08/11/2016

Common side effects of anti-cancer therapies

Disclosure • Honoraria: Speaker and Advisory Board: Roche, Pfizer, Novartis, Celgene, Apotex Astellas

Incorporated,

Kian Khodadad, MD Assistant Professor in Medicine Dalhousie University Cape Breton Cancer Centre Sydney November 9, 2016

Learning Objective • To review potential side effects of systemic anti-cancer therapies, particularly immunotherapies • To review common systemic therapies for common solid tumors • To review the management of adverse reactions to systemic anticancer therapies particularly irARs

Proportion of deaths due to cancer and other causes, Canada, 2012

Audience • Family Doctors and ER physicians • Nursing staff • Pharmacists

Lifetime probability of dying from cancer, Canada 2010

Canadian Cancer Statistics 2016 Canadian Cancer Statistics 2016

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Percent distribution of estimated cancer deaths, by sex, Canada 2016

Geographic distribution of estimated cancer deaths and age-standard mortality rates by province and territory, both sexes, Canada 2016

Canadian Cancer Statistics 2016 Canadian Cancer Statistics 2016

Goal of cancer treatment

Categories of systemic therapies

- Curative: eradicate cancer cells, prevention of disease recurrence *Adjuvant: post local therapy ( surgery, radiation) *Neo-adjuvant: prior to local therapy *Concurrent chemoRT - Palliative: provide comfort, improve/prolong QoL

• Cytotoxic agents (chemotherapy): alkylating, anthracyclines, platinum • Hormonal therapy: Tamoxifen, aromatase inhibitors (letrozole, anastrozole, exemestane), biclatumide, enzalutamide, abiraterone • Antibodies: EGFRI (cetuximab, panitumumab, trastuzumab, pertuzumab), VEGFI (bevacizumab)

Categories of systemic therapies • Immunotherapies: immune checkpoint inhibitor (nivolumab, pemprolizumab, ipilimumab) • Targeted therapies (TKI): BRAF (vemurafenib), MEK (trametinib), VEGFR (pazopanib, axitinib, sunitinib, sorafenib), EGFR (Erlotinib, afatenib), ALK (crizotinib, alectinib) • Tumour vaccine: sipuleucel-T

Cytotoxic Agents (chemotherapy)

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Mechanisms of action of cytotoxic agents (cell cycle dependent or independent)

Cytotoxic Agents cathegories • Alkylating agents (e.g. cyclophosphamide) • Antimetabolites (e.g. MTX, 5FU) • Vinca alkaloids (e.g. Vinblastin, vinorelbine) • Antimitotic antibiotic (e.g. Doxorubicin, bleomycin) • Taxanes (docetaxel, paclitaxel) • Miscellaneous compounds: e.g. Platinum, nitrosurea

https://www.mycancergenome.org/content/molecular-medicine/pathways/cytotoxic-chemotherapy-mechanisms-of-action

Cytotoxic agents - common chemo protocols -

Cytotoxic agents - common chemo protocols -

• Breast cancer: AC(doxorubicin/cyclophosphamide),

• Prostate cancer: Docetaxel, cabazitaxel, mitoxantrone

TC(docetaxel/cyclophosphamide), FEC-D (5FU/epirubicin/cyclophosphamide-docetaxel), dose-dense AC/T • Colon cancer: oral capecitabine, 5FU, XELOX (cap/oxaliplatin), FOLFOX (5FU/FA/oxaliplatin), FOLFIRI (5FU/FA/irinotecan) • Lung cancer: paclitaxel/carboplatin, etoposide/platin, vinorelbine/cisplatin, gemcitabine/carboplatin, pemetrexed/platinum

Cytotoxic agents - Side Effects • Nausea/Vomiting • Constipation/Diarrhea • Mucositis • Thrombocytopenia (pemetrexed, gemcitabine, carboplatin) • Capillary leak syndrome (gemcitabine, docetaxel) • Cardiotoxicity  anthracyclines: type I cardiotoxicity: dose related, underlying comorbidities (HTN, CAD, HLP), age, causing CHF, irreversible, prophylactic beta blockers/ACE inhibitors? 5FU/cape.: MI • Afebrile/Febrile neutropenia

