+

Chemotherapy for the Family PhysicianDr. Jan-Willem Henning MBChB FRCPCMedical OncologistTom Baker Cancer Centre

+Objectives

Case Based

List the different classes of systemic therapies

To review an approach to all (some) of these agents

Understand (not memorize) side effects

Manage some of the side effects

Appreciate the advances of systemic therapies

+Why Chemotherapy?

+Cancer:

If left untreated-lethal Disease

+Cancer:

Hallmarks of Cancer Growth

+Case

45 year women stage IIB (Lymph node +) right-sided Breast Cancer

Post Segmental and SLND procedure

Tumour: Estrogene Receptor postive ER (+)/PgR (+)

HER-2 Overexpressed (IHC-3+)

FEC-DH followed by Tamoxifen

Whole Breast and local-regional Irradiation

What kind of doctors see breast cancer patients?

family physicians radiologists pathologists general surgeons plastic surgeons medical oncologists radiation oncologists geneticists

They ask for your advice!

neurologists neurosurgeons cardiologists psychiatrists gynecologists emergency physicians respirologists orthopedic surgeons

+History of Chemotherapy

+

Cytotoxics/Chemotherapies

Alkylators & Platinums

Antimetabolites

Topoisomerase I & II Inhib.

Antimicrotubule Agents

Proteosome inhibitors

Corticosteroids

Systemic Treatment of Cancer

Hormones:AntiestrogensAromatase InhibitorsProgestinsGnRH Analogues(Anti)-AndrogensOctreotide

Immunologics:Interferon, IL-2BCGVaccineMonoclonal AntibodiesThalidomide

New Approaches:Host: Bisphosphonates/RANK-Ligand Anti-angiogenesisDifferentiation: retinoids (ATRA)Molecular Targeted Therapy

Tyrosine kinase inhibitors EGFR, BCR-ABL

Farnesyl transferase inhibitorsOncolytic viruses

+Let’s simplify matters

Chemotherapy

Hormonal agent

Targeted Agents: “Nibs and Mabs”

Immunologic agent

Supportive Medications

+Reasons To Give Chemotherapy

(systemic)

Improve Amount of Life Cure

e.g. Lymphoma, AML, Germ Cell & Ovarian ca, Ewing’s sarcoma Adjuvant therapy for breast

and colorectal ca Limited SCLC

Lengthen Survival e.g. above, Bladder, NSCLC

Improve Quality of Life Palliate symptoms

e.g. Breast, Bladder, Lung ca Delay symptom onset (disease-free

survival) e.g. Adjuvant Therapy

Organ Preservation e.g. Sarcoma, H&N ca, Breast, Anal & Bladder ca Less morbid surgery

+Reasons To Give Chemotherapy

(systemic)

We use our own language:

-Curative Intent

-Adjuvant/Neo-adjuvant

-Conversion therapy

-Palliative

+ Cell Cycle NonspecificCell Cycle Specific

+

Alkylators & Platinums: cyclophosphamide, chlorambucil, busulfan, thiotepa, CCNU cisplatin, carboplatin

Antimetabolites: methotrexate, 5-fluorouracil, Ara-C, gemcitabine, 6-MP, fludarabine,

Cladribine (2CDA), Pentostatin

Topoisomerase I Inhibitors: irinotecan, topotecan

Topoisomerase II Inhibitors: etoposide, teniposide, anthracyclines, mitoxantrone, actinomycin-D,

amsacrine

Chemotherapy Classification

+ Chemotherapy Classification

Antimicrotubule Agents vinca alkaloids: vincristine, vinblastine, vinorelbine taxanes: paclitaxel, docetaxel

Proteosome inhibitors bortezomib (Velcade®)

Corticosteroids: prednisone, dexamethasone

Miscellaneous: bleomycin: DNA intercalation, Fe2+ complex, O2 radicals L-asparaginase: depletes asparaginase, inhibits protein synth suramin: inhibits PDGF, FBF,TGF, EGF, ILGF and others

+Chemotherapy Side-

Effects

Alopecia Fatigue Mucositis Nausea and Vomiting Diarrhea or constipation Cystitis Neutropenia (F.N.) Anemia and

Thrombocytopenia Skin-HFS

Allergic Reactions

Capillary Leak Syndrome

Peripheral Neuropathy

Nail Changes

Myalgia's and Arthralgia's

Acute (All) Acute (Taxane common)

+Chemotherapy Side-Effects

• Late

1. Premature menopause/infertility

2. Secondary Malignancies (Leukemia)

3. Cardiomyopathy

4. Pulmonary Fibrosis (Pneumonitis)

+

+Medical Emergency:Febrile Neutropenia

+NCI CTCAE Grading Systemfor NeutropeniaNeutropenia: • Absolute blood neutrophil count (ANC) <2 SDs below normal1

