Secondary Cancers: Education, Postgraduate Healthcare What the Pharmacist Education, Inc • Dr

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Faculty Disclosures Patient Safety • Dr. Holle is a consultant for McGraw Hill Secondary Cancers: Education, Postgraduate Healthcare What the Pharmacist Education, Inc • Dr. Holle has received honoraria for continuing Needs to Know education program development from: AXIS Medical Education; Hematology/Oncology Lisa Holle, PharmD, BCOP, FHOPA, FISOPP Pharmacy Association; HMP CME; Pharmacy Associate Clinical Professor UConn School of Pharmacy & School of Medicine Times Continuing Education; and Postgraduate UConn Health Neag Cancer Center Healthcare Education, Inc [email protected] 860‐679‐5195

Off‐Label Information Learning Objectives At the completion of this activity, the participant • This activity may contain discussion of will be able to: unlabeled/unapproved use of drugs. • Identify risk factors for developing secondary • The content and views presented in this cancers educational program are those of the faculty and • Differentiate treatment options for secondary do not necessarily represent those of YNHH or cancers from those of primary cancers at the University of Connecticut School of Pharmacy. same site Please refer to the official prescribing information • Demonstrate pharmacist‐driven interventions to for each product for discussion of approved reduce risk of, screen for, and optimally manage indications, contraindications, and warnings. secondary cancers

Factors Which Can Lead to Secondary Cancers: What are They? Secondary Cancers

• Second primary cancer vs disease that has Childhood metastasized from the primary cancer Cancer

Family Lifestyle • Rare but becoming more frequent History – Occurs in children and adults Secondary – Survivors are living longer Cancers – Prior Better supportive care Cancer Aging – More patients receiving treatment Treatment Field Effect of Cancer

Rheingold SR, et al. Secondary Cancers in Kufe DW, et al, eds. Holland‐Frei Cancer Medicine 6th edition; Hamilton (ON): BC Decker, 2003 National Comprehensive Cancer Network. Available at: https://www.nccn.org/patients/resources/life_after_cancer/understanding.aspx. April 9, 2021. 56

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Most Common Types of Secondary Therapy‐Related Myeloid Cancers Cancers • Myeloid‐related cancers • Incidence: 5‐20% – Acute myeloid leukemia – Myelodysplastic syndrome • Highest incidence – Myelodysplastic syndrome/Myeloproliferative disorders – Hodgkin lymphoma • Cutaneous malignancies – Non‐Hodgkin lymphoma • Solid tumors – Breast cancer – Breast cancer – Bone cancers and sarcomas – Gynecologic cancers – Gastrointestinal cancers – Squamous cell carcinoma of skin/oral cavity • Diseases progresses quickly; more resistant to – Thyroid cancer conventional therapy; inferior outcomes

National Comprehensive Cancer Network (NCCN) Guidelines Version 3.2021. Available at: https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed April 12, 2021.

DNA‐Damaging Agents Therapy‐Related Myeloid Cancers Alkylating Agents Topoisomerase II PARP Inhibitors Other Agents Inhibitors • Exposure to DNA‐damaging agents Busulfan Daunorubicin Niraparib Docetaxel – Cytotoxic chemotherapy Carboplatin Doxorubicin Olaparib Fludarabine • Alkylating agents Carmustine Etoposide Rucaparib Methotrexate • Topoisomerase II inhibitors Chlorambucil Mitoxantrone Talazoparib Paclitaxel • Other agents (chemotherapy/colony‐stimulating growth factors)? Cisplatin Teniposide Vincristine • Poly (ADP‐ribose) polymerase (PARP) inhibitors Cyclophosphamide Vinblastine – Radiation therapy Dacarbazine • Additional factors Lomustine – Age Melphalan Filgrastim Mitomycin Pegfilgrastim – Inherited predisposition Procarbazine Thiotepa Swerdlow SH, et al, eds. World Health Organization classification of tumours of haemoatopoietic and lymphoid tissues. 2017; Churpek JE, et al. Best Pract Res Clin Swerdlow SH, et al, eds. World Health Organization classification of tumours of Haematol. 2013;26:309; Churpek JE, et al. Cancer. 2016;122:304. haemoatopoietic and lymphoid tissues. 2017. 910