Cytotoxic agents - Side Effects • Carcinogenic: AML (e.g. anthracyclins) • Teratogenic • Reproductive toxicity: infertility and early ovarian failure • Local thrombophelebitis/extravasation: hydrocortisone, analgesics, care of ulcer when develops • Hyperglycemia: corticosteroids • Hypersensitivity/anaphylactic reactions

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Cytotoxic agents Side Effects • Tumor lysis syndrome • Electrolyte imbalances: Hypocalcemia,

hypokalemia, hypomagnesemia (cetuximab, cisplatin) • Pulmonary toxicity: pulmonary fibrosis • Nephrotoxicity: cisplatin • Neurotoxicty: taxanes (paclitaxel, docetaxel), vinca alkaloids (vincristine, vinorelbine), cisplatin, oxaliplatin (early- and late-onset)

5 Fluorouracil/capecitabine • Cardiovascular: angina pectoris, cardiac arrhythmia, cardiac failure, ischemic heart disease, MI • Dermatologic: palmar-plantar erythrodysesthesia, skin fissures • Ophthalmic: lacrimal stenosis, lacrimation, photophobia • Dihydropyrimidine dehydrogenase (DPD) deficiency: diarrhea, neutropenia, neurotoxicity Warfarin interaction

Hormonal Therapies

Hormonal Therapies

Tamoxifen - side effects • Thromboembolic events 2-5% • vasomotor symptoms: hot flashes, sweating 5-20% • vaginal bleeding 2-23% (regular gyne exam) • endometrial cancer 1% • altered lipid profile with decreased total/LDL/HDL cholesterol • depression 5-10% • cataracts 65 years) • venous thromboembolism 5-20% • wound healing complications 5-20% (bevacizumab should be held for at least 28 days prior to elective surgery, and should not be initiated for at least 28 days following major surgery and until surgical wound is fully healed to prevent complications)

• GI fistula/perforation 3% • epistaxis 20-25% • mucocutaneous hemorrhage 20-40%, • reversible posterior leukoencephalopathy syndrome (RLPS) 1% (seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension, brain imaging confirms the diagnosis) • proteinuria 65 years)

Novel Immunotherapies

prior or concurrent use of antihypertensive medications higher cumulative dose of anthracycline prior to trastuzumab a lower left ventricular ejection fraction (LVEF) at baseline a declining LVEF (25) at screening

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CTLA-4 and PD-1/L1 Checkpoint Blockade for Cancer Treatment Priming phase (lymph node)

- immune checkpoint inhibitors: CTLA4 antibody: Ipilimumab PD-1 blockers: Nivolumab, Pembrolizumab PD-L1 blocker: Atezolizumab - IL-2, IFN, BCG

Effector phase (peripheral tissue) T-cell migration

Dendritic cell

MHC

TCR

TCR

CD28

Dendritic cell

T cell B7

Cancer cell

T cell

T cell

T cell

Immunotherapeutic agents

MHC

PD-1 PD-L1

Cancer cell

CTLA-4

Ribas A. N Engl J Med. 2012;366:2517-2519.

Tumors Shown to Respond to Anti-PD1 or Anti-PD-L1 Therapy

Spectrum of toxicity of immune checkpoint blockade agents

• Melanoma • Pembrolizumab, nivolumab, ipilimumab, RAF/MEK inhibitors

• RCC • NSCLC • Bladder • Head and Neck cancer • Lymphomas • ???