• Normal neutrophil levels vary with age & race2

• Normal: 1.8-7.0 x 109/L, mean = ~4.0 x 109/L

6

1. Lima et al. Ann Hematol 2006;85:705-9.2. Sievers, Dale. Types of severe chronic neutropenia. www.neutropenia.ca 2006. 3. Adapted from NCI CTCAE v4.03. http://evs.nci.nih.gov

CTCAE = common terminology criteria for adverse events; LLN = lower limit of normal;NCI = National Cancer Institute; SD = standard deviation

Grade ANC (x 109/L)3

Grade 1Mild

<LLN to 1.5

Grade 2Moderate

<1.5 to 1.0

Grade 3Severe

<1.0 to 0.5

Grade 4Life-threatening, disabling

<0.5

+NCI CTCAE Grading System for Febrile Neutropenia

7

Adapted from NCI CTCAE v4.03. http://evs.nci.nih.gov

NCI = National Cancer Institute; CTCAE = common terminology criteria for adverse events

Grade ANC (x 109/L)3

Grade 1Mild

--

Grade 2Moderate

--

Grade 3Severe

ANC <1.0 x 109/L with a single temperature of >38.3C (101 F)

or sustained temperature of ≥38C (100.4 F) for >1 hour

Grade 4Life-threatening, disabling

Life-threatening consequences;urgent intervention indicated

+Clinical Signs of Infection in Patients with Neutropenia• Signs and symptoms of infection are often absent or muted in the

absence of neutrophils• Fever remains an early sign• Examples of clinical presentations suggestive of infection• Sinus/nasal tenderness• Abdominal pain• Diarrhea• Respiratory tract symptoms• Wounds or lesions• Urinary tract symptoms• Central nervous system symptoms

9

Baden et al. www.NCCN.org V1.2013

+

0

1

2

3

4

ANC

(109 /L

)

7-14 days post chemotherapy*

Highest Risk of Infection is During the Nadir Period

11

Adapted from: Crawford et al. N Engl J Med 1991;325:164-70.

*On average 3 weeks post radiation, case dependent

ANC decrease and nadir duration are dependent upon therapy, dose and route of administration

Recovery period also dependent on regimen and

patient status

0

1

2

3

4

ANC

(109 /L

)

7-14 days post chemotherapy*

Highest Risk of Infection is During the Nadir Period

11

Adapted from: Crawford et al. N Engl J Med 1991;325:164-70.

*On average 3 weeks post radiation, case dependent

ANC decrease and nadir duration are dependent upon therapy, dose and route of administration

Recovery period also dependent on regimen and

patient status

+Risk of Infection Increases with Duration and Severity of NeutropeniaIncidence of serious infection in patients with neutropenia (n=52)

10

Adapted from Crawford et al. Cancer 2004;100:228-37.

10%

30%

45%50%

65%

28%

50%

72%

85%

100%

0

25

50

75

100

≤ 1 wks 2 wks 3 wks 4 wks ≥ 6 wks

Patie

nts

(%)

Duration of neutropenia

ANC nadir <1.0 x 10 /LANC nadir <0.1 x 10 /L

Note: Based on data from Bodey et al. (n=52 patients with acute leukemia)

9

9

+Case

45 year women stage IIB (Lymph node +) right-sided Breast Cancer

Post Segmental and SLND procedure

Tumour: Estrogene Receptor postive ER (+)/PgR (+)

HER-2 Overexpressed (IHC-3+)

FEC-DH followed by Tamoxifen (Herceptin=Trastuzumab)

Whole Breast and local-regional Irradiation

+ Monoclonal Antibodies“Mabs”

HER-2 is a cell surface signaling protein

<10,000 HER2 proteins on normal breast cell

HER-2 gene amplification results in marked

overexpression of HER2 proteins

2,000,000 HER2 proteins on cancer cell

+Single Agent Trastuzumab

Her-2+ MBC Setting: Prior to 2012/2013

+Cytotoxic Mechanisms of MoAbs

Effector cells/Complement

Apoptosis Radiation/Radionuclide

Toxin/Drug

+Examples of Monoclonal

Antibodies

Remember “mabs”

Rituximab (Rituxan) Lymphoma

Trastuzumab (Herceptin) Breast

Pertuzumab (Perjeta) Breast

Cetuximab (Erbitux) Colon, Heand&Neck

Panitumumab (Vectibix) Colon

Bevacizumab (Avastin) Colon, GBM, Lung

Ipilumumab (Yervoy) Melanoma

+Potential side-effects of MoAbs

Drug Specific

Reversible Cardiomyopathy

Myalgia’s

Allergic Reactions

Electrolyte abnormalities: Mg, K, Calcium

Bevacizumab (Avastin): Hypertension, Trombotic events-CVA/MI, Wound dehiscence, Fistula’s, Bleeding, Proteinuria.