Therapy‐Related Myeloid Cancers AML Treatment • Incidence varies with treatment exposure and underlying disease •7+3: cytarabine 100‐200 mg/m2 CIVI daily day 1‐ 7 + anthracycline (either idarubicin 12 mg/m2/d – Median diagnosis age: 61 yr 2 Induction OR daunorubicin 60 mg/m /d IV) day 1‐3 – Prior malignancy: 80% – Hodgkin lymphoma > breast cancer – First 5 yr after treatment: highest risk •High‐dose cytarabine x 3‐4 cycles • Type of prior malignancy • Matched sibling hematopoietic stem cell – Solid tumor: 70% Consolidation transplantation (HSCT) – Hematologic malignancy: 30%

Granfeldt Ostgard LS, et al. J Clin Oncol. 2015;33:3641; Morton LM, et al. Blood. National Comprehensive Cancer Network (NCCN) Guidelines Version 3.2021. 2013;121:2996; Morton LM, et al. JAMA Oncol. 2019;5:318 Available at: https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed April 12, 2021.

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Therapy‐Induced AML Treatment Daunorubicin/Cytarabine Liposome Remission Rates 60 •Dual liposomal encapsulation of cytarabine 48% 2 2 (100 mg/m ) and daunorubicin (44 mg/m ) 50 • Daunorubicin/ Induction days 1, 3, and 5 x 1 cycle; 2nd induction days 1 1 yr cytarabine and 3 only 40 Survival liposome: 42% •7+3 33% •7+3 28% 30

20 •Dual liposomal encapsulation of cytarabine (65 mg/m2) and daunorubicin (29 mg/m2) 10 • Daunorubicin/ Consolidation days 1 and 3 x 1‐2 cycles 5‐yr Cytarabine •Matched‐sibling HSCT Liposome: 18% 0 Survival •High‐dose cytarabine Daunorubicin/Cytarabine 7+3 •7+3: 8% Liposome CR Cri

National Comprehensive Cancer Network (NCCN) Guidelines Version 3.2021 Acute myeloid leukemia. Available at: https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed April 12, 2021. 13 14

Daunorubicin/Cytarabine Liposome Daunorubicin/Cytarabine Liposome (Vyxeos®) At‐a‐Glance Drug Information FDA Approval Adults with newly diagnosed therapy‐related AML or MDS Dosing changes Toxicity, hepatic and renal dysfunction Metabolism Same as convention but longer half‐life (30‐40 hr) DDIs No significant; cardiotoxic, hepatotoxic Warnings • BBW: Do NOT interchange with other daunorubicin or cytarabine‐containing products • Hemorrhage • Cardiotoxicity • Hypersensitivity • Copper overload • Tissue necrosis • Embryo‐fetal toxicity Toxicities Hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain

BBW; black box warning; DDI, drug‐drug interaction. Vyxeos [package insert]. Jazz Pharmaceuticals; Palo Alto, CA, 2021. 15 16

PARP Inhibitors and Myeloid Diseases PARP Inhibitors and Myeloid Diseases • Few case reports • Poly ADP ribose polymerase (PARP) plays • Carry warnings of MDS/AML important role in DNA repair pathways – Incidence 0.3‐1.7% • PARP inhibitors – Duration of therapy 0.1 mo –4.9 yr – Most also had previous platinum or other DNA‐damaging – Niraparib agents – Olaparib – Prostate cancer trials report no incidence – Rucaparib • Meta‐analysis 2021 – – Talazoparib Significant increased risk, odds ratio 2.63; P=0.026 – Incidence: 0.73% (95% CI, 0.5‐1.07) • Used in breast, ovarian, pancreatic, and – Median treatment duration: 9.8 mo (IQR: 3.6‐17 mo) prostate cancers – Latency period: 17.8 mo (range, 8.4‐29 mo) Niraparib [package insert]. Research Triangle Park, NC: GlaxoSmithKline; April 2020; Olaparib [package Morice P‐M, et al. Lancet Haematol. 2021;8:3122‐34. insert]. Wilmington, DE: AstraZeneca Pharmaceuticals, Inc.; March 2021; Rucaparib [package insert]. Boulder, CO: Clovis Oncology, Inc; October 2020; Talazoparib [package insert]. New York, NY: Pfizer Labs; October 2020; . 17 18

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PARP Inhibitors and Myeloid Diseases Pause and Ponder

Remain vigilant during and after therapy How does secondary AML from PARP inhibitors differ than that from cytotoxic chemotherapy? Monitor CBC+ diff baseline & monthly; weekly if toxicity occurs

