Assessment, Management and Prevention of anticancer Adverse Reaction a Clinical Pharmacy Perspectives.pptx

Presentation outline
1. Supporters
2. Target audience
3. Biography
4. Disclosure information
5. Class details
6. An overview
7. Toxicities associated factors
8. Common acute toxicities
1. Haematological toxicity
2. Dermatological toxicity
3. Gastrointestinal toxicities
1. Neurotoxicity
2. Cardiac Toxicities
3. Nephrotoxicity
4. Pulmonary Toxicities
5. Hepatotoxicity
10.Infections in People with
Cancer
11.Long-Term Complications of
Chemotherapy Second
Malignancies After
Chemotherapy

Supporter
The class and presentation is supported by
Primrose Pharmaceuticals, Dodoma, Tanzania

Target Audience
Pharmacozimbwe Class is designed to meet the clinical
training needs for pharmacists and other health care
professionals who manage patients illness.

Biography
Zimbwe Kauke Bakari, a Haemato-Onco-Clinical Pharmacist in the
Oncology Department at the Benjamin Mkapa Hospital, Dodoma,
Tanzania and an AMU/C Surveillance-Human Health Fleming Fellow.
The head of Pharmacy and Compounding Department at the Benjamin
mkapa hospital.
Holds Masters of Pharmacy in Hospital and Clinical Pharmacy from the
Muhimbili University of Health and Allied Sciences and a Bachelor's
degree in Pharmacy from St. John University of Tanzania. Served as a
clinical pharmacist notably at Ocean Road Cancer Institute. He worked
as a part-time Tutorial Assistant at Muhimbili University-School Allied
Sciences and the University of Dodoma, as Assistant Lecturer at St.
Augustine University in Tanzania.
He is a member of the National Medicine and Therapeutics Committee.
He participated in the preparation of Standard Treatment Guidelines and
Essential Drug List, 2021 and Medicine Policy Guidelines, 2021.
Participated in preparation of Hospital Formulary, Hospital Therapeutics
Committees, Ethical
Prescribing and Dispensing and Standard Treatment Guideline and
Essential Medicine List training package materials. Coordinate and is a
principal auditor of the Benjamin Mkapa Hospital Formulary, 1st edition,
2021. Take part in Technical Team and Consultant advisor on National
Pharmaceutical Action Plan, 2021-2026 formulation, for Tanzania
Mainland. MOHCDGEC (on progress).
He is committed Clinical Pharmacist, having a better understanding of
infectious disease control and rational antimicrobial use and certified by
the Pharmacy Council, a member of the Pharmaceutical Society of
Tanzania, and member of Tanzania Oncology Society
He is an expert in solid and hematologic malignancies, chemotherapy
and provide pharmaceutical care to oncology patients, assisting in the
optimization of patient outcomes. Responsible to evaluate medication
orders, prescriptions, and treatment plans received by authorized
prescribers for safety, accuracy, and appropriateness. Provides
pharmaceutical education to patients, family members, and other health
care professionals and serves as a resource to the interdisciplinary team
for medication-related information and issues at institution and national
level. The expert and pharmacy focal person of planned Bone marrow
transplants program at the Benjamin Mkapa Hospital which will be
launched soon.
Assisting in researching and developing treatment plans to assure safe,
complete, appropriate, and compliant ordering and administration for
patients receiving chemotherapy or supportive care.
.

Disclosure Information
1. Clinical Pharmacist, Haemato-Oncology Expert, BMT Pharmacy Focal
Person, The Benjamin Mkapa Hospital
2. Fleming Fund AMU/C Surveillance – Human Health Fellow
3. C.E.O and Proprietor of Primrose Pharmaceutical, Dodoma Tanzania
I have no relevant financial relationships to
disclose as it relates to the content of this
presentation.

Class Details
Purpose
To apply clinical pharmacy insights on Assessment,
Management and Prevention of Antineoplastic Associated
Adverse Events
Learning Objectives
1. To assess Antineoplastic Associated Adverse Events
2. To applied therapeutics approaches in management of Antineoplastic
Associated Adverse Events
3. To understand and apply prophylactic and preventive measures of
Antineoplastic Associated Adverse Events

An Overview
Chemotherapy adverse events
a. Common and acute toxicities:- due to inhibition of host
cell division
a. Most affected lymphoid tissues, bone marrow, and epithelium
of the gastrointestinal (GI) tract and skin
b. Nausea and vomiting, hypersensitivity reactions
b. Specific organ toxicities
c. Long-term complications
PHARMACOZIMBWE CLASS 8
5/9/2021

Toxicities Associated Factors
Chemotherapy factors include
 Incidence
 Predictability
 Severity
 Reversibility of the adverse effects.
Patient-specific factors
 Stage of disease
 Concomitant illnesses
 Concurrent medications (mimic the ADR associated with
chemotherapy)
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Common and Acute Toxicities
Haematological toxicities
Gastrointestinal tract toxicities
Dermatological toxicities
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Haematological
Toxicities
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Effects of Chemotherapy on Bone Marrow(1)
 Pluripotent stem cells in bone marrow capable of self
renewal and differentiation:-myeloid cell line(RBC, PTs &
WBC) and lymphoid cell line
 Precursor cells->mitosis->cell division, normal cells line
pass from mitotic to post-mitotic pool under normal resting
condition (~10-14days)
 Cytokine surveillance/GF can expand mitotic pool and
accelerate maturation and differentiation to ~5-7days
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Effects of Chemotherapy on Bone Marrow(2)
 Platelet cells/thrombocytes: Span is ~10days
 White blood cells/granulocytes: span is 6-8hrs
 Thus, granulocytopenias happen before thrombocytopenia
 Both may occur after the first or subsequent chemo
course
 Peripheral blood depression following chemo can help to
determine dosage and concurrent chemo for the
subsequent course
 And the need of prophylactic and treatment medication
like haematinics, GSFs, ESA and IL-1 (Oprelvekin)
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Red Blood Cells/Erythrocytes
 The development and circulating life span of
hematopoietic cell lines determines the severity of
the depression of that cell line (nadir) and the time
course of peripheral cytopenias.
 RBCs have 120days span peripherally, thus
anaemia wont occur in production, happens slowly
after series of chemo courses

Myelosuppression
Risk factors of myelosuppression
 Host factors
 Patient age-Younger patients tolerate
 Bone marrow reserve, leukemias & lymphomas
 Previous chemotherapy, radiation therapy, or both
 Liver or kidney ability to metabolize and excrete
 Agent factor
 Chemotherapy agent:-alkylating agents, antimetabolites and mAbs
 Dose intensity DI: drugs dose delivered/time as mg/m2/week
 Dose density DD: give drugs more frequently than allocated time with less
time between the doses
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Myelosuppression
 WBCs and platelets fall in 5 to 7 days of chemo administration, reach a nadir
within 7 to 10 days, and recover within 14 to 26 days.
 Phase-specific chemo has slow onset > phase-nonspecific agents
 The cytotoxicity occur during the resting phase/GO of the cell cycle,
mitomycin can cause two neutropenic nadirs, 1st nadir occurs immediately
after agents initiation and 2nd nadir manifest ~4 to 6 weeks post therapy.
 6-week cycles is recommended for many combos to avoid treatment before
the second nadir, dosing intervals of 3/21-4/28 weeks/days to allow the bone
marrow time to recover.
 Targeted therapies do not exhibit bone marrow suppression, precise for a
specific molecular/biomarkers event rather than an entire metabolic process,
be ideal agents to add-on chemo
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Myelosuppression Prevention
 The colony-stimulating factors (CSF) are a class of glycoprotein
hormones that regulate the production and function of blood
cells(1).
 Clinical usefulness of CSFs in Myelosuppression therapeutics(2):
 Accelerate regeneration of protective WBCs
 Mobilize stem cells to the peripheral blood in convenient numbers
for transplantation
 Enhance anticancer immune responses
1. Glaspy JA, Golde DW. The colony-stimulating factors: biology and clinical use. Oncology (Williston Park). 1990 Sep;4(9):25-32; discussion 32-4. PMID: 2145019.
2. Metcalf D. The colony-stimulating factors and cancer. Cancer Immunol Res. 2013;1(6):351-356. doi:10.1158/2326-6066.CIR-13-0151
5/9/2021

