelzine, Moclobomide, Isocarboxazid AntibioticsLinezolidOthersSelegiline

Reduction in serotonin reuptake

SSRIsFluoxetine, Fluvoxamine, Sertraline, Paroxetine, Citalopram, EscitalopramSNRIsVenlafaxine, Duloxetine, MirtazapineTCAsAmitriptyline, Nortriptyline, Imipramine, ClomipramineOpiatesFentanyl, Meperidine, Methadone, TramadolOtherCocaine, MDMA, Amphetamine, Dextromethorphan, TrazodoneCAMSt. John’s Wort

Elevation of serotonin precursors or agonists

Anti-Migraine MedicationsSumatriptan, Ergot AlkaloidsOtherBuspirone, LSDCAML-Tryptophan

Increase release of serotonin

OtherAmphetamine, Cocaine, MDMA, Methylphenidate, Buspirone, Lithium, Reserpine

Other AntiemeticsOndansetron, Granisetron, MetoclopramideAnticonvulsantsValproic Acid, CarbamazepineCAMGinseng

MAO = Monoamine Oxidase; SSRI = Selective Serotonin Reuptake Inhibitor; SNRI = Serotonin and Noradrenaline Reuptake Inhibitor; TCA = Tricyclic Antidepressant; CAM = Complimentary and Alternative Medicine

Part two of this article will appear in the May issue of Hot Spot.

6

Vol. 17, Issue 1, February 2015Founders: Dr. L. Andersson, Dr. C. Danjoux

Editor: Dr. E. Chow

Associate Editor: Dr. C. Danjoux

Consultant: Dr. S. Wong

Advisers: Dr. E. Barnes, Dr. R. Goldman, Ms. L. Holden, Dr. A. Husain, Dr. A. Sahgal, Dr. E. Szumacher, Dr. M. Tsao

Editorial and Financial Manager: Ms. S. Yuen

Odette Cancer Centre, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5 Tel: 416-480-4998, Fax: 416-480-6002 E-mail: stacy.yuen@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:

Astellas

AstraZeneca

Amgen

Bayer

Boehringer Ingelheim

Janssen Inc.

Kyphon

Lilly

Novartis

Pfizer

Purdue Pharma

Roche

Sanofi

Takeda

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

Continuing Medical Education (CME) can update health care 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 CME activities in palliative medicine that are of interest to our readers. Please forward details of the CME activities to: Ewa.Szumacher@sunnybrook.ca

• February 13–15, 2015. IAPCON 2015, 22nd International Conference of Indian Association of Palliative Care, Hyderabad, India.

• February 25–28, 2015. AAHPM & HPNA, Annual Assembly, Philadelphia, PA.

• February 26–28, 2015. Genitourinary Cancers, ASCO, Orlando, Florida, USA. http://gucasym.org/

• March 5–7, 2015. 16th World Congress of Pain Clinicians, Miami, Florida, USA.

• April 8–11, 2015. ADEC 37th Annual Conference (Association of Death Education and Counseling), San Antonio, Texas. http://www.adec.org/annual_conference_home.htm

• April 16–18, 2015. Champions Palliative Care, EAPC Palliative Course, Mondello Palace Hotel, Palermo, Italy. http://www.eapcnet.eu/linkClick.aspx?fileticket=b4DIK5DD1EA53d

• April 18–22, 2015. American Association for Cancer Research Annual Meeting 2015, Pennsylvania Convention Center, Philadelphia, PA, USA. http://www.aacr.org/Meetings/Pages/MeetingDetail.aspx?EventItemID=25#.U8AQM0P_BaQ

• April 30–May 3, 2015. Transforming Palliative Care, Asia Pacific Hospice Conference 2015, Taipei, Taiwan.

• May 8–10, 2015. EPAC 2015, 14th World Congress of the European Association of Palliative Care, Copenhagen, Denmark. http://www.eapc-2015.org/

• May 28–30, 2015. CSPCP – Canadian Society of Palliative Care Physicians, Calgary, Alberta. www.cspcp.ca/save-the-date-2015conference

• May 29–June 2, 2015. ASCO – American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, USA. ascoregistration@jspargo.com; http://am.asco.org/

• June 25–27, 2015. MASCC/ISOO 2015, Medical, Oncology, Health, Healthcare, Supportive Care In Cancer, Medicine, Cancer, Health Care, Copenhagen, Denmark. http://www.mascc.org

• September 9–12, 2015. CARO, Delta Grand Okanagan, Kelowna, BC

• October 18–21, 2015. ASTRO – 57 Annual Meeting, Henry B Gonzalez Convention Centre, San Antonio, Texas. www.astro.org Abstract submission deadline: Feb. 26/15

• Oct. 29–Nov. 1, 2015. The Canadian Hospice Palliative Care Conference, Ottawa Westin Hotel, Ottawa, On. www.conference.chpca.net

Continuing Medical Education 2015By Ewa Szumacher, MD, FRCP(C)

Supplement to Hot Spot, the newsletter of the Rapid Response Radiotherapy Program of the Odette Cancer Centre – February 2015

First line – HER2-positiveBackground• Thehumanepidermalgrowthfactorreceptor2(HER2)isover-expressedinupto25%ofgastriccancers.SomestudieshaveshownthatHER2over-expressionisassociatedwithpooroutcomesandaggres-sivedisease.