Do not start medication until adequate recovery from hematologic toxicity

Refer to hematologist if no recovery in 4 wk

Niraparib [package insert]. Research Triangle Park, NC: GlaxoSmithKline; April 2020; Olaparib [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals, Inc.; March 2021; Rucaparib [package insert]. Boulder, CO: Clovis Oncology, Inc; October 2020; Talazoparib [package insert]. New York, NY: Pfizer Labs; October 2020. 19 20

Secondary Cutaneous Malignancies Secondary Cutaneous Malignancies

• Basal cell carcinoma • Keratoacanthoma • Squamoproliferative lesions • Squamous cell carcinoma • Second primary melanoma

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Anticancer Therapy Associated with BRAF Inhibitors & Cutaneous Malignancies Anticancer Drugs Within Class Approved Indications Cutaneous Malignancy Squamoproliferative Lesions Therapy BRAF inhibitors Dabrafenib, Melanoma, NSCLC, papillary Keratoacanthoma; • 31% of patients develop premalignant and malignant vemurafenib thyroid cancer, colorectal cancer, squamoproliferative lesion; lesions renal cell carcinoma squamous cell carcinoma Multikinase Sorafenib, sunitinib Hepatocellular carcinoma, renal Basal cell carcinoma; • Accelerated transition within weeks to months of inhibitors cell carcinoma keratoacanthoma; therapy initiation squamoproliferative lesion; squamous cell carcinoma • Factors associated with increased risk of SCC Ripretinib Gastrointestinal sarcomas Keratoacanthoma; squamous cell carcinoma – Older age

Janus kinase Ruxolitinib Myelofibrosis, polycythemia vera Squamous cell carcinoma – Recent treatment initiation inhibitors – Previous sun damage PD‐1 inhibitors Cemiplimab, Melanoma, NSCLC, head and Basal cell carcinoma; nivolumab, neck, squamous cell carcinoma, keratoacanthoma; squamous – Vemurafenib > dabrafenib pembrolizumab many many others cell carcinoma • Combination therapy with MEK inhibitor decreases risk XRT NA Solid tumors Basal cell carcinoma • Close monitoring during and after therapy Sonic hedgehog Vismodegib Basal cell carcinoma; basal cell Squamous cell carcinoma inhibitors nevus syndrome

BRAF, b‐type rapidly accelerated fibrosarcoma kinase; NA, not applicable; NSCLC, non‐small cell BRAF, b‐type rapidly accelerated fibrosarcoma kinase; MEK, mitogen activated protein kinase; lung cancer; PD‐1, programmed cell death 1; XRT, radiation therapy. Deutsch A, et al. J Am Acad SCC, squamous cell carcinoma. Deutsch A, et al. J Am Acad Dermatol. 2020;83:1425‐33. Dermatol. 2020;83:1425‐33. 23 24

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BRAF Inhibitors & Second Cutaneous Multikinase Inhibitors and Cutaneous Melanoma Malignancies • Less common • More frequent with sorafenib (13.5%) vs sunitinib (6.3%) vs Ripretinib (4.7%) • Develops weeks to months after BRAF therapy • Risk factors not clearly established initiation • Manifest on sun‐exposed areas and in those with • Pathogenesis unknown other cutaneous events • Timeframe: months after initiation • Close monitoring during and after therapy • Treatment – Maintain treatment for underlying malignancy – Surgically remove if possible – Temporary hold until resolution

BRAF, b‐type rapidly accelerated fibrosarcoma kinase. Deutsch A, et al. J Am Acad Dermatol. Deutsch A, et al. J Am Acad Dermatol. 2020;83:1425‐33; Ripretinib [package insert]. Waltham, 2020;83:1425‐33. MA; Deciphera Pharmaceuticals, LLC. May 2020.

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Vismodegib and Cutaneous Ruxolitinib and PD1 Inhibitors and Malignancies Cutaneous Malignancies • Sonic hedgehog inhibitor used in treatment of • Ruxolitinib used • Checkpoint inhibitors locally advanced or metastatic BCC or basal – Hematologic and used in a variety of solid cell nevus syndrome rheumatologic disorders tumors – Dermatologic conditions • Case reports (n=5) of • Typically no history of SCC – Graft vs host disease basal cell carcinoma, • Timeline: weeks to months after initiation • Evolving data on squamous cell • Pathogenesis hypotheses incidence and carcinoma, progression keratoacanthoma – Selection of SCC cells already present • Full body skin • Continued reporting is – Activation RAS/MAPK pathway examinations recommended • Close dermatologic monitoring recommended recommended

Deutsch A, et al. J Am Acad Dermatol. 2020;83:1425‐33. Deutsch A, et al. J Am Acad Dermatol. 2020;83:1425‐33.

