Supplement to Hot Spot, the newsletter of the Rapid Response Radiotherapy Program of the Odette Cancer Centre – August 2012

Metastatic breast cancerWe have seen an overall improvement

in outcome of patients with breast cancer with a reduction in mortality in the range of 30% to 40% over the last two decades. This has been mostly due to effective screening strategies and improved adjuvant therapy for breast cancer patients. The survival of patients with metastatic disease has not improved significantly and the median sur-vival is generally around 26 to 28 months.

The overall aim of systemic treatment for patients with metastatic breast cancer is:1. Improve/maintain quality of life2. Decrease in symptoms 3. Improved/prolongation of survival.

Tumour biology and need for re-biopsy

There are three key subtypes of breast cancer:• Hormone receptor positive breast cancer

~ 60%–70% of all breast cancer• Her 2 receptor positive breast cancer

~ 15%–20% of all breast cancer• Triple negative breast cancer ~ 15% of all

breast cancer

Over the last few years there has been an increased understanding of tumour subtypes and intra-tumour heterogeneity. One key area of research has focused on the change in receptor profile between the early stage breast cancer pathology and metastatic lesion. Studies have suggested that the receptor dis-cordance is seen in up to 30% of cases, with the most frequent change seen in hormone receptor profile, changing from positive to negative status in the metastatic setting.

The biopsy of metastatic disease should be considered if there is:• Solitary metastasis• Unusual clinical course of disease • Confirm primary/evidence of metastatic

disease• Research studies.

Factors to consider when selecting appropriate systemic treatment

There are a number of factors to consider when selecting the right systemic treatment for patients presenting with metastatic disease:

Tumour factors• Receptor profile• Burden of disease including number of

metastatic sites• Visceral vs. non-visceral disease• Symptomatic vs. asymptomatic disease

Patient factors• Relevant co-morbidities• Patient support structure• Performance status• Patient goals of care• Patient preference

Treatment-related factors• Prior adjuvant treatment• Toxicity related to previous treatment• Disease-free interval • Funding including private drug plan coverage

The focus of this article is specifically on the management of Hormone receptor positive and Her 2 receptor negative breast cancer subtype.

Anti-estrogen treatment optionsAn anti-estrogen treatment is generally

selected in the first-line setting for patients who have HR positive metastatic disease and are not in visceral crisis requiring immediate response to therapy. There are a number of available treatment options for patients in a metastatic setting.

Selective estrogen receptor modulators (SERMs)TamoxifenAdvantages• Has been the mainstay in the management

of HR+ve MBC• Generally efficacious and very well tolerated • Response rate in the range of 50% in first-

line setting • Can be used in pre and postmenopausal

patients

Disadvantages• Extensively used in the adjuvant setting

and limited data on re-challenge after patients relapse after completion of adju-vant tam

• Increased risk of thromboembolic dis-ease—a concern in the metastatic setting

Aromatase inhibitorsNon-steroidal aromatase inhibitors (Letrozole and Anastrozole)Advantages• Superior to Tamoxifen in the first-line MBC

setting with improved time to progression• Now the mainstay as first-line agent for

MBC patients• No significant increase in risk of thrombo-

embolic disease

Hormone receptor positive metastatic breast cancerBy Dr. Sunil Verma, MD, MSc, FRCPC, Associate Professor, Division of Medical Oncology, Department of Medicine, University of Toronto; Staff Medical Oncologist, Sunnybrook Odette Cancer Centre

Generously supported by an educational grant from AstraZeneca Canada Inc.

Disadvantages• Should only be used in the postmeno-

pausal setting• Increased use in the adjuvant setting and

may not be used in first-line setting if patients progressed while on adjuvant AI or short DFI (< 6 months) after comple-tion of adjuvant AI therapy

Steroidal (Exemestane)Advantages• Patients can achieve a clinical benefit rate

in the range of 25% even after progres-sion on NSAI

• Well tolerated with favourable toxicity profile

Disadvantages• Unlikely to be effective if patients have

not responded to first-line or second-line anti-estrogen strategies

Selective estrogen receptor downregulator (SERD)FulvestrantAdvantages• May be more effective than AIs in the

first-line setting (FIRST study) either alone or in combination with an AI (SWOG0226)

• We finally have a confirmed dose 500 mg IM day 0,14,28 and then monthly—shown to be superior to the 250 mg dose (CONFRIM trial)

• Considered now in earlier line of therapy as many patients have had prior adjuvant tamoxifen and aromatase inhibitors

• Well tolerated• Improved compliance as monitored

therapy

Supplement to Hot Spot, the newsletter of the Rapid Response Radiotherapy Program of the Odette Cancer Centre – August 2012