Champiat S et al. Ann Oncol (2016) 27 (4): 559-574

The five pillars of immunotherapy toxicity management

Immune checkpoint blockade toxicities Frequent (>10%) ICB toxicities • Ipilimumab (anti-CTLA4): diarrhea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite and abdominal pain • Nivolumab (anti-PD1): fatigue, rash, pruritus, diarrhea and nausea • Pembrolizumab (anti-PD1): diarrhea, nausea, pruritus, rash, arthralgia and fatigue

Rare ( 20%)

Rare (< 2%)

• Rash, pruritus

• • • •

• Diarrhea/colitis

Occasional (3% to 20%) • Hepatitis/liver enzyme abnormalities • Endocrinopathies: hypophysitis, thyroiditis, adrenal insufficiency

Episcleritis/uveitis Pancreatitis Nephritis Neuropathies, Guillain-Barré, myasthenia gravis • Lymphadenopathy (sarcoid) • Thrombocytopenia • Toxic epidermal necrolysis, StevensJohnson syndrome

Toxicity Grade

• Fevers, chills, lethargy

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2

4

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Weeks Weber JS, et al. J Clin Oncol. 2012;30:2691-2697. Weber JS, et al. J Clin Oncol. 2015;[Epub ahead of print].

Typical management of irAEs

Weber JS, et al. J Clin Oncol. 2012;30:2691-2697.

Ipilimumab: Managing Immune-Related Adverse Events System GI tract

Management Moderate enterocolitis: hold ipilimumab, administer antidiarrheal. Persistent diarrhea (> 1 wk): systemic corticosteroids. 7+ stools/day: start methylprednisone, permanently discontinue ipilimumab. Consider infliximab for corticosteroid-refractory patients

Skin

Rash (± itching) Blistering/peeling Oral sores

Moderate/nonlocalized rash: hold ipilimumab, start topical or systemic corticosteroids. Severe dermatitis: permanently discontinue ipilimumab, start corticosteroids

Liver

Jaundice Nausea/vomiting

Assess ALT/AST, bilirubin, and thyroid function before each dose and as necessary. Hold ipilimumab if ALT/AST > 2.5 x but ≤ 5 x ULN; permanently discontinue if AST/ALT > 5 x ULN or bilirubin > 3 x ULN. The immunosuppressant mycophenolate can be used for hepatotoxicity in corticosteroid-refractory patients

CNS

Weakness in extremities Numbness/tingling Sensory changes

Moderate neuropathy: hold ipilimumab. New or worsening neuropathy: permanently discontinue ipilimumab. Consider corticosteroids

Headaches Fatigue Behavior/mood changes Menstruation changes Dizziness/light-headedness

Moderate endocrinopathy: hold ipilimumab, start corticosteroids. Endocrine abnormalities can be difficult to detect, due to nonspecific symptoms. Consider having an endocrinologist follow the patient

Vision problems Irritation

Monitor for redness suggesting uveitis, treat with topical steroidal eye drops

Endocrine

Eyes

Champiat S et al. Ann Oncol (2016) 27 (4): 559-574

Symptoms Diarrhea Abdominal pain Dark, bloody stools

Ipilimumab adverse reaction management guide.

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Checkpoint Inhibition: Managing Grade 3/4 Treatment-Related AEs Grade 3/4 pneumonitis, nephritis, enterocolitis, hepatitis, or infusionrelated reaction New or worsening neuropathy Any life-threatening or grade 4 AE Any severe or grade 3 recurrent AE Hepatitis associated with  AST/ALT > 5 x ULN  AST/ALT ≥ 50% ↑ from baseline lasting ≥ 1 wk*  Total bilirubin > 3 x ULN

Grade 4 elevation of pancreatic enzymes

Initiate steroid therapy Permanently discontinue PD-1 tx Usually resolves with tx interruption‡

If no improvement in colitis or pneumonitis, infliximab or mycophenolate† If no improvement in hepatitis, consider mycophenolate; infliximab contraindicated

Diarrhea/Colitis

- management • R/O C. diff. and other infectious causes • Stools < 4 × baseline: loperamide, budesonide • Stools ≥ 4 and < 7 × baseline: 1 mg/kg of prednisone • Stools > 7 × baseline or refractory to oral steroids: - Hospitalize for intravenous methylprednisolone (1–2 mg/kg) - Consider colonoscopy and computed tomography scan for further evaluation - Consider infliximab (Remicade 5 mg/kg)

*In pts with liver metastasis who begin treatment with grade 2 elevation of AST/ALT. †Pts receiving ipilimumab may tolerate treatment with PD-1/PD-L1 inhibitor alone. ‡Steroids do not appear to accelerate the rate of improvement.