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Tamoxifen and Tamoxifen and Endometrial/Uterine Cancer Endometrial/Uterine Cancer • Women >50 yr: increased risk of endometrial • Women with intact uterus cancer (RR, 4.01; 95% CI, 1.70‐10.90) – Baseline gynecologic assessment • Updated results of NSABP studies – Follow‐up gynecologic exams at each visit – Increased endometrial cancer – Prompt evaluation of vaginal bleeding – Increased uterine sarcomas • No routine role of endometrial • FDA issued “black box” warning ultrasound/biopsy • Raloxifene: not associated with risk • Discontinue treatment if cancer occurs; at least until fully treated

CI, confidence interval; RR, relative risk. Fisher B, et al. J Natl Cancer Inst. 1998;90:1371‐1388; Fisher CI, confidence interval; RR, relative risk. NCCN Guidelines Version 1.2021 Breast B, et al. J Natl Cancer Inst. 2005;97:1652‐1662; NCCN Guidelines Version 1.2021 Breast Cancer Risk Cancer Risk Reduction. Available at: Reduction. Available at: https://www.nccn.org/professionals/physician_gls/pdf/breast_risk.pdf. https://www.nccn.org/professionals/physician_gls/pdf/breast_risk.pdf. Accessed Accessed April 13, 2021. April 13, 2021. 29 30

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Radiation Therapy and Secondary Radiation Therapy and Cutaneous Malignancies Malignancies • 5% incidence • Develop 2 years after radiation therapy • Basal cell carcinoma most common • Risk factors • Risk factors – Age at exposure – Higher total irradiation dose – Modality of radiation (2‐dimensional conformal > intensity‐modulated – Gender > 3‐dimensional > proton therapy) – Temporal association – Increased elapsed time from radiotherapy – Increased ultraviolet susceptibility/lighter skin type – Radiation technique – Younger age at time of radiation therapy – Radiation type – Genetic predisposition – Lifestyle aspects • Often occurs at within – Exposure to other carcinogens the field of radiation • More aggressive, harder to eradicate, more prone to recurrence • Close, lifelong dermatologic evaluation

Deutsch A, et al. J Am Acad Dermatol. 2020;83:1425‐33. Dracham CB, et al. Radiat Oncol J. 2018;36:85‐94.

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Radiation Therapy and Sarcoma Radiation Therapy and Sarcoma Risk Factors • 3‐6% of all sarcomas • Prognosis: • Mean age of diagnosis Radiation dose – Adults: 50‐67 yr – 5‐yr survival: 10‐50% – Children: 16‐33 yr Age of radiation • Treatment • Common primary cancers in adults therapy – Breast cancer – Similar to primary – Gynecologic cancers Genetic sarcomas – Head and neck cancers predisposition – Lymphomas Chemotherapy • Common primary cancers in children exposure – Ewing’s sarcoma – Hodgkin lymphoma – Rhabdomyosarcoma Chronic edema – Retinoblastoma

Maki R, et al. Radiation‐associated sarcoma. Maki R, et al. Radiation‐associated sarcoma. UptoDate. 2021. UptoDate. 2021. 33 34

Radiation Therapy and Thyroid Cancer Radiation Therapy and Thyroid Cancer

• Radiation exposure during childhood increase • Surveillance recommended for children with history of – radiation exposure to neck risk of – environmental exposure – Thyroid cancer • Includes – Benign thyroid nodules – Annual history – Annual physical examination – Hypothyroidism – Assessment of thyroid function tests • Exposure from • Medical exposure – – Minimize Diagnostic radiographs – Consider risks/benefits – Therapeutic radiation • Nuclear accident – Internal exposure – Potassium iodide tablets

Scheider AB, et al. Radiation‐induced thyroid cancer. Scheider AB, et al. Radiation‐induced thyroid cancer. UptoDate. 2021. UptoDate. 2021.

