Contents I. Bone Metastasis in Breast Cancer II. Process III. Complication IV. Imaging modality V. Treatment

Management of metastatic, recurrent and intractable breast cancer Nursing Care in Bone Metastasis Ewha Womans University Mokdong Hospital Ewha Womans University Cancer Canter For Woman Breast & Thyroid Cancer Center Hyejin Cho, RN, OCN.

Bone Metastasis in Cancer I. Bone Metastasis in Breast Cancer 100 80 60 40 20 Incidence(%) Median Survival(months) 5yr Survival(%) 0 Myeloma Breast Prostate Lung Kidney Melanoma Coleman, R. E. (1997).

I. Bone Metastasis in Breast Cancer Bone Metastasis in Breast Cancer Bone is one of the earliest and most common sites of breast cancer metastasis. [Singletary, S. E(2003)] Between 30-85% of patients with metastatic breast cancer will develop bone metastases during the course of the disease. [Vassiliou, V (2013)] Median survival for bone only metastasis was 24-48months. [Solomayer, E.(2000)] As high as 72months in one study [Briasoulis, E(2004)] Median survival for Visceral metastasis was 12months [Solomayer, E.(2000)] 5-year Survival rate was 39% [Dürr, H. R(2002)] The Nursing needs to focus on Quality of Life

I. Bone Metastasis in Breast Cancer Incidence of Bone Metastasis Axial skeleton >> extremities Vertebrae > Pelvis > Ribs > Skull > Femur Galasko, C. S. (1972).

Contents I. Bone Metastasis in Breast Cancer II. Process III. Complication IV. Imaging modality V. Treatment

Bone remodeling process II. Process

II. Process Process of Bone Metastasis Mundy, G. R. (2002).

Vicious cycle of Osteolytic Bone Metastasis II. Process RANKL : Receptor Activator of Nuclear Factor Kappa B Ligand RANK von Moos, R., & Haynes, I. (2013)

II. Process Type of Bone Metastasis Osteolytic metastasis Breaking down old bone without making new bone weaken the bones easily break Breast cancer Detected on X-ray (after 3wks, except spine) https://www.cancer.org/ Osteoblastic metastasis Making new bone without breaking down old born the bone harder (sclerosis) easily break Prostate cancer Not detected on X-ray Bone scan

Contents I. Bone Metastasis in Breast Cancer II. Process III. Complication IV. Imaging modality V. Treatment

III. Complication Complication of Bone metastasis Pain SREs (Skeletal-Related Events) Pathologic Fracture Radiation Therapy Surgical intervention Spinal cord compression Hypercalcemia NCCN Guideline Version 2.2016

III. Complication Pain associated Bone metastasis The hallmark symptom of bone metastasis Character of bone pain on metastasis Dull aching pain Usually develops gradually Increasing at night Increasing in weight bearing Monczewski, L. (2013).

III. Complication Pain assessment Parameters Physical Onset - Acute, chronic, Breakthrough Location Duration Type of pain - sharp, dull, etc. Aggravating factors and Relieving factors Treatment Psychological History of anxiety, depression or other illness Cognition Usual coping strategies Psychological responses Social Interferenece of pain with activities of daily living Family communication and response to illness and support system Spiritual Presence of a spiritual community and belief Itano, J. K., Brant, J., Conde, F., & Saria, M. (2015)

III. Complication Pain management Diffused pain Analgesics : WHO Pain Ladder Adjuvant agent of Bone metastasis : Bisphosphonate, steroid, etc. Radiopharmaceutical (Strontium-89 chloride : Metastron) Localized pain External Beam Radiation Therapy Nerve Block Vassiliou, V., Chow, E., & Kardamakis, D. (Eds.). (2013)

III. Complication Pain management Education Reporting New or worsening signs and symptom (pain, neurologic change) Keeping a Diary of pain score or other adverse event Emotional Support Depression Anxiety Monczewski, L. (2013).