The Colony-Stimulating Factors
(CSF)
1. Myeloid cells--granulocyte-macrophage colony-stimulating factor
(GM-CSF) eg: filgrastim and Pegfilgrastim
2. Granulocyte colony-stimulating factor (G-CSF); sargramostin
3. Macrophage colony-stimulating factor (M-CSF),
4. Interleukin-3 (IL-3)-
 G-CSF and GM-CSF have potential clinical in prevention of
chemotherapy-induced neutropenia
 Treatment of cytopenias associated with myelodysplastic syndromes
and aplastic anemia
 Shown promise in the treatment of congenital and idiopathic
neutropenias.
3. Glaspy JA, Golde DW. The colony-stimulating factors: biology and clinical use. Oncology (Williston Park). 1990 Sep;4(9):25-32; discussion 32-4. PMID:
2145019.
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CSFs Therapeutics
 Filgrastim, 300mcg stat/od>3/7(5mcg/kg/day)SC as single jab
per-cycle
 Pegfilgrastim LA given as 6mg/0.6ml once/cycle, no weight
consideration.
 GMCSFs: sargramostim dose 250mcg/m2/day SC
 The ASCO guideline: rounding the dose of either agent to the
nearest vial size may enhance patient convenience and reduce
cost without clinical detriment.
 Available strength either 300/480 mcg of G-CSF, adult patients
<75 kg receive 300 mcg once and >75 kg receive 480 mcg daily
and in GM-CSF; patients who weigh >60 kg receive 500 mcg daily
and patients who weigh <60 kg should receive 250 mcg daily.
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Febrile Neutropenia/Neutropenic sepsis(1)
 Neutropenia is defined as:
 a ‘neutrophil count of <0.5 x 10^9 /l or total WBC count <1.0X10^9/L(4)
 fever of 38°C > or last for an hour or > 38.5°C on one occasion
 Conversely a patient may be septic and not have a raised temperature:
corticosteroids & antipyretics in the preceding few hours or very
immunosuppressed with a normal neutrophil count (e.g. post allogeneic bone
marrow transplant)-> use high index of suspicion of sepsis to treat
 Severity and duration of neutropenia determine infections risks while
bacteremia incidence and death is greatest in patients with a neutrophil
count <0.1 x 10^9 /l.
4 Ribton, J, Corrigan, A and Marshall, E (2008) Chemotherapy Related Neutropenic Sepsis: Out of Hours Emergency Care. Cancer Action. Edition 25
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Febrile Neutropenia/Neutropenic sepsis (2)
Signs and Symptoms of Infection
From Febrile Neutropenia(5)
Risk Assessment for Febrile
Neutropenia for Prophylaxis with
G-CSF(7)
5. Neutropenia and risk of infection. CDC website. www.cdc.gov/cancer/ preventinfections/pdf/neutropenia.pdf. Accessed August 2, 2017.
6. Klastersky J, de Naurois J, Rolston K, et al; ESMO Guidelines Committee. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2016;27(suppl 5):v111-
v118.
7. NCCN Clinical Practice Guidelines in Oncology. Myeloid Growth Factors, version 1.2017. National Cancer Comprehensive Network website. www.nccn.org/
professionals/physician_gls/PDF/myeloid_growth.pdf. Published April 28, 2017. Accessed August 2, 2017
Classification of Risk for Infection
With Febrile Neutropenia(6)

FNP Workup
 FBP: LFT: RFT: Malaria screen:
 Urine analysis Urine/blood/stool culture: Serum
Electrolytes: Throat Swab
TREATMENTS
 Initial (first-line) and subsequent (second-line –
deteriorating patients) empiric antibiotic use, first dose
must be administered within 1 hour of suspicion of
neutropenia sepsis.
 Antipyretics and analgesic
8. Standard Treatment Guidelines/National Essential Medicines List. 6th Ed, 2021, Ministry Of Health, Community Development, Gender, Elderly and Children,
Tanzania Mainland
9. National Cancer Treatment Guidelines. 1st Ed. 2020, Ministry Of Health, Community Development, Gender, Elderly And Children, Tanzania Mainland

Treatments FN(1)
 Patients with no significant betalactam reactions:
1. piperacillin+tazobactam 4/0.5mg (FDC) (IV) IV qid PLUS Gentamicin 3-
6mg/kg once daily.
2. meropenem (IV) 500mg 8 hourly PLUS amikacin (IV) 15mg/kg/dose in 2-
3 devided dose OR
3. ciprofloxacin 200– 400 mg IV 12 hourly PLUS vancomycin 15 -
20mg/kg/dose 8 - 12 hourly
 Patients with history of definite anaphylaxis to Beta Lactams
1. ciprofloxacin (IV) as above, metronidazole (IV) 500mg – 750mg dose 8
hourly AND amikacin dose as above AND vancomycin dose as above
Tanzania Mainland

Treatment FN (2)
Culture Negative Patients in First 48 hours
1. Single spike of fever (patient’s temperature returns to normal within 4 hours
of the initial fever), antibiotics may be discontinued
2. More fever spikes, continue antibiotics for a minimum of 7 afebrile days and
consider the following:
a. If oral herpes occur or severe mucositis, commence IV Aciclovir
b. Suspect candida add fluconazole IV; other fungal– Amphoteracin B IV.
c. Diarrhoea and vomiting – culture stool and commence ciprofloxacin and metronidazoles
or signs of skin infection – add vancomycin
3. Patients deteriorating rapidly/extremely unwell – consider adding
vancomycin
4. If by day 5-7 patient remains febrile, neutropenic, consider performing a
fungal work-up, prior to commencing empiric appropriate antifungal
treatment

Thrombocytopenia
 IL-1, Oprelvekin first platelet growth factor 50 mcg/kg/day SC used until the
postnadir platelet count is >50,000 cells/mm3 or up to 21 days following
chemotherapy.
 ~20% of patients respond to oprelvekin, requiresadditional platelet
transfusions(10)
 Pharmacoeconomically, oprelvekin use vs platelet transfusions, some oncologist
recommend
 in patients receiving dose-intensive chemotherapy to maintain the high-dose
regimen that may provide a survival advantage for the patient with cancer(11)
 in reducing the need for platelet transfusions in patients who undergo dose-
intensive chemotherapy(10).
 SE: peripheral edema, dyspnea, pleural effusions, tachycardia, and conjunctival
redness(12).
10. Isaacs C et al. Randomized placebo-controlled study of recombinant human interleukin-11 to prevent chemotherapy-induced thrombocytopenia in patients with
breast cancer receiving dose-intensive cyclophosphamide and doxorubicin. J Clin Oncol 1997;15:3368.
11. Adams VR, Brenner T. Oprelvekin (Neumega), first platelet growth factor for thrombocytopenia. J Am Pharm Assoc (Wash). 1999 Sep-Oct;39(5):706-7. doi:
5/9/2021

13. Cantor, S.B., Elting, L.S., Hudson, D.V., Jr. and Rubenstein, E.B. (2003), Pharmacoeconomic analysis of oprelvekin (recombinant human
interleukin-11) for secondary prophylaxis of thrombocytopenia in solid tumor patients receiving chemotherapy. Cancer, 97: 3099-
3106. https://doi.org/10.1002/cncr.11447
The economic consequences of the
routine use of this platelet growth
factor and the usual standard of
platelet transfusions for prophylaxis
of severe chemotherapy-induced
thrombocytopenia have not been
compared.
From the payer's perspective, rhIL-11
cannot be considered a cost-saving
clinical strategy compared with
routine platelet transfusions for
patients with severe chemotherapy-
induced thrombocytopenia.
5/9/2021
Routine platelet transfusions
remain the best and reliable
options