Pembrolizumab adverse reaction management guide. Nivolumab adverse reaction management guide. Ipilimumab adverse reaction management guide.

Endocrinopaties/Hypophysitis

Pneumonitis

- management -

- management -

• Chemistry panel + TSH (baseline and F/U) • Change may be permanent • Prompt steroids • In case of hypophysitis: levothyroxine, low dose hydrocortisone, medical alert bracelets (adrenal crisis)

Adjunctive Therapies • Bone modifying agents:  Bisphosphonate: Zoledronic acid,  RANK-L blocker: Denosumab • Filgrastim (G-CSF)

• Cough and dyspnea  R/O pulmonary mets, pulmonary disease progression, PE, effusion • Withhold therapy, high dose steroids, O2? • Bronchoscopy

Bone Modifying Agents pamidronic acid

• Indications: cancer-related hypercalcemia, bone metastasis, osteoporosis • Side effects: Bisphosphonates: Bone necrosis (jaw bone necrosis), hypocalcemia 510%, nephrotoxicity 8-18%, myalgia 20%, fever 30-45%, arthralgia, flulike symptoms Denosumab (Prolia, Xgeva): bone necrosis (jaw bone necrosis), hypocalcemia 3-18% • Administer ca/vit D in non-hypercalcemic patients • Hydrate pt prior to treatment • Acetaminophen after administration may reduce the incidence of acute reactions

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Osteonecrosis of the jaw (ONJ)

- risk factors • invasive dental procedures (e.g. tooth extraction, dental implants, bony surgery) • cancer diagnosis • concomitant therapy (e.g. chemotherapy, corticosteroids, angiogenesis inhibitors) • poor oral hygiene, ill-fitting dentures, pre-existing dental disease • comorbid disorders (e.g. anemia, infection) • longer duration of bisphosphonate use

Filgrastim (G-CSF)

Filgrastim - indications -

Filgrastim - therapeutic indications -

• Primary prophylaxis:

• Secondary prophylaxis • Therapeutic

• Neutropenia without fever : no established role • Neutropenic fever: controversial; the results of randomized trials have been mixed.  Probably in pts with poor clinical outcome: - expected prolonged (>10 day) or profound (65 - pneumonia or other clinically documented infections, sepsis syndrome, invasive fungal infection, prior episode of febrile neutropenia - comorbidities (heart failure, pulmonary embolus, lung, renal, liver, cerebrovascular disease)

Filgrastim

Conclusion

 anticipated incidence of neutropenic fever is approximately 20 percent or higher with a given regimen  may be appropriate in a number of clinical settings in which the estimated risk of neutropenic fever is between 10 and 20 percent  not in a metastatic setting

• Bone pain 5-30%, fever 10-50%, chest pain 5-15%, arthralgia 5-10% • Allergic reactions: usually with the initial exposure 2-10% • Pulmonary toxicity: bleomycin, cyclophosphamide • Capillary leak syndrome 1%: hypotension, hypoalbuminemia, edema, hemoconcentration  INF alpha, IL-2, gemcitabine, docetaxel (fluid retention?)

• Treating physician must have a high index of suspicion for potential AE of any anticancer therapy • Communication with other health care workers is very important • Serious adverse events may present initially in a subtle manner • Early treatment makes a difference

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Conclusion - Novel Immunotherapies • Routine B/W (endocrine surveillance) is essential • Late SEs may emerge months (or yrs) after exposure to checkpoint inhibitors. • Late SEs may be severe and/or unusual • Patients have to be pressed on AE symptoms, which they will often not volunteer • Family members must be trained to recognize AE • Patients and family members may be educated in the importance of reporting any change from baseline.

Questions?

Other references • UpToDate • BC Cancer Agency Drug Information

Thank You!

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