• TheseminalToGAtrialwasthefirstphaseIIItrialtoshowasurvivalbenefitwiththeadditionoftheanti-HER2monoclonalantibodytrastuzumab(Herceptin®)tofirst-linetherapyforadvancedHER2-positivegastriccancer.

• Theadditionoftrastuzumabtoachemo-therapybackbone(cisplatinpluseither5-FUorcapecitabine)improvedoverallsurvivalcomparedtochemotherapyalone(13.8versus11.1mos,HR0.74).PFSwasalsoimprovedfrom5.5to6.7months.

• InREAL-2,anotherlandmarktrialcom-paringdifferentchemotherapyregimensasfirst-linetherapy,thecombinationofepirubicin,oxaliplatin,andcapecitabine(EOX)achievedthebestsurvivalandwassuperiortotheECFreferenceregimen(11.2versus9.9,HR0.80,p=0.02).

New data•Gongetal.reportedasinglearmphaseIIstudyevaluatingtheuseoftrastu-zumabplusoxaliplatinandcapecitabine

asfirst-linetherapyforHER2-positiveadvancedgastric/GEjunctioncancer.

• 51patientswereenrolledandtreated.Oxaliplatinwasadministeredforamaxi-mumofsixcycles,whilecapecitabineandtrastuzumabwerecontinueduntilprogres-sionofdiseaseorintolerabletoxicity.

• PFSwas312days(10.4mos)andresponseratewas74%.

•Grade3-4toxicityobservedwascompa-rabletothatseenintheToGAtrial.LVEFdecreaseof≥10%wasseenin12%ofpatients,comparedwith5%intheToGAtrial.

Implications for practiceThesepreliminarydatasuggestthat

theadditionoftrastuzumabtooxaliplatinandcapecitabinerepresentsaviableandefficacioustherapy,althoughfinalsurvivaloutcomeisyettobereported.ThehigherratesofcardiacdysfunctioncomparedtothoseseenintheToGAtrialbearsfurtherscrutiny.

Second line – ChemotherapyBackground• Forpatientswithadvancedgastriccancerwhoinevitablyprogressonfirst-linetherapy,therehasbeennowidelyacceptedstandardsecond-linetherapy.

•Cytotoxicagentsthatpreviouslyhavedemonstratedefficacyinthesecond-linesettingincludeirinotecanandthetaxanes.

New dataDocetaxel monotherapy•Theefficacyofdocetaxelinthesec-ond-linesettingwasexaminedintheCOUGAR-02trial.Fordetal.recruited168patientswithadvancedadenocarci-nomaoftheesophagus,gastroesophageal

junction(GEJ),orstomachwhopro-gressedonorwithinsixmonthsoffirst-lineplatinum-fluoropyrimidinecombinationchemotherapy.Ofthesepatients,nearlyhalf(76/168)hadgastriccancerastheirprimarysiteofdisease.

• Patientswererandomizedtodocetaxelorbestsupportivecare(BSC).Docetaxelwasadministeredat75mg/m2everythreeweekstoamaximumofsixcycles.

•Atamedianfollow-upof12months,docetaxelledtoimprovementinoverallsurvival(5.2versus3.6months,HR0.67,p=0.01)comparedtobestsupportivecare.Theoutcomedidnotdiffersignificantlybyprimarysiteofdisease.

• Tumourresponserateswerelow,withonlyfourpatients(7%)inthedocetaxelgroupachievingapartialresponse.

•Docetaxelwasassociatedwithgreaternumberofinfections,aswellasneutrope-niaandfebrileneutropenia,butpatientsinthedocetaxelarmnonethelessreportedlesspain,nausea,andconstipation.Overallqualityoflifewasnotdifferentbetweenthearms.

Cisplatin plus irinotecan• SingleagentirinotecanhaspreviouslybeendemonstratedinmultiplephaseIIItrialstomodestlyimproveoverallsur-vivalcomparedtoBSC.Itwasunknownwhethertheadditionofasecondagentcouldfurtherimproveoutcomes.

•Higuchietal.randomized130patientswithadvancedgastriccancertoirinote-canwithorwithoutcisplatin.Patientshadpreviouslyprogressedonorwithinsixmonthsoffirst-lineS-1,afluoropy-rimidinewidelyusedinAsiaforgas-triccancer,butnotapprovedinNorthAmerica.