Anemia and Erythropoietin
 RBCs DNA synthesis inhibition cause anisocytosis and
macrocytosis in commencement of antimetabolites, but is rarely
the sole factor to low hemoglobin (Hgb) levels that necessitate BT
 Anemia occurs due to:-
 Impaired erythrocyte response to erythropoietin
 Reduced hematopoietic precursors caused by chemotherapy or
radiation therapy,
 Disrupted marrow architecture caused by invasion of malignant
cells
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Erythropoietin
 Ameliorate anemia associated with cancer and chemotherapy by
 Reducing the need for transfusions
 Enhance the patient's quality of life.
 Two erythropoiesis-stimulating agents (ESA) are currently
available for patient use.
1. Recombinant human erythropoietin (r-HUEPO, epoietin-α)
2. Darbepoietin-α Chinese hamster ovary cells by
recombinant DNA Technology
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Recombinant Human Erythropoietin(r-HUEPO,epoietin-α)
 Starting dose for r-HUEPO is 150 U/kg X3/52 rounded to a
standard dose of 10,000 U (vial size) or 40,000 U
once/weekly(14)
 Initial doses should be given for 4/52, if the Hgb increases
<1 g/dL, then increased to 300 U/kg X3/52 or 60,000 U
1x/week.
 8 weeks of treatment may be required to decrease
transfusion requirements, 50% of patients respond to
erythropoietin, if there is no positive response in 6 to 8
weeks discontinue therapy to avoid Hypertension,
seizures, and angina
14. 20030125 Study Group Trial, Glaspy J, Vadhan-Raj S, Patel R, Bosserman L, Hu E, Lloyd RE, Boccia RV, Tomita D, Rossi G. Randomized comparison of every-2-week
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Darbepoietin-α
 Darbepoetin>EPO by 2X longer t1/2 (extended dosing interval) &
potency.
 Glaspy JA, 2002: 429 patients found that darbepoetin-α 1.5
mcg/kg/1X/week, achieved the same mean Hb same as r-HUEPO 150
U/kg 3X/week, At 3mg/kg/w dose, darbopoetin-α elicited a
hematopoietic response after 2 weeks same as r-HUEPO 40,000-
60,000 U/week(15)
 Multicenter open-label study of darbepoetin, 500 mcg every 3 weeks
was effective in increasing and maintaining hb levels and was well
tolerated(16).
 The FDA: initial doses is 2.25 mcg/kg/wk or 500 mcg SC every 3
weeks, can be escalated to 4.5 mcg/kg/wk if no response in 6 weeks
post initial dose(17)
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Epoietin-α and darbepoietin-α congruence
 Epoetin-α & darbepoetin-α have been shown to be equal in
efficacy: hemoglobin responses & decreases in transfusions(18-
21)
 Provide a safe and effective treatment for chemotherapy-
associated anemia to reach and maintain a target hemoglobin
level of 11 g/dL
 Not recommended to be used in pts with Hb levels >12mg/dl,
associated with thromboembolism, HTN, angina and mortality(22)
18. 120030125 Study Group Trial, Glaspy J, Vadhan-Raj S, Patel R, Bosserman L, Hu E, Lloyd RE, Boccia RV, Tomita D, Rossi G. Randomized comparison of every-2-week
darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia: the 20030125 Study Group Trial. J Clin Oncol. 2006 May 20;24(15):2290-7. doi:
10.1200/JCO.2005.03.8570. PMID: 16710026.
19. Schwartzberg LS, Yee LK, Senecal FM, Charu V, Tomita D, Wallace J, Rossi G. A randomized comparison of every-2-week darbepoetin alfa and weekly epoetin alfa for the
treatment of chemotherapy-induced anemia in patients with breast, lung, or gynecologic cancer. Oncologist. 2004;9(6):696-707. doi: 10.1634/theoncologist.9-6-696. PMID: 15561813.
20. Mirtsching B, Charu V, Vadhan-Raj S, Colowick AB, Rossi G, Tomita D, McGuire WP. Every-2-week darbepoetin alfa is comparable to rHuEPO in treating chemotherapy-induced
anemia. Results of a combined analysis. Oncology (Williston Park). 2002 Oct;16(10 Suppl 11):31-6. PMID: 12435171.
21. Ross SD, Allen IE, Henry DH, Seaman C, Sercus B, Goodnough LT. Clinical benefits and risks associated with epoetin and darbepoetin in patients with chemotherapy-induced
anemia: a systematic review of the literature. Clin Ther. 2006 Jun;28(6):801-31. doi: 10.1016/j.clinthera.2006.06.003. Erratum in: Clin Ther. 2007 May;29(5):985-6. Erratum in: Clin
5/9/2021

Chemotherapy-Induced Thrombocytopenia
 L-asparaginase/PEG-L-asparaginase, block the synthesis of fibrinogen,
protein and vit K (Coumarin)coagulation factors produced by the liver,
Lead to prolonged PT and PTT.
 Antiangiogenic therapies: thalidomide,lenalidomide and bevaciziumab
(VEGFInx), venous thromboembolic events when used in the treatment of
MM(1)
 Surgical, Central Venous Catheter, procedures and bedrest can increase
the risk of thrombosis.
 Maintain a high index of suspicion with regular workout of PT, INR,
LMWH/Enoxaparin monthly shots INR>3, in bleeding/ INR<2,
Tranexamic acid,???
23. Zangari M, Siegel E, Barlogie B, Anaissie E, Saghafifar F, Fassas A, Morris C, Fink L, Tricot G. Thrombogenic activity of doxorubicin in myeloma patients receiving
thalidomide: implications for therapy. Blood. 2002 Aug 15;100(4):1168-71. doi: 10.1182/blood-2002-01-0335. PMID: 12149193.
5/9/2021

Tumor Lysis Syndrome-TLS
 MASSIVE CANCER CELLS LYSIS;Occur in cancers with a rapid
proliferation index such as Burkitt’s lymphoma, AML,, and seldom in
solid tumors of small-cell type, breast cancer, and medulloblastoma
 Manifested: hyperuricemia, hyperkalemia, hyperphosphatemia,
hypocalcemia, acute renal failure, ECG changes & Metabolic acidosis
 Work Up
 FBP: RFT: LFT: LDH
 Serum phosphates and calcium
 Urine pH and output
 ECG: CXR
 CT-Scan: Abdomen and Pelvis USS
Tanzania Mainland
5/9/2021