Disadvantages• Requires an IM injection, which can be

nuisance for some patients• Limited government funding—covered by

most private drug plans• Limited evidence in premenopausal patients

Novel targeted agents to help overcome endocrine resistance mTOR inhibitors – Everolimus• Recent data (BOLERO-2) study suggest

that patients receiving Everolimus and Exemestane had a superior RR, PFS (7m vs. 3m) compared with Exemestane alone

Advantages• Oral approach • Can help improve PFS and delay time to

initiation of chemotherapy• An ideal treatment for patients who may

have endocrine resistance—i.e., progres-sion of disease while on adjuvant AI or short PFS or no response to anti-estrogen approach in metastatic setting

Disadvantages• Toxicity profile—significant risk of stoma-

titis (Grade 3 rate of 8%)• Lack of experience by breast cancer

physicians

Please note that Everolimus is not yet approved for breast cancer indication and we need this approval prior to consideration of this agent in routine practice.

Main conclusionThere are now a number of effective treat-

ment options for patients with HR positive MBC. One needs to consider relevant factors and response to prior therapy to help select the ideal treatment strategy for patients.

Our goal is to maintain and improve patient’s quality of life by selecting the ideal treatment strategy that would decrease patient symptom burden and delay the need for chemotherapy. Patients should be encouraged to participate in clinical trials to help advance our understanding of this disease and improve the therapeutic options for patients.

1ST

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Supplement to Hot Spot, the newsletter of the Rapid Response Radiotherapy Program of the Odette Cancer Centre – August 2012

Background• Cancer patients in Canada are living lon-

ger. The five-year relative survival for all cancers combined is 62%. Even those who succumb to their disease live longer.

• One-third of cancer patients suffer from pain during disease-modifying treatment and more than two-thirds of patients suffer from pain in advanced stages of cancer

• About one-third of cancer survivors suffer from chronic cancer treatment-related pain after curative treatment

• Pain in cancer and cancer survivors is still frequently undertreated

• Opioids may be useful analgesics in cancer patients in the context of a multidimen-sional bio/psycho/social/spiritual approach to pain management

• Despite their proven analgesic efficacy, opioids are associated with adverse effects, medical complications and risks

• There are increasing concerns about the misuse, abuse and diversion of opioid analgesics

• In the U.S., more than 70% of people who use opioids non-medically obtain them from friends or relatives (provided free, bought or stolen)

• Most health care professionals (HCPs), including oncologists, radiation oncolo-gists, oncology nurses, palliative care physicians, other cancer specialists and family doctors, have been inadequately trained in appropriate risk assessment and risk management with respect to opioids

• Everyone has a role to play in the respon-sible use and prescribing of opioids

The population of licit opioid-treated cancer patients is heterogeneous

• The majority of cancer patients treated with opioids are adherent to their treatment regimen

• Chemical coping (Bruera, Passik)—mal-adaptive use of opioids (and other substances) to self-treat emotional distress (depression, anxiety, stress, worry, fear…) is common in the cancer population (11% to 28%)

• Opioid misuse and substance abuse in gen-eral are growing problems among cancer patients

• A cancer diagnosis does not protect against addiction/substance use disorder (SUD)

How can we identify and reduce the risk of misuse, abuse and diversion of opioids while optimizing pain management for those who need it?• Cancer patients and their families need

to be screened for opioid misuse/abuse potential. This is important even in the end-of-life setting; diversion of opioids by families and friends is always a concern

• Screen for chemical coping and emotional distress/mental health issues; treat appro-priately with non-pharmacological and/or appropriate pharmacological means

• A thoughtful risk-benefit calculation should be done for each patient for each and every treatment modality

• “Universal Precautions” (Gourlay, Heit) should be applied to all patients trialed on opioid therapy

• Strategies and tools from chronic non-cancer pain (CNCP) management can be adapted for use in the cancer setting

• The Canadian Guideline for Safe and Effective Use of Opioids for Chronic Non-Cancer Pain1 is available at: http://nationalpaincentre.mcmaster.ca/opioid

Risk assessment and risk stratification• Key questions are: Is the patient

likely to be a reliable drug taker? AND Is the family likely to reliably manage opioids in the home?

• Need insight into: current/past sub-stance abuse (alcohol, illegal drugs, prescription drugs, smoking), psycho-logical/mental health/social issues, chemical coping, history of physical/sexual abuse or PTSD, age…

Validated screening tools from CNCP guidelines may be helpful (e.g., ORT, SOAPP®, COMM®)1 to assess which patients may be at risk for developing aber-rant drug-related behaviours in the future, and to risk stratify patients as low, moderate, high risk (Figure 1).• Risk stratification in cancer pain manage-

ment needs to also address the patient’s current/changeable disease state (e.g., chronic condition vs. disabling/rapidly progressive disease)

• Remember risk can change over time

M.D. Anderson Cancer Center (Texas) has reviewed 524 charts with completed SOAPP® data. They found: 29% of cancer patients were “high risk”.