• Irinotecanmonotherapywasadministeredat150mg/m2onceeverytwoweeks,whileinthecombinationtherapyarmirinotecanwasdosedat60mg/m2andcisplatinwasdosedat30mg/m2,bothgivenonceeverytwoweeks.Treatmentwasadministereduntildiseaseprogression,unacceptabletoxicity,orwithdrawalofconsent.

• PFSwasimprovedwiththeadditionofcisplatintoirinotecan(3.8versus2.8mos,HR0.68,p=0.040),however,overallsurvivalwasnotsignificantlydifferentbetweentreatmentarms(10.7versus10.1mos,HR1.00,p=0.982).Tumourresponseratesbetweenarmswerealsosimilar(22versus16%,p=0.50).

• Severe(grade3-4)toxicitiesweresimilarinbotharms.Febrileneutropeniawasseeninthreepatients(5%)intheirinotecanmonotherapygrouponly.

Implications for practiceThesestudiesprovidephaseIIIdatain

supportofsystemicagentsthatareavail-ableinsecondtherapy.Todate,althoughdocetaxelimprovessurvival,ascomparedtobestsupportivecare,nocytotoxicagenthasclearlydemonstratedsuperiorityinoverallsurvivalorqualityoflifecomparedtoothercytotoxicagents.

Second line – Targeted therapyBackground•Ramucirumabisafullyhumanmonoclo-nalantibodytargetingvascularendothelialgrowthfactorreceptor2(VEGFR-2)

• Inpreclinicalandclinicalmodels,high-circulatingVEGFlevelsareasso-ciatedwithtumouraggressiveness,andVEGFR-2inhibitionleadstodecreasedtumourgrowthandvascularization.

New updates in the treatment of advanced gastric cancerBy Drs. Xiaofu Zhu, MD, FRCPC, and Yoo-Joung Ko, MD, MMSc, FRCPC, Division of Hematology/Medical Oncology, Sunnybrook Odette Cancer Centre, University of Toronto

Generously supported by an educational grant from Eli Lilly

Canada Inc.

Supplement to Hot Spot, the newsletter of the Rapid Response Radiotherapy Program of the Odette Cancer Centre – February 2015

• PrevioustrialsexploringtheefficacyofVEGFpathwayinhibitionusingtheVEGFinhibitorbevacizumabincombinationwithchemotherapyinthefirst-linesettingdidnotdemonstrateimprovementinsurvival.

New dataRamucirumab• Fuchsetal.conductedaphaseIIItrial(REGARD)randomizing355patientswithadvancedadenocarcinomaofthestomach(75%)orGEJ(25%)toramucirumaborplacebo.Patientshadpreviouslypro-gressedwithinfourmonthsofplatinumorfluoropyrimidine-containingfirst-linetherapyforadvanceddiseaseorwithinsixmonthsofadjuvanttherapyforresectabledisease.

• Patientsreceivedbestsupportivecarepluseitherramucirumab8mg/kgorplacebointravenouslyonceeverytwoweeks.Treatmentwascontinueduntildiseasepro-gression,unacceptabletoxicity,ordeath.

•Overallsurvivalwasimprovedwithramu-cirumabcomparedtoplacebo(5.2versus3.8mos,HR0.78,p=0.047).

• PFSwasimprovedfrom1.3to2.1mos.Tumourresponserateswereapproxi-mately3%forbotharms.EfficacydataarepresentedinTable1.

•Highergrade3hypertensionwasseenwithramucirumabbut,overall,bothgroupshadsimilarratesofgrade3–4toxicity.

•Althoughmorepatientsinramucirumabarmreportedstableorimprovedglobalqualityoflife,thedifferencewasnotsignificant(p=0.23).

Ramucirumab plus paclitaxel•Wilkeetal.alsoexaminedtheefficacyoframucirumabbycomparingthecombi-nationofweeklypaclitaxelplusramu-cirumabwithpaclitaxelaloneinthephaseIIIRAINBOWtrial.

• 665patientswithadvancedadenocar-cinomaofthestomach(80%)orGEJ(20%)whoprogressedwithinfourmonthsoffirst-lineplatinumandfluoropyrimi-dine-basedtherapywererandomizedtopaclitaxelwithorwithoutramucirumab.

• Patientsreceivedpaclitaxel80mg/m2ondaysone,eight,and15,ora28-daycyclepluseitherramucirumab8mg/kgorplaceboondaysoneand15.Treatmentwascontinueduntildiseaseprogression,unacceptabletoxicity,ordeath.

•Overallsurvivalwassignificantlyimprovedwithdoublettherapycomparedwithpaclitaxelalone(9.6versus7.4mos,HR0.81,p=0.017).