Management of TLS(1)
 Monitor: BUN), Cr, UA,K+, Na+, PO4, Ca2+ levels & LDH at least 3x/day for 24 to 48
hours post chemo
 Urine Alkalization with NaHCO3 100 mEq/L in IV fluids 24-72 hours after start of
chemotherapy, reduce or prevent UA from precipitating in the renal tubules and collection
ducts, note; increased pH may increase the risk of Ca(PO4)2ppt in soft tissue and
kidney tubules, and it may aggravate hypocalcemia
 Pre-Post chemo hydration: 12-48hrs pre-chemotherapy and 48- 72hrs post
chemotherapy 2–3 L/day then 3 L/daily, resulting in urine volumes of at least 3L/Day,
provide perfusion, salt solubility and fluid compensation(24)
 Allopurinol 300-600mg/day, stop when UA normal or LOW WBC??
 Hyperkalemia give calcium gluconate iv/ calcitriol and exchange resins
 Empiric antibiotics, opportunistic infections prophylaxis , TPN and GCF may be indicated.
 Leukapheresis and dialysis for patient with experiencing hyperviscosity(not routinely)
24. Flombaum CD. Metabolic emergencies in the cancer patient. Semin Oncol. 2000 Jun;27(3):322-34. PMID: 10864220.
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Management of TLS(2)
 Rasburicase recombinant urate oxidase product, for with rapid
reduction and well tolerated (25), catalyse enzymatic oxidation
of UA-> allantoin a is 5x > soluble than UA with rapid renal
excretion, for both prevention and treatment dose is 0.2
mg/kg/dose
 In trials suggest that rasburicase is equally effective in adults(26
& 27) but remains to be demarcated due high cost and lack of a
randomized trial comparing its effect with other interventions
25. Pui CH, Mahmoud HH, Wiley JM, Woods GM, Leverger G, Camitta B, Hastings C, Blaney SM, Relling MV, Reaman GH. Recombinant urate oxidase for the prophylaxis or treatment of
hyperuricemia in patients With leukemia or lymphoma. J Clin Oncol. 2001 Feb 1;19(3):697-704. doi: 10.1200/JCO.2001.19.3.697. PMID: 11157020.
26. Pui CH, Jeha S, Irwin D, Camitta B. Recombinant urate oxidase (rasburicase) in the prevention and treatment of malignancy-associated hyperuricemia in pediatric and adult patients: results
of a compassionate-use trial. Leukemia. 2001 Oct;15(10):1505-9. doi: 10.1038/sj.leu.2402235. PMID: 11587206.
27. Bosly A, Sonet A, Pinkerton CR, McCowage G, Bron D, Sanz MA, Van den Berg H. Rasburicase (recombinant urate oxidase) for the management of hyperuricemia in patients with cancer:
report of an international compassionate use study. Cancer. 2003 Sep 1;98(5):1048-54. doi: 10.1002/cncr.11612. PMID: 12942574.

Dermatological Toxicities

Dermatologic Toxicities
a. Alopecia
b. Dry skin
c. Nail changes
d. Blistering
e. Hypersensitivity reactions: specific skin eruptions, nonspecific
eruptions, or “rashes
f. Extravasations: vesicant properties chemo
g. Hyperpigmentation: skin interact with ultraviolet (UV) light or
radiation
Occur when chemotherapy agents
reduce or inhibit mitosis in the epidermis
and nail matrix.

Alopecia: Anagen Effluvium
 Hair follicles growth phase: phases of growth (anagen), involution/transition (catagen), and
rest (telogen).
 Hair loss (usually abrupt) during the anagen phase due to an event that impairs the mitotic or
metabolic activity of the hair follicle, 65% anagen effluvium is after chemotherapy
(cyclophosphamide and doxorubicin(28).
 Naturally, 100 scalp hairs loss/day, patients with cancer can lose substantially more, beards,
eyebrows, eyelashes, axillary, and pubic hair can be affected, usually begins 7-10 days after
one treatment, noted within 1 or 2 months.
 Chemo induced alopecia is reversible begin regenerating in1-3 months after therapy is
completed, the new hair may be lighter, darker, or curlier as it regrows, permanent alopecia is
rare (29 & 30)
 Scalp cooling an intervention that significantly reduced the risk of chemotherapy-induced
anagen but discouraged because it may minimize delivery of chemotherapeutic drugs to the
scalp, leading to cutaneous scalp metastases(31).
28.Trüeb RM. Chemotherapy-induced alopecia. Semin Cutan Med Surg. 2009;28(1):11-14.
29. Kirkwood J. Cancer immunotherapy: the interferon-alpha experience. Semin Oncol 2002;29(3 Suppl 7):18.
30. McGarvey EL, Baum LD, Pinkerton RC, Rogers LM. Psychological sequelae and alopecia among women with cancer. Cancer Pract. 2001;9(6):283-289
31. Münstedt K, Manthey N, Sachsse S, Vahrson H. Changes in self-concept and body image during alopecia induced cancer chemotherapy. Support Care
Cancer. 1997;5(2): 139-143

Cold Caps and Scalp Cooling
Systems
 A tightly fitting, helmet-like hats filled with a cold
gel or liquid that you wear during chemotherapy
infusions.
 It narrowing the blood vessels beneath the skin
of the scalp, then reduces the amount of chemo
in the hair follicles, less likely to fall out.
 Decreases the hair follicles’ metabolic activity,
makes the cells divide more slowly and protects
the follicles from the chemotherapy.
 Wear the cap for 20 minutes to 4 or 5 hours
before and during the infusion, affected by
chemotherapy type and the type of scalp cap
32. http://www. aafp.org/afp/2009/0815/ p373.html.

Chemotherapy Induced Nail Changes
 The impacts is cosmetic and resolve in 6 to 12 months after post
chemotherapy
 A reduction or a cessation of mitotic activity in the nail matrix causes a
horizontal depression of the nail plate, in weeks, these pale horizontal lines
(“Beau's lines”) appear
 Manifested in >6 months post chemo, as nails grow lines move distally and
disappear in ~6 months,
 S/S: hemorrhagic onycholysis, discoloration, and acute exudative
paronychia are seen in ~40% of patients receiving paclitaxel and
docetaxel, nail pigmentation may be due to use of anthracyclines and
antimetabolites
33. Payne AS et al. Dermatologic toxicity of chemotherapeutic agents. Semin Oncol 2006;33:86.
34. DeMarinis M et al. Nail pigmentation with daunorubicin therapy. Ann Intern Med 1978;89:516.
35. Priestman TJ et al. Adriamycin and longitudinal pigmented banding of fingernails. Lancet 1975;1:1337.
36. Shetty MR. Case of pigmented banding of the nail caused by bleomycin. Cancer Treat Rep 1977;61:501.

Chemotherapy Induced Hyperpigmentation
 Antitumor antibiotics, alkylating agents, and antimetabolites
cause diffused, localized or generalized hyperpigmentation,
(mucous membrane, hair, or nails), peculiar serpiginous, linear or
flagellate streaks hyperpigmentation can occur over veins after
fluorouracil and bleomycin use(37&38)
 Thiotepa hyperpigmentation occur on skin occluded by bandages,
due to secretion of thiotepa in sweat(39), interestingly, while direct
contact of skin-thiotepa cause hypopigmentation(40).
 Intermittent high-dose methotrexate cause hyperpigmented
banding of light-colored hairs (the “flag sign” of chemotherapy)(41).
 No treatment but counseling and refer the dermatologist
37. Hrushesky WJ. Serpentine supravenous fluorouracil hyperpigmentation. JAMA 1976;236:138.
38. Fernandez-Obregon AC et al. Flagellate pigmentation from intrapleural bleomycin. A light microscopy and electron
microscopy study. J Am Acad Dermatol 1985;13:464.
39. Horn TD et al. Observations and proposed mechanisms of N,N′,N′-triethylenethiophosphoramide (Thio-TEPA)-induced
hyperpigmentation. Arch Dermatol 1989;125:524.
40. Harben DJ et al. Thiotepa-induced leukoderma. Arch Dermatol 1979;115:973.
41. Wheeland RG et al. The flag sign of chemotherapy. Cancer 1983;51:1356.

Chemotherapy Induced Hand–Foot Syndrome
 Chemotherapy -associated acralerythema or the palmar-plantar
erythrodysesthesia syndrome” Antimetabolites , anthracycline , MRTKIs -sunitinib
and sorafenib(42,43)
 Tender, erythematous skin on the hand palms and feet soles, tingling, burning, or
shooting sensations in their hands or feet experienced but not painful with bullous
lesions when desquamate.
 No specific therapy exists, offending agent is discontinued at least until recovery
occurs.
42. Tsai KY et al. Hand-foot syndrome and seborrheic dermatitis-like rash induced by sunitinib in a patient with advanced renal cell carcinoma. J Clin Oncol
2006;24:5786.
43. Lai SE et al. Hand-foot and stump syndrome to sorafenib. J Clin Oncol 2007;25:341.