+Common effects you may

see/manage: Acneiforme Rash

Rash Management

Acneiforme Rash

Associated with tumor response.

Sunscreen, topical combination steroid-antibiotic cream, oral minocycline.

Resolves afterwards

Cetuximab

+Common effects you may

see/manage: Hypertension

Hypertension: Reported 17-80%

Both MoAbs and Tyrosine Kinase Inhibitors (“nibs”)

Also related with tumor response and improved OS if HTN optimized

Sunitinib in RCC and Bevacizumab (Colon and Lung)

Recommendation: Treat as per HTN guidelines

CCB (Norvasc) , ACE-Inhibitor, Diuretic.

Trastuzumab Emtansine: First in Class HER2 Antibody-Drug Conjugate (ADC)

Highly potent cytotoxic agent**24-270-fold more potent than taxanes

Cytotoxic agent: DM1

Monoclonal antibody: Trastuzumab

Target expression: HER2

Systemically stable

Linker: MCC

T-DM1

+

The New Era T-DM1 (Trastuzumab-Emtansine) for HER-2 + MBC in the

Second Line

+Overall Survival: Confirmatory

Analysis

Unstratified HR=0.70 (P=0.0012)Verma et al. N Eng J Med 2012;367:1783-91

496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5

Cap + LapT-DM1

No. at risk:Time (months)

78.4% 64.7%

51.8%

85.2%

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 360.0

0.2

0.4

0.6

0.8

1.0

Prop

ortio

n su

rvivi

ng

Median (mos) No. eventsCap + Lap 25.1 182T-DM1 30.9 149

Stratified HR=0.682 (95% CI, 0.55, 0.85) P=0.0006

Efficacy stopping boundary P=0.0037 or HR=0.727 Data cut-off Jan 14, 2012

+ Adverse Events for T-DM1 Grade ≥3 AEs With Incidence ≥2%

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Adverse Event

Cap + Lap (n=488) T-DM1 (n=490)

All Grades, % Grade ≥3, % All Grades, % Grade ≥3, %Diarrhea 79.7 20.7 23.3 1.6Hand-foot syndrome 58.0 16.4 1.2 0.0Vomiting 29.3 4.5 19.0 0.8Neutropenia 8.6 4.3 5.9 2.0Hypokalemia 8.6 4.1 8.6 2.2Fatigue 27.9 3.5 35.1 2.4Nausea 44.7 2.5 39.2 0.8Mucosal inflammation 19.1 2.3 6.7 0.2Thrombocytopenia 2.5 0.2 28.0 12.9

Increased AST 9.4 0.8 22.4 4.3

Increased ALT 8.8 1.4 16.9 2.9

Anemia 8.0 1.6 10.4 2.7

Verma et al. N Eng J Med 2012;367:1783-91

Data cut-off Jan 14, 2012

+Many more examples in almost

all Tumor Sites

+ Intracellular Pathways leading to developing the TKI’s-“Nib’s”

+Imatinib targets the cause of CML

Imatinib: a specific inhibitor of a small family of tyrosine kinases, including Bcr-Abl

+One step closer moving away from chemo and now curing

CML

+Tyrosine Kinase Inhibitors

“Nib’s”

Imatinib (Gleevec) CML, GIST

Sunitinib (Sutent) RCC, Neuro-Endocrine

Sorafenib (Nexavar) HCC, RCC

Pazopanib (Votrient) RCC, GIST

Erlotinib (Tarceva) and Gefitinib (Iressa) Lung

Regorafinib (Stivarga), Colon, GIST

Vemurafenib (Zelboraf) Melanoma

…and many others “nibs”

+TKI Toxcicities

Common

Rashes (response)

Fatigue (asthenia)

Diarrhea

Anorexia

HTN

Electrolyte abnormalities

Liver Transaminitis

Myelosuppression

Rare

Cardiac: MI, CHF, pQTC

Thyroid

Impaired Wound Healing

Nephrotic syndrome/AKI

Myopathy

Bleeding (hemoptysis/intra-tumoral)

+Case

45 year women stage IIB (Lymph node +) right-sided Breast Cancer

Post Segmental and SLND procedure

Tumour: Estrogene Receptor postive ER (+)/PgR (+)

HER-2 Overexpressed (IHC-3+)

FEC-DH followed by Tamoxifen

Whole Breast and local-regional Irradiation

+Hormonal Therapies

Antiestrogens (SERM’s and Blockers)

Aromatase Inhibitors

Progestins

GnRH Analogues

(Anti)-Androgens

Octreotide

+Summary

Improvement in better chemotherapies: Does not kill patient faster than the cancer

Better Supportive Medications

New agents (mabs/nibs) alone or in combination with chemotherapy has increased OS

More options available

Still more novel treatments to come

$$$