• PFSwasimprovedwithcombinationther-apy(4.4versus2.9mos,HR0.64),aswasresponserate(28versus16%).EfficacydataarepresentedinTable2.

•Ramucirumabandpaclitaxelwereassoci-atedwithhighergrade3–4toxicity,includ-ingneutropenia,leucopenia,hypertension,abdominalpain,andfatigue.

•Nosignificantdifferencesinqualityoflifemeasurementswereseenbetweengroups.

Implications for practiceRamucirumabisthefirsttargetedtherapy

toofferimprovementinoverallsurvivalforpatientsbeingtreatedinthesecond-linesetting,whetheradministeredasmonother-apyoraddedtopaclitaxel.Additionally,thecombinationoframuciruabpluspaclitaxelisthefirstregimentodemonstratesurvivalbenefitagainstacytotoxicagentinthissetting.Toxicityappearedmanageable,withonlyhypertensionbeingthemostsignif-icantVEGFinhibition-relatedtoxicity.RamucirumabhasbeenapprovedbytheFederalDrugAdministrationintheUnitedStatesbothasmonotherapyandincombi-nationwithweeklypaclitaxelassecond-linetherapy.Thisagentwilllikelygraduallycomeintouseandformthebasisforfuturecomparativestudies,aswellasbeingtestedinthefirst-linemetastaticsetting.

Third lineBackground•Dataarescarceregardingoptimaltherapyforpatientswhohaveprogressedontwopreviouslinesoftreatment.

• Publishedcaseserieshavesuggestedthatinhighlyselectedpatients,chemotherapyagentssuchasdocetaxelmaybefeasiblyadministered.

•ApatinibisasmallmoleculetyrosinekinaseinhibitortargetedagainstVEGFR-2.ApreviousmulticentrephaseIItrialhaddemonstratedimprovementinsurvivalagainstplaceboforpatientswhohadfailedtwoormorelinesoftherapy.

New data•Qinetal.conductedaphaseIIItrialcom-paringapatinibagainstplaceboforpatientswhohavefailedtwopreviouslinesoftherapy.

• 270patientswererandomizedina2:1fashiontoapatinibversusplacebo.

•Apatinibsignificantlyimprovedoverallsurvivalcomparedtoplacebo(195versus140days,HR0.71).

• PFSwasimproved,aswell(78versus53days,HR0.44).Responserateswereminimal(2.8%).

•Mostcommongrade3–4toxicitieswerehypertension,hand-footsyndrome,pro-teinuria,fatigue,anorexia,andelevatedliverenzymes.

Implications for practiceThisisthefirstphaseIIItrialdemonstrat-

ingprolongationofsurvivalwithsystemictherapyinthethird-linesetting.Althoughthemagnitudeofimprovementwasclin-icallymodest(<2mos),itwassimilartoresultsfromrecentlycompletedsecond-linestudies.Iffoundtobecosteffective,apati-nibmaybecomeastandardthird-linether-apeuticoptionforpatientswithadvancedrefractorygastriccancer.

REFERENCESReferences available upon request

Table 1: Efficacy of ramucirumab vs placebo from REGARD trial

Ram Placebo

Median OS (mos) 5.2 3.8p=0.0470

6-mo OS 42% 32%

12-mo OS 18% 12%

Median PFS (mos) 2.1 1.3p<0.0001

12-wk PFS 40% 16%

Response rate 3% 3%p not reported

Disease control rate

49% 23%p<0.0001

Table 2: Efficacy of ramucirumab and pacli-taxel vs placebo and paclitaxel from RAINBOW trial

Ram + Paclitaxel

Placebo+ Paclitaxel

Median OS (mos) 9.6 7.4p=0.0169

6-mo OS 72% 57%

12-mo OS 40% 30%

Median PFS (mos) 4.4 2.9p<0.0001

6-mo PFS 36% 17%

9-mo PFS 22% 10%

Response rate 28% 16%p=0.0001

Disease control rate 80% 64%p<0.0001

Supplement to Hot Spot, the newsletter of the Rapid Response Radiotherapy Program of the Odette Cancer Centre – February 2015

Latest update in MASCC/ESMO Antiemetic GuidelinesBy Drs. Carlo DeAngelis, PharmD, Clinician Scientist—Oncology Pharmacy Department of Pharmacy, Sunnybrook Odette Cancer Centre, and Edward Chow, MBBS, MSc, PhD, FRCPC, Professor, Department of Radiation Oncology, Sunnybrook Odette Cancer Centre

Generously supported by an educational grant from Takeda

Supplement to Hot Spot, the newsletter of the Rapid Response Radiotherapy Program of the Odette Cancer Centre – February 2015

Ondansetron also available in rapidly dissolving film (RDF)—Ondissolve