Acneiform–Erythematous Rash
 Caused by EGFRIx: inhibition of the TK pathways in EGFR-
dependent tissues(keratinocytes in the skin), Erlotinib and
lapatinib, TKIs target the intracellular domain of the EGFR while
Cetuximab and panitumumab are mAb that target the
extracellular domain of EGFR.
 A pustular or maculopapular eruption appears on the upper body,
face, and scalp in the first 1 to 2 weeks of treatment, rashes are
predominantly grade 1 or 2 in severity, may be associated with
dry skin and itching, and completely resolve without sequelae
when the drug is discontinued.
 No supportive therapy but manage by: Moisturizing creams,
steroid creams, sunscreen, antibiotics (e.g., topical clindamycin or
systemic tetracyclines), and topical calcineurin inhibitors (e.g.,
tacrolimus cream), minimize sun exposure.
44. Lynch TJ et al. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical
management. Oncologist 2007;12:610.
45.. Perez-Soler R. Rash as a surrogate marker for efficacy of epidermal growth factor receptor inhibitors in lung cancer. Clin
Lung Cancer 2006;8(Suppl 1):S7.
46. Cunningham D et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal
cancer. N Engl J Med 2004;351:337.

Extravasations
 Extravasations of agents with vesicant properties can produce devastating tissue
damage
 Risk of extravasation and subsequent tissue damage associate with the following
factors(47)
1. venous fragility and instability or decreased local blood flow
2. Elevated venous pressure, in obstructed superior vena cava/venous drainage
after axillary dissection
3. Prior radiation therapy to the injection site
4. Recent venipuncture in the same vein
5. use of injection sites over joints, needle dislodgement
 Prevention
 Central venous catheters
 Skilled nurse to administer Vesicant/irritant properties
 Patients counseling on any changes in sensation(pain, burning, or itching
47. Goolsby TV et al. Extravasation of chemotherapeutic agents: prevention and treatment. Semin Oncol 2006;33:139.

Recommended Extravasation Antidotes(48,49,50)
Class/Specific Agents LocalAntidote
Recommended
Specific Procedure
Cisplatin
Oxaliplatin
sodium thiosulfate Mix 4 mL 10% sodium thiosulfate USP with 6 mL of sterile water for
injection, USP for a 1/6-M solution. Into site, inject 2 mL for each 100 mg
of cisplatin extravasated.
Mitomycin-C Dimethylsulfoxide 99%
(w/v)
Apply 1–2 mL to the site Q 6 hr for 14 days. Allow to air dry; do not cover.
Doxorubicin
Cold compresses
Dimethylsulfoxide 99%
(w/v)
Apply immediately for 30–60 min for 1 day.
Apply 1–2 mL to the site Q 6 hr for 14 days. Allow to air dry; do not cover.
Vinblastine,
Vincristine
Warm compresses
Hyaluronidase
Apply immediately for 30–60 min, then alternate off/on every 15 min for 1
day.Inject 150 U into site.
Etoposide Warm compresses
Hyaluronidase
Apply immediately for 30–60 min, then alternate off/on every 15 min for 1
day. Inject 150 U into site.
Docetaxel
Paclitaxel
Coldcompresses,
Hyaluronidase
Apply immediately for 30–60 min Q 6 hr for 1 day and Inject 150 U into
site.
48. Alley E et al. Cutaneous toxicities of cancer therapy. Curr Opin Oncol 2002;14:212.
49. Clamon GH. Extravasation. In: Perry MC, ed. The Chemotherapy Source Book. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001.
50. Goolsby TV et al. Extravasation of chemotherapeutic agents: prevention and treatment. Semin Oncol 2006;33:139.

Suggested Procedures for Management of
Suspected Extravasation of Vesicant Drugs
a. Stop the injection immediately, but do not remove the needle and aspirate content
b. Contact a physician as soon as possible.
c. Instill an antidote in the infiltrated areas if needed
d. Remove the needle.
e. Apply ice/warm press to the site and elevate the extremity for the first 24–48 hr
f. Use yellow form to document suspected drugs
g. Check the site frequently for 5–7 days.
h. Consult a surgeon for regular patient review if ulcers, debridement or excision occur
advocated
51. Alley E et al. Cutaneous toxicities of cancer therapy. Curr Opin Oncol 2002;14:212.
52. Clamon GH. Extravasation. In: Perry MC, ed. The Chemotherapy Source Book. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001.
53. Goolsby TV et al. Extravasation of chemotherapeutic agents: prevention and treatment. Semin Oncol 2006;33:139

Hypersensitivity Reactions(1)
 Type I (Anaphylactic/IgE-mediated) are immediate and immunologically
mediated and occur during the first dose administration
 Reactions occur when an Ag interacts with IgE bound to a mast cell membrane, causing degranulation of mast cells
 S/S: urticaria, angioedema(vasoactive), rash, bronchospasm,
abdominal cramping, and hypotension(histamine).
 The reaction is further classifies as as(54)
 grade 1 (transient rash, mild)
 grade 2 (mild bronchospasm, moderate) by the National Cancer Institute
(NCI) Common Terminology Criteria for Adverse Events
54. National Cancer Institute. Common Terminology Criteria for Adverse Events v3.0. (CTCAE) Publish date August 9, 2006. Available at http://
ctep.cancer.gov/forms/CTCAEv3.pdf. Accessed June 5, 2007

Hypersensitivity Reactions(2)
 Other uncome reactions:
 Type II: hemolytic anemia
 Type III: deposition of Ag–Ab complexes lead intravascular and
tissue injury.
 Type IV: Sensitized T lymphocytes that react with antigens causing
a release of lymphokines
 Antihistamines and steroids premedications are required for
prevention of common reactions

Monoclonal Antibodies (1)
 Genetically engineered humanized monoclonal antibodies
containing foreign proteins that can trigger the reaction:
rituximab, trastuzumab, and cetuximab (cross reactivity
observed)
 S/S: Rash, diarrhea, hypomagnesemia, headache,
nausea, and hypersensitivity reactions.
 In 15%-20% of patients receiving their first infusion
experience severe hypersensitivity reactions including
allergic and anaphylactic reactions
55. Lenz HJ. Management and preparedness for infusion and hypersensitivity reactions. Oncologist 2007;12:601.

Prophylaxis and Treatment of Hypersensitivity Reactions From
Antitumor Drugs
Prevention and prophylaxis
 IV access must be established.
 BP monitoring must be available.
 Premedication: Dexamethasone 20 mg PO and diphenhydramine 50 mg PO 12 and 6 hr before treatment,
then the same dose IV immediately before treatment
 Consider addition of H2-antagonist with similar schedule
 Epinephrine and diphenhydramine readily available for use in case of a reaction.
 Observe the patient up to 2 hr after discontinuing treatment.
Treatment
 Discontinue the drug (immediately if being administered IV).
 Administer epinephrine 0.35–0.5 mL IV Q 15–20 min until reaction subsides or a total of 6 doses are
administered or diphenhydramine 50 mg IV. If hypotension is present that does not respond to epinephrine,
administer IV fluids.
 If wheezing is present that does not respond to epinephrine, administer nebulized albuterol solution 0.35
mL.
 Although corticosteroids have no effect on the initial reaction, they can block late allergic symptoms. Thus,
administer methylprednisolone 125 mg (or its equivalent) IV to prevent recurrent allergic manifestations.