Evolving issues in the use and prescribing of opioids for cancer painBy Erica L. Weinberg, BSc, MSc, MPhil, MD, MCFP, General Practitioner practising in palliative care and pain management, Rouge Valley Health System, Toronto, ON

Generously supported by an educational grant from

Purdue Pharma

Adherent Chemical copers

Substance abusers

Addicted (SUD)

Figure 1: ORT (Opioid Risk Tool) by Lynn R. Webster, MD

Patient spectrum of behaviours (Passik)

Supplement to Hot Spot, the newsletter of the Rapid Response Radiotherapy Program of the Odette Cancer Centre – August 2012

Risk management• Should include collaboration and commu-

nication between the patient (and family), a single prescribing physician and dispens-ing pharmacy, and all the members of the “circle of care” team

• Patients (and families) must clearly under-stand and be educated on their role and their responsibility in the safe and effec-tive use of opioids, including Prescribing Ground Rules (Table 1)

• Monitoring by level of risk in cancer pain management must also acknowledge the patient’s disease state (Figure 2)

• For patients at increased risk for opioid misuse/abuse choose opioids/opioid for-mulations wisely for both background and breakthrough pain, increase frequency of contact/visits, ensure incorporation of risk management strategies (below) and poten-tially use third parties to control opioids. Concurrent/collaborative psychosocial and mental health care is optimal

Useful strategies for risk management of all patients on opioids from CNCP guidelines include:Informed consent: goal setting (including potential benefits and expectations), adverse effects, medical complications and risks

Treatment agreements: oral or written

Table 2: Urine drug screening (UDS)

• Use it• Determine what your lab measures/what abnormal results may mean1

• Start acting on inappropriate results in a non-judgmental way1

6 A’s of follow-up documentation for patients on opioids

• Analgesia (pain relief)• Activities of daily living (physical and psychosocial function)• Adverse effects (and suggested remedies)• Ambiguous drug-taking behaviours (and your response)• Accurate medication record• Affect

Table 1: Prescribing ground rules

• Patient and/or family take(s) a reliable and active role in treatment management • Need for freedom of information; consent to all required compliance monitoring

procedures• Safe storage of opioids—locked• No sharing of opioids• Appropriate disposal of opioids• No driving/operating heavy machinery if sedated• No use of alcohol/sedating medications while on opioids without consent of prescribing

HCP• Never take more than the prescribed dose of opioid without approval of prescribing HCP• Do not use opioids to facilitate sleep or to treat emotional distress• One prescriber• One dispensing pharmacy

Figure 2: Patient monitoring by level of risk

Structured opioid therapy: frequent dispensing (small number of pills/patches dispensed per interval), and reassessment and monitoring at regular intervals accord-ing to level of risk

Compliance monitoring: use of drug information/drug monitoring systems or prescription review/prescription monitor-ing/triplicate prescription programs (where available), scheduled &/or random Urine Drug Screening (UDS),1 pill/patch counts and 6 A’s of follow-up documentation/monitoring (Table 2).

M.D. Anderson Cancer Center utilizes strat-egies and tools such as: screening, informed consent, written treatment agreements, UDS, pill boxes and pill counts, frequent outpa-tient visits, documentation and ongoing psychiatric care for cancer patients treated with opioids

Using technology to improve patient care• Electronic medical records, decision sup-

port tools, e-prescribing, drug information/drug monitoring systems or prescription review/prescription monitoring/triplicate prescription programs, and electronic health records all may have incremental benefits

• Abuse-deterrent and/or abuse-resistant opioid formulations may be of benefit

• Pill boxes, including those that may be pre-programmed by HCPs, may be of benefit

Using collaboration to improve patient care• Educate patients regarding disclosure of

their personal health information within their “circle of care”

• Involve families/caregivers to assess comfort, function and possible overuse of medication

• Pharmacists can: alert physicians if opioid misuse or double-doctoring is suspected,

suggest partial fill prescriptions for patients having difficulty with control and facilitate appropriate counselling to patients

• Multimodal and interprofessional pain management is optimal

Everyone has a role to play in the responsible use and prescribing of opioids—Let’s ALL do our part

Reference1. National Opioid Use Guideline Group.

(2010). Canadian Guideline for Safe and Effective Use of Opioids for Chronic Non-Cancer Pain. Retrieved from http://nationalpaincentre.mcmaster.ca/opioid

Lower Risk Moderate Risk Higher Risk

• Pain relief satisfaction

• Mental clarity satisfaction

• Diversion

• Mental health changes

• Level of stress• Disease

progression• Involve family and

friends to assess comfort, function, possible overuse

• Frequent visits/contact

• Choice of drug influenced by disease state

• Use of third party to control opiods with greater abuse potential

Webster and Dove. (2007). Avoiding opioid abuse while managing pain. A guide for Practitioners.

ORT score 0–3 ORT score 4–7 ORT score ≥ 8