III. Complication SREs (Skeletal-Related Events) Pathologic Fracture Radiation Therapy to Bone Surgery to Bone Spinal Cord Compression Hypercalcemia Consequences SREs decrease patients functional independence and thus limit their autonomy SREs are associated with increases in

III. Complication Pathologic Fracture 9-29% of patients with bone metastasis Fractures have been associated with decreased survival. Symptom Sudden Onset of sharp bone pain Nerve involvement Radiated pain Most frequent site : Long bone Intervention : Surgery Patient Education : High risk for injury Call light in reach, Well-lit environment Bed in a low position Use of handrail while ambulating Non-slip footwear Removal throw rugs and cords from floor area Monczewski, L. (2013).

III. Complication Spinal Cord Compression Oncologic Emergency 5% of all patient with cancer Early sign Pain : local, radicular or both Motor weakness or dysfunction, Sensory loss Late sign Loss of sensation for deep pressure, vibrations, position Incontinence or retention of urine or stool Sexual impotence Paralysis, Muscle atrophy Loss of sweating below lesion Intervention : Steroid Surgery ± Radiation Therapy Patient Education Possibility of SCC, Early sign & Late sign Itano, J. K., Brant, J., Conde, F., & Saria, M. (2015).

III. Complication Hypercalcemia Oncologic Emergency 5% of all patient with cancer 80% Parathyroid hormone released protein produced by solid tumor 20% Local Osteolytic hypercalcemia Serum Total Calcium Range Mild 10.5-11.5mg/dL Moderat 11.5 - e 13.5mg/dL Intervention Symptoms Anorexia, Lethargy, Urinary frequency, Orthostatic hypotension Constipation, Weakness, Dehydration, Arrhythmia Severe >13.5mg/dL Ileus, Seizure, Renal failure, Arrest Massive N/S hydration & loop diuretic Bisphosphonate or Denosumab Itano, J. K., Brant, J., Conde, F., & Saria, M. (2015).

Contents I. Bone Metastasis in Breast Cancer II. Process III. Complication IV. Imaging modality V. Treatment

IV. Imaging modality Optimal imaging Modality Skeletal Scintigraphy (Bone scan) X-ray CT (Computed Tomography) MRI (Magnetic Resonance Imaging) PET (Positron Emission Tomography) Purpose Diagnosis Check the response of treatment J Clin Oncol 2004 by ASCO

IV. Imaging modality Skeletal Scintigraphy (Bone scan) Most common modality for Detecting bone metastasis Uses of Radiopharmaceuticals reflects bone metabolism Appearance ; Hot spot Sensitivity ; Varies (62-100%) Advantage ; Produce Whole body image at a reasonable cost Disadvantage ; Low specificity, Flare phenomenon Preferred Sites ; Appendicular bone J Clin Oncol 2004 by ASCO Active bone lesion in the sternum, L1, L4, sacrum. multiple bony metastases.

IV. Imaging modality X-ray Appearance Osteolytic lesion ; Faint or Absent density Osteoblastic lesion ; Sclerotic lesions or rims Sensitivity ; Low (44-50%) Advantage Demonstrates structural changes of bone Assesses risk of pathologic fracture No need for contrast injection Less expensive Disadvantage Delayed appearance of response J Clin Oncol 2004 by ASCO Suspicious osteoblastic lesion, L1 -r/o bone metastasis

IV. Imaging modality CT (Computed Tomography) Appearance Lytic, sclerotic, mixed for bone, Higher attenuation for marrow Sensitivity ; High (71-100%) Advantage Higher specificity than Bone scan and X-ray Evaluates cortical and cancerous bone and calcifications more accurately than MRI Disadvantage Local images Preferred Sites ; Axial skeleton J Clin Oncol 2004 by ASCO bony metastasis at L1

IV. Imaging modality MRI (Magnetic Resonance Imaging) Appearance ; Lower or higher intensity Sensitivity ; High (82-100%) Advantage Higher specificity than Bone scan and X-ray Evaluates spinal cord compression and soft tissue more accurately than CT No ionizing radiation Disadvantage Poor cortical bone detail Expensive J Clin Oncol 2004 by ASCO

IV. Imaging modality PET (Positron Emission Tomography) Appearance ; Hot spot Sensitivity ; Varies (62-100%) Advantage ; Detects new marrow lesions Disadvantage Not specific to bone False-positives after G-CSF Very Expensive Preferred Sites ; Bone marrow Newly HM bone lesions in L1, L4, sacrum HM bone lesion in sternum. J Clin Oncol 2004 by ASCO

Contents I. Bone Metastasis in Breast Cancer II. Process III. Complication IV. Imaging modality V. Treatment

Treatment in Bone Metastasis 1) Endocrine Therapy 2) Chemotherapy 3) Radiation therapy 4) Surgical Intervention 5) Bone modifying agent

Endocrine Therapy & Chemotherapy V. Treatment 한국유방암학회제 6 차진료권고안 한국유방암학회제 6 차진료권고안 Compliance of treatment

V. Treatment Radiation therapy Purpose Pain relief (the Best method : response rate 80-90%) Local control Dose 30Gy in 10 fraction 8Gy in 1 fraction Side effect Fatigue Nausea, anorexia Skin irradiation Low blood count Diarrhea( in case of pelvic area radiation) ASTRO Guideline (2017)

V. Treatment Surgical Intervention Purpose Prevent pathologic fracture Treat an actual fracture Stabilize the spine Monczewski, L. (2013)

V. Treatment Indication Bone modifying agent 한국유방암학회제 6 차진료권고안

V. Treatment Bone modifying agent Bisphosphonate Pamidronate 90mg IV over 2hours q 3-4weeks Zoledronic acid 4mg IV over 15minutes q 3-4weeks Denosumab 120mg SC q 4weeks Dose adjustment for saving renal function Adherence to dosing time and interval ASCO Guideline 2011

건강보험심사평가원의급여기준 V. Treatment

V. Treatment 건강보험심사평가원의급여기준 가. 악성종양으로인한과칼슘혈증 : albumin-corrected calcium 13mg/ dl이상인경우에 1차적으로투여시인정하고, 12mg/ dl이상 13mg/ dl미만인경우에는 1차적으로 pamidronate 제제투여후재차투여하는경우에한하여인정나. 다발골수종의골병변또는유방암, 전립선암의골전이에표준항암요법과연계하여투여시다음과같이인정함 -다음- (1) 투여조건단순방사선검사 (plain X-ray) 상 lytic 소견을보이는경우, 또는 X-ray 상정상이나 CT 또는 MRI로골파괴가명확히입증된경우에인정함. 단, bone scan만으로이상소견이확인된경우는인정하지아니함 (2) 표준항암요법의범위및연계투여의범주항암제또는호르몬제치료가해당되며, 항암제또는호르몬제를치료중인경우에인정하되, 최근 4 주이내에적절한항암제또는호르몬제가투여된경우에인정함 ( 항암제치료 cycle 중휴약기간등은사례별적용 ) - 다만, 호르몬수치조절목적으로수술 ( 전립선암의경우고환적출술, 유방암의경우난소적출술 ) 을실시한경우에는호르몬제치료로간주함 - 항암제및호르몬제치료에실패한환자에서 weight-bearing bone의전이등으로방사선치료를시행하는경우 zoledronic acid 주사제사용을인정함

V. Treatment 건강보험심사평가원의급여기준 (3) 암종별적용기준 전립선암 : 허가사항 ( 최소 1회이상호르몬치료후병이진전된경우에사용 ) 범위내에서필요ᆞ 적절하게투여시인정함 유방암 : 허가사항범위내에서필요ᆞ적절하게투여시인정함 다발골수종 : pamidronate 제제사용후반응이없는경우에한하여인정함 (4) 투여중지기준동약제투여기간중매 3개월마다단순방사선검사 (plain X-ray) 등으로골병변또는골전이에대한평가를실시하여새로운골관련합병증 (SRE, skeletal-related events) 이발생한경우에는투약을중단토록하되, 중지의기준이되는 SRE의범주는다음과같음 - Pathologic fracture( 병적골절 ) - Surgery to bone( 뼈수술 ) - Hypercalcemia of malignancy( 새로발생한고칼슘혈증 ) 허가사항범위이지만상기인정기준이외에투여하는경우의비용부담은보건복지부고시 개정제2016-263호 :2016.12.28 에따라약값전액을본인이부담토록함

Bone modifying agent Bisphosphonate V. Treatment Mechanism Inhibition of osteoclast activity Promote osteoclast apoptosis Slow down the action of osteoclast http://www.nature.com

Bone modifying agent Bisphosphonate V. Treatment Relative Potency =1,000,000 Coleman, R. E. (2001).

Bone modifying agent Denosumab V. Treatment Fully human monoclonal antibody against RANKL Action RANKL : Receptor Activator of Nuclear Factor Kappa B Ligand RANK Denosumab von Moos, R., & Haynes, I. (2013)

V. Treatment Bone modifying agent Effect Reducing bone pain Slowing down bone damage caused by the cancer Lowering the risk of broken bones Reducing high blood calcium levels Improved Quality of life & Overall survival Monczewski, L. (2013) https://www.cancer.org

V. Treatment Bone modifying agent Side effect Acute-phase reaction (Denosumab < Bisphosphonate) Including Flu-like symptom and increasing bone pain During the first 3 days following initial therapy & Self limiting Relief by NSAIDs and Antipyretics(Acetaminophen) Renal toxicity : serum creatinine level check (Creatinine Clearance >60mL/min) Hypocalcemia (Denosumab > Bisphosphonate) Incidence : 5% With Vitamin D, Calcium Creatinine clearance <30mL/min or on dialysis close monitoring for hypocalcemia ONJ Osteonecrosis of the jaw (Denosumab NCCN Guideline Version 2.2016, Monczewski, L. (2013) Bi h h t )

V. Treatment ONJ (Osteonecrosis of the jaw) Uncommon but potentially serious condition (Incidence 5.48%) Definition An area of exposed bone in the maxillofacial or mandibular region that does not heal within 8 weeks after identification by a health care provider Patient who was receiving or had been exposed to a bisphosphonate administered orally or IV Patient who had not had radiation therapy to the craniofacial region NCCN Guideline Version 2.2016, ASCO Guideline 2011

V. Treatment ONJ (Osteonecrosis of the jaw) Risk factor IV bisphosphonate (zoledronic acid) Duration exposure (longer) Cumulative dose of drug Inflammatory condition Osteomyelitis of the jaw Invasive dental procedure Education Dental examination with preventive dentistry prior to initiation of bisphosphonate therapy Maintain optimal oral hygiene - Including brushing and flossing after meals and use of a fluoride mouth rinse Avoid invasive dental procedures that involve manipulation of the NCCN Guideline Version 2.2016 jaw bone or periosteum

Summary Bone is the most common site of breast cancer. The survival of bone metastasis in breast cancer is relatively long. The complications of bone metastasis are Pain, Pathologic fracture, Radiation therapy, Surgical intervention, Spinal cord compression and Hypercalcemia. Treatments are Endocrine Tx, CTx, RTx, OP and the Bone modifying agents. Adverse events of the bone modifying agents are acute phase reaction, renal toxicity, hypocalcemia and osteonecrosis of the jaw.

Take Home message Skillful Assessment Prompt recognition of complication & prevent complications Knowledge of the treatment plan Implementing interventions & promote positive outcomes Emotional support of Phychosocial distress (especially depression and axiety) The nurse will help patients throughout their cancer journey and maintain the highest quality of life.

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