Gastrointestinal Tract
Toxicities

Gastrointestinal Tract Toxicities
 Nausea and vomiting
 mucositis/stomatitis
 xerostomia (dry mouth
 infection, and bleeding
 esophagitis,
 lower bowel disturbances

Chemotherapy-Induced Nausea & Vomiting (CINV)
 Chemotherapy agents, their metabolites, or neurotransmitters
stimulate dopamine, NK-1, or 5-HT receptors in the GI tract, the
chemoreceptor trigger zone, or the CNS which ultimately act on
the vomiting center.
 Emesis most commonly occurs on the first day of chemotherapy
and often persists for several days thereafter(55)
 Traditional chemotherapy agents require antiemetics use pre-post-
chemo, appropriate antiemetic regimen is based on patient- and
agent-specific factors.
 Novel targeted agents are less emetogenic
56. Lindley CM. Incidence and duration of chemotherapy-induced nausea and vomiting in an outpatient cancer population. J Clin Oncol 1989;7:1142.

Chemotherapy-Induced Nausea and
Vomiting (CINV) Classes
1. Acute phase CINV symptoms: within a few hours,
peak several hours after the admin of the chemotherapy
and can last for the first 24 hours.
2. Delayed CINV symptoms: peak in~2 to 3 days and can
last 6 to 7 days.
3. Anticipatory N/V (conditioned): difficult to treat and
triggered by poor N/V control in previous cycles.
4. Breakthrough N/V: failure of antiemetics prophylaxis

Patients Factors that increase the risk of
acute-phase CINV
 CINV accelerated by: age <50 years, female, poor
control of N/V prior cycles, history of motion
sickness or nausea with pregnancy, anxiety,
depression, disease site and stage, comorbid
conditions, absence of alcohol abuse, and use
non-prescription drug use
 CINV delayed by: age>50, use antiemetics(57)
57. Innes HE et al. Oral antibiotics with early hospital discharge compared with in-patient intravenous antibiotics for low-
risk febrile neutropenia in patients with cancer: a prospective randomised controlled single centre study. Br J Cancer
2003;89:43.

Chemotherapy-Related factors of CINV
 Risk increased by: infusion time, higher dose and chemo cycles
 Based on emetogenicity, chemotherapy agents classified as:
1. Highly emetogenic: >90% patients get CINV
2. Moderate emetogenic: 30% -90% patients get CINV
3. Low emetogenic: 10%-30% patients get CINV
4. Minimal emetogenic:<10% patients get CINV
 It is difficult to estimating the emetogeniticity of chemo combos but
regimens with platinums/cyclophosphamide/anthracycline-highly
emetogenic
58. Ettinger DS et al. Antiemesis: clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network 2007;5:12.
59. Grunberg SM et al. Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity—an update. Support Care Cancer 2005;13:80.
60. Kris MG et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006;24:2932.

Antiemetic Therapy
 CINV involves many neurotransmitters thus combinations
of antiemetics of different therapeutic classes is prefered
than a single agent
 The predominant classes of antiemetics used for CINV:
 Serotonin (5HT3) antagonists: Ondasentrone,
Palonesentrone, Granisentrone
 Neurokinin-1 (NK-1) antagonist: aprepitant
 Corticosteroids: MP and dexamethasone

5-HT3 Antagonists
 The 5-HT3 antagonists inhibit the action of serotonin in the GI tract
and the CNS and thereby block the transmission of emetic signals
to the VC.
 5-HT3 antagonists are both highly effective and have minimal side
effects.
 5-HT3 antagonists have a threshold effect and so a sufficiently
large dose must be given to block the relevant receptors,
ondasentrone iv 16mg stat given pre-post chemo, 8mg PO given
od/bd/tds based on emetogenicity
 Dexamethasone addition enhance effectiveness by about 15% to
20% (61&,62)
61. Grunberg SM. Antiemetic activity of corticosteroids in patients receiving cancer chemotherapy: dosing, efficacy, and tolerability analysis. Ann Oncol

Corticosteroids
 Decreases serotonin release, antagonize serotonin receptors,
and activate corticosteroid receptors in the Nucleus Tractus
Solitarius-NTS of the medulla in the CNS(63).
 Dexamethasone (0.5MG PO, 8mg IV) preferred:- more studied,
inexpensive and available in both IV and oral formulations.
 A single 8-mg PO is effective as larger doses or prolonged
administration (64) and in the setting of highly emetogenic
cisplatin-based chemotherapy, higher doses of 12 or 20 mg were
superior to doses of 4 and 8 mg(65)
63. Grunberg SM. Antiemetic activity of corticosteroids in patients receiving cancer chemotherapy: dosing, efficacy, and tolerability analysis. Ann Oncol 2007;18:233.
64. The Italian Group for Antiemetic Research. Randomized, double-blind, dose-finding study of dexamethasone in preventing acute emesis induced by anthracyclines, carboplatin, or
cyclophosphamide. J Clin Oncol 2004;22:725.
65. The Italian Group for Antiemetic Research. Double-blind, dose-finding study of four intravenous doses of dexamethasone in the prevention of cisplatin-induced acute emesis. J Clin Oncol
1998;16:2937.

Corticosteroids
 For prevention of delayed CINV symptoms, the most commonly used dose of
dexamethasone is 8 mg twice daily on days 2 and 3 after chemotherapy without aprepitant.
 The dose should be reduced to 8 mg daily when used with aprepitant., inhibition of steroid
metabolism by aprepitant (66)
 Hyperglycemia can occur, especially in patients with pre-existing diabetes, glucose
monitoring necessary(67).
 Corticosteroids also have antitumor properties and are part of antineoplastic regimen(R-
CHOP) for some malignancies,; lymphoma, lymphoid, and myeloma, no need of additional
dexamethasone for the antiemetic protection; however, the corticosteroid should be
administered before the rest of the chemotherapy to provide antiemetic activity and If
aprepitant is part of an antiemetic regimen the dose of the corticosteroid should not be
reduced (67)
66. Kris MG et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006;24:2932.
67. Grunberg SM. Antiemetic activity of corticosteroids in patients receiving cancer chemotherapy: dosing, efficacy, and tolerability analysis. Ann Oncol 2007;18:233.

Neurokinin-1 Receptor Antagonists
 The potential use of NK-1 receptor antagonists as antiemetics
became apparent when the role of substance P in the peripheral
and CNS was recognized in the emetic stimulus pathway.
 Dose is a 125 mg on day 1 and 80 mg on days 2 and 3, is not
replace a 5-HT antagonist, combo with corticosteroids and 5-HT3
antagonist is highly preferred.
 Aprepitant increases the AUC of dexamethasone such that the
dexamethasone dose (when used as an antiemetic) should be
reduced by about one-half of the usual dose when these drugs are
used together(68)
68. McCrea JB et al. Effects of the neurokinin-1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin
Pharmacol Ther 2003;74:17.

Other Antiemetics in CINV
 Dopamine antagonists (prochlorperazine, promethazine),
benzodiazepines (lorazepam), butyrophenones (droperidol,
haloperidol), benzamides (metoclopramide), and cannabinoids.
 Many of these agents have more side effects than standard
agents, especially sedation and extrapyramidal side effects, such
as dystonia and akathesia.
 Lorazepam is commonly used as a rescue antiemetic.
 Treatment guidelines have been developed by several groups
 The American Society of Clinical Oncology (ASCO)
 The National Comprehensive Cancer Network (NCCN)
 The Multinational Association of Supportive Care in Cancer (MASCC)

Clinical advise
 Patients have to refrain from heavy avoid heavy, greasy,
strong aromas meals, 8 to 12 hours before the chemo.
 Chewing gum can mask the metallic taste and dry, salty
foods can also help settle the stomach.
 Antiemetic efficacy, or complete emetic response, is
usually defined as no emesis and no nausea or only mild
nausea in the first 24 hours after chemotherapy
administration.

Complications of the Oral Cavity
 Oral cavity cells undergoing rapid division and renewal with a turnover
time equal to 7 to 14 days.
 Chemotherapy reduces the renewal rate of the basal epithelium and
can cause mucosal atrophy, as well as glandular and collagen
degeneration(69)
 Complication include: infection(myelosuppression, altered oral flora),
bleeding(thrombocytopenia and traumatised vessels)
 Xerostomia can accelerate the development of mucositis, dental caries
and local infection while mucositis can clearly predispose the oral cavity
to local bleeding and infection and sepsis.
 Complication can cause discomfort and compromised nutritional status.
69. Lockhart PB, Sonis ST. Alterations in the oral mucosa caused by chemotherapy agents. J Dermatol Surg Oncol 1981;7:1019.

Xerostomia
 Amifostine
 an organic thiophosphate chemoprotectant agent, is approved to
reduce the incidence of moderate to severe xerostomia in patients
having postoperative radiation treatment for head and neck cancer
when the radiation port includes a substantial portion of the parotid
glands.

Mucositis and Stomatitis
 Nonkeratinized mucosa is affected mostly: buccal, labial, and soft
palate; the ventral surface of the tongue; and the floor of the mouth
 Lesions are usually discrete initially, progress to ulcers, may extend to
the esophagus and the entire GI tract, but not outside the mouth
 Manifested in 5-7days post-chemo or at almost any point during
chemoradio
 The antimetabolites-methotrexate, fluorouracil, and cytarabine) and the
antitumor antibiotics commonly produce direct stomatotoxicity
 Lesions generally regress and resolve in ~1-3/52
 S/S: pain, bleeding, decreased ability to eat and speak, and local or
systemic infections (Bacterial, fungal, or viral).

Management of Mucositis
Treatment of mucositis is palliative.
 Topical anesthetics: lidocaine or dyclonine hydrochloride 0.5 or 1%
 Kaolin, PPIs, diphenhydramine, and magnesium-aluminum antacids
can be used for their anesthetic and astringent properties(BMX/SBX-
4:4:1) and sucralfate coat the lesion and reducing discomfort
 Analgesics and corticosteroids for pain relief and inflammatory relief
resp.
 Antibiotics for bacteria infection and nystatin for oral candidiasis
 Orabase(benzocaine) & ice chips (dry affected area with a sponge to
apply)
 Gelclair is a bioadherent oral gel containing polyvinylpyrrolidone and
sodium hyaluronate, give adherent barrier over the mucosal surfaces,
thereby shielding oral lesions from the effect of food, liquids, and saliva

The use topical anesthetics agents
 All the topical anesthetic-containing preparations are
recommended for use as “swish-and-spit” preparations
(??)
 Generally, 5 to 10 mL is used three to six times a day.
 The longer the patient can hold the solution in the mouth,
the longer the contact, and, theoretically, the better the
symptom relief.
 Therefore, patients should be advised to hold and swish
the solution around the mouth for as long as possible
before spitting it out.

Prevention of Mucositis
 Placed ice chips in mouth 5min before chemotherapy and retained for 30
minutes, will reduce blood flow to the mouth, thereby protecting the dividing
cell population from toxins(70).
 Oral glutamine reduce severity and duration of oral pain after chemotherapy.
 Chlorhexidine gluconate 0.12% soln bd, reduce the frequency and severity of
mucositis, infection by eliminating microorganisms in the oral cavity(71-72),
burning sensetion-alochol- reduced by diluting it with water), superficial brown
tooth staining, which polishes off easily
 Palifermin a recombinant keratinocyte GF, hematologic malignancies patients
having BMT to reduce the incidence and duration of severe oral mucositis.
70. Mahood D et al. Inhibition of fluorouracil-induced stomatitis by oral cryotherapy. J Clin Oncol 1991;9:449.
71. Okuno SH et al. Phase III controlled evaluation of glutamine for decreasing stomatitis in patients receiving fluorouracil (fluorouracil)-based chemotherapy. Am J Clin Oncol 1999;22:258.
72. Ferretti GA et al. Chlorhexidine in prophylaxis against oral infections and associated complications in patients receiving bone marrow transplantation. J Am Dent Assoc 1987;114:292.

Esophagitis
 Dysphagia is a cardinal symptom of esophagitis rule out
ddx, patient may develop infectious esophagitis, bacterial,
viral, and fungal
 Management of esophagitis is similar to mucositis.
 Adequate oral hydration and nutritional intake and
instructed to avoid acidic or irritating foods.
 Symptoms should resolve in 1 to 2 weeks as
myelosuppression resolves.

Lower GI Tract Complications
 Malabsorption, diarrhea, and constipation: GI tract structural changes that
occur after chemotherapy or radiation therapy, villus atrophy and mitosis
ceasation within GI crypts in patients seen
 Swelling and dilation of mitochondria and endoplasmic reticulum and
shortening of the microvilli
 Diarrhea: regimens containing irinotecan, high-dose cytarabine, or fluorouracil
 Constipation is rare: vinca alkaloids, produce colicky abdominal pain,
constipation, and adynamic ileus caused by autonomic nerve
dysfunction(stool softeners and mild stimulants) and thalidomide
 Chemotherapy induced Diarrhea /constipation is difficult to discern: because
opioid analgesics, antiemetics, antacids and immobility commonly associated
with cancer and can cause these symptoms as well.
73. Shaw MT et al. Effects of cancer, radiotherapy and cytotoxic agents on intestinal structure and function. Cancer Treat Rev 1979;6:141.
74. Wurth MA et al. Mechlorethamine effects on intestinal absorption in vitro and on cell proliferation. Am J Physiol 1973;225:73.
75. Roche AC et al. Correlation between the histological changes and glucose intestine absorption following a single dose of 5-fluorouracil. Digestion 1970;3:195.

IRINOTECAN INDUCED DIARRHOEA
EARLY-ONSET-WITH 24HRS
LATE-ONSET OCCURRING >24 HOURS AFTER TREATMENT
PARASYMPATHETIC STIMULATION,
CHOLINERGIC SYMPTOMS (RHINITIS,
SALIVATION, MIOSIS, LACRIMATION,
DIAPHORESIS, FLUSHING, AND ABDOMINAL
CRAMPING
PREVENTED OR MANAGED WITH
ATROPINE IV OR SC 0.25 TO 1 MG.
DEHYDRATION, ELECTROLYTE IMBALANCES, AND SIGNIFICANT MORBIDITY
LOPERAMIDE 4 MG STAT THEN 2 MG EVERY 2 HOURS UNTIL 12 HOURS
HAVE PASSED WITHOUT A BOWEL MOVEMENT(1),
OCTREOTIDE (SOMATOSTATIN) 100 TO 2,000 MCG SC TDS DAILY OR
20 TO 40 MG OD OF LONG-ACTING OCTREOTIDE
IF NO RESPONSE GIVEN 4 MG EVERY 2 HOURS/EVERY AFTER A RUN
FLUID AND ELECTROLYTE REPLACEMENT
Management of chemotherapy induced diarrhoea 76. Camptostar package insert. New York, NY: Pfizer Inc.; June 2006.

Specific Organ Toxicities

Specific Organ Toxicities
 Neurotoxicity
 Peripheral Nerve Toxicity
 Cranial Nerve Toxicity
 Autonomic Neuropathy
 Cardiac Toxicities
 Nephrotoxicity
 Pulmonary Toxicities
 Hepatotoxicity

Neurotoxicity: Cytarabine
 Generalized encephalopathy: confusion, obtundation, seizures,
and coma
 Cerebellar dysfunction, presenting as ataxia, gait and coordination
difficulties, dysmetria (inability to arrest muscular movement when
desired and lack of harmonious action between muscles when
executing voluntary movement), progressive leukoencephalopathy
and chemical meningitis.
 Leukoencephalopathy: progressive personality and intellectual
decline; dementia; hemiparesis; and, sometimes, seizures.
 May partially resolve over days to weeks after discontinuation of
therapy.

Neurotoxicity: L-Asparaginase
 Symptoms can be late/early: Stupor, coma, excessive
somnolence, disorientation, hallucination, or severe depression.
 The acute syndrome-rapidly while delayed syndrome can last
several weeks.
 Other agents: methotrexate, fluorouracil, fludarabine, ifosfamide
and oxaliplatin.
 Early diagnosis is challenging: comorbid conditions, metastatic
disease and paraneoplastic syndromes
 Prevention: dose modifications/ discontinuation of the agent.
77. Sul JK et al. Neurologic complications of cancer chemotherapy. Semin Oncol 2006;33:324.

Peripheral Nerve Toxicity:
Vincristine
 Paresthesia: feet and hands numbness and tingling, loss of ankle jerks,
and depression of deep tendon reflexes appears within the first few
weeks of therapy.
 Areflexia(absent reflexes) typically occurs in about 50% to 70% of
patients treated with a cumulative dose >6 to 8 mg.
 Pain, temperature sensory loss, foot drop or muscle atrophy.
 Risk: young, combo chemo
 Bilateral/symmetric is referred to as a “stocking-glove” neuropathy.
 Other agents: vinblastine, vinorelbine, cisplatin, etoposide, oxaliplatin,
paclitaxel, docetaxel, bortezomib, thalidomide, and lenalidomide.
77. Sul JK et al. Neurologic complications of cancer chemotherapy. Semin Oncol 2006;33:324.

Peripheral Nerve Toxicity: Prevention
 Calcium gluconate 1 g IV and magnesium sulfate 1 g IV 15 minutes
before and immediately after completion of chemo( oxaliplatin)
 Consequently, calcium and magnesium infusions are given routinely
with (platinum analogues) oxaliplatin administration
78. Cersosimo RJ. Cisplatin neurotoxicity. Cancer Treat Rev 1989;16:195.

Cranial Nerve Toxicity: Vinca
alkaloids
 Ptosis or ophthalmoplegia(3rd cranial nerve damage), 1-10% cases (79
& 80)
 Others: Trigeminal neuralgia, facial palsy, depressed corneal reflexes,
vocal cord paralysis, jaw pain(81)
 Cranial nerve toxicities (vincristine) may be dose limiting
 Other agents: Ifosfamide, vinblastine, and cisplatin
 Ototoxicity (sensorineural hearing loss-cochlea)-cisplatin/radio(82
& 83), stop medication or carboplatin can be used instead(84)
79. Sandler SG et al. Vincristine-induced neuropathy: a clinical study of fifty leukemic patients. Neurology (Minn) 1969;19:367.
80. Albert DM et al. Ocular complications of vincristine therapy. Arch Ophthalmol 1967;78:709.
81. Holland JF et al. Vincristine treatment of advanced cancer: a cooperative study of 392 cases. Cancer Res 1973;33:1258.
82 Granowetter L et al. Enhanced cisplatinum neurotoxicity in pediatric patients with brain tumors. J Neuro Oncol 1983;1:293.
83. Schaefer SD et al. Ototoxicity of low-and moderate-dose cisplatin. Cancer 1985;56:1934.
84. Canetta R et al. Carboplatin, the clinical spectrum to date. Cancer Treat Rev. 1985;12:125.

Autonomic Neuropathy: Vincristine
 Colicky abdominal pain -/+ constipation 33%-50%(85 &
86)
 Because severe constipation (or include adynamic ileus)
 Stimulant laxatives: senna derivatives, lactulose, bisacodyl
are believed to be the most effective agents, and stool
softeners also may be used concurrently.
 Other autonomic dysfunction:bladder atony(urinary
retention) impotence, and orthostatic hypotension(87&88).
85. Sandler SG et al. Vincristine-induced neuropathy: a clinical study of fifty leukemic patients. Neurology (Minn) 1969;19:367.
86. Albert DM et al. Ocular complications of vincristine therapy. Arch Ophthalmol 1967;78:709.
87. Carmichael SM et al. Orthostatic hypotension during vincristine therapy. Arch Intern Med 1973;126:290.
88. Gottlieb RJ et al. Vincristine-induced bladder atony. Cancer 1971;28:674.

Cardiac Toxicities: Doxorubicin
 Cardiomyopathy: myocyte damage (Ø cytotoxic effect on tumor cells-
myocytes stop dividing in infancy) whose cytotoxicity relies on
actively cycling cells(89,90).
 Risk factors: Dose-dependent, repeated administration, mediastinal
radiatiotherapy, pre-existing CVD, terminal age and concurrent
chemo agents (cyclophosphamide, trastuzumab, paclitaxel,
vincristine, bleomycin)(91).
 In PK, paclitaxel increases AUC-doxorubicin and its active
metabolite, doxorubicinol, thus, doxorubicin should be given at least
30 minutes before paclitaxel, guidelines restrict the total cumulative
dose of doxorubicin to 450 mg/m2 in high-risk patients and to 550
mg/m2 in low-risk patients
89. Tan C et al. Adriamycin—an antitumor antibiotic in the treatment of neoplastic diseases. Cancer 1973;32:9.
90. Lefrak EA et al. A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 1973;32:302.
91. Ng R et al. Anticancer agents and cardiotoxicity. Semin Oncol 2006;33:2.

Prevention of Cardiomyopathy
 Limiting the total cumulative dose of doxorubicin 450–500 mg/m2
 Monitoring systolic time intervals, an electrocardiogram (ECG) (92,93)
 Doxorubicin encapsulated in liposomes (liposome doxorubicin), liposomal pegylated
doxorubicin may be similar to conventional doxorubicin with decreased cardiotoxicity(94, 95).
 Additionally, the equivalent dose of liposomal preparations to conventional doxorubicin is not
confirmed.?
 Dexrazoxane is a chemoprotectant that reduces the incidence and severity of cardiomyopathy: a
cumulative doxorubicin dose of 300 mg/m2 in dose ratio dexrazoxane : doxorubicin is 10:1 slow
IV push 30 minutes before starting doxorubicin.
 The ASCO guidelines do not support the routine use of dexrazoxane in patients unless a plan
exists to continue doxorubicin beyond a total cumulative dose >300 mg/m2.
92. Bloom K et al. Echocardiography in adriamycin cardiotoxicity. Cancer 1978;41:1265.
93. Biancaniello T et al. Doxorubicin cardiotoxicity in children. J Pediatr 1980;97:45.
94. O'Brien M et al. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin versus conventional doxorubicin for first-line treatment of metastic breast
cancer. Ann Oncol 2004;15:440.
95. Waterhouse DN, Tardi PG, Mayer LD, Bally MB. A comparison of liposomal formulations of doxorubicin with drug administered in free form: changing toxicity profiles. Drug Saf. 2001;24(12):903-
20. doi: 10.2165/00002018-200124120-00004. PMID: 11735647.

Anthracycline-induced CHF
 Anthracycline-induced Biventricular CHF
 Treated with diuretics, activity restriction, inotropic
agents, and vasodilators, but these measures often
are ineffective.
 The use of spironolactone, beta blockers, and
angiotensin-converting enzyme (ACE)
inhibitors(Enalapril), which have decreased morbidity
and mortality in non–anthracycline-induced CHF

Nephrotoxicity: Cisplatin
 Acute: The proximal renal tubules damaged(β2-microglobulin,
alanine aminopeptidase, and N-acetyl glucosamine) where the
highest concentration of platinum occurs.
 Enzymes titer correlate with protein excretion, decrease
magnesium, salt and water reabsorption
 Chronic: GFR decrease(>25% case), increase in
SrCr/decrease of CrCL receiving multiple courses(96-97)
 CrCl done by a 12- to 24-hour urine collection for creatinine