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Hodgkin Lymphoma and Survivors and Secondary Cancers Secondary Cancers Radiation dose and fields

Chemotherapy agents and doses administered

Patient age at treatment

Length of time after treatment

Family history

Smoking history

Genetic predisposition

Bonnadonna G, et al. N Engl J Med. 1973;288:1242; Cannelllos GP, et al. Lancet. 1975;1:947; Arsenauau JC, et al. N Engl J Med. 1972;287:1119; Schaapveld M, et al. N Engl J Med. 2015;373:2499. 37 38

Hodgkin Lymphoma and Hodgkin Lymphoma and Secondary Cancers Secondary Cancers •Treatment summary provided to primary care provider • Solid tumors most common •Patient education Overall – Breast •History and physical exam annually after 5 yr

– Lung •Thyroid stimulating hormone (TSH) annually if XRT to neck Thyroid – Gastrointestinal cancers Cancer • Relative risk compared with general population •Complete blood count annually – Leukemia: 10‐80 fold relative risk Leukemia – Non‐Hodgkin lymphoma: 3‐35 fold relative risk •Breast cancer screening annually (starting 8‐10 yr post therapy or age 40, whichever first) – Solid tumors: > 2‐fold relative risk •Other routine cancer screening per guidelines (cervical, colorectal, endometrial, lung Solid tumors and prostate) • Prognosis: worse than primary cancers •Self breast and skin exams NCCN Guidelines Version 3.2021 Hodgkin lymphoma. Available at: LaCasce AS, et al. Second malignancies after treatment of classic https://www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. Accessed Hodgkin lymphoma. UptoDate. 2021 April 12, 2021. 39 40

Testicular Cancer and Pause and Ponder Secondary Cancers

• Solid tumors What can you do as a pharmacist to help survivors of – 2‐fold increased risk cancer who are at risk of secondary cancers? – Lung, colon, bladder, pancreas, stomach – Median latency: 12.5 yr • Skin cancers • Hematologic malignancies • Contralateral testicular cancer: 1‐3%

Gilligan T, et al. Urol Oncol. 2015;33:413; Motzer RJ, et al. J Natl Compr Canc Netw. 2012;10:502; Bosl GJ, et al. N Engl J Med. 1997;337:242, Ritchie JP, et al. Urology. 2011;78:S425. 41 42

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Pharmacist’s Role Survivorship Guidelines • Patient education • National Comprehensive Cancer Network Survivorship – Importance of close follow‐up long term Guidelines and Adolescent and Young Adult Oncology – Self screening https://www.nccn.org/professionals/physician_gls/pdf – Healthy lifestyle habits /survivorship.pdf • Advocate for screening and early detection • Monitor for long‐term toxicities https://www.nccn.org/professionals/physician_gls/pdf – Refer patients with signs and symptoms to physician /aya.pdf – Participate in screening/early detection programs • Recommend appropriate treatment for secondary • Children’s Oncology Group Long‐Term Follow‐up cancers Guidelines http://www.survivorshipguidelines.org/

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Example Screening Guidance Healthy Lifestyle Recommendations

Treatment Increased Screening and Early Detection Other Achieve and maintain healthy bodyweight throughout life Cancer Risk Recommendations Chest XRT Breast Breast MRI and mammogram annually at Consider Engage in physical activity daily 30 yr or 8 yr after XRT chemoprevention based on risk Minimize alcohol intake Skin cancer Annual skin exam and/or dermatology Counsel sun safety and referral regular sunscreen SPF Avoid/stop using tobacco products >30 Sarcoma Image as indicated Practice sun safety Lung cancer Image as indicated Counsel tobacco cessation; lung cancer Ensure adequate amount of sleep screening based on risk Follow‐up with primary care provider regularly Tamoxifen Uterine Assess vaginal pain or bleeding annually; if Increased in cancer bleeding refer to gynecology for postmenopausal transvaginal ultrasound and biopsy women Obtain nutrients from food sources

NCCN Guidelines Version 1.2021 Survivorship. Available at: https://www.nccn.org/professionals/physician_gls/pdf/survivorship.pdf. NCCN Guidelines Version 1.2021 Survivorship. Available at: Accessed April 12, 2021. https://www.nccn.org/professionals/physician_gls/pdf/survivorship.pdf. Accessed April 12, 202 45 46

Summary Questions? • Although secondary cancers are rare, understanding risk and having a high suspicion can facilitate early diagnosis and better outcomes • Both general risk factors as well as treatment or disease‐ specific risk factors for developing secondary cancers exist • General secondary cancers are treated similarly to primary cancers at same origin • Except to treatment is secondary AML/MDS which benefits from daunorubicin/cytarabine liposome • Pharmacists can play an important role in education and facilitating survivors of cancer to engage in risk reduction and screening practices • Pharmacists should remain up‐to‐date and vigilant with caring for survivors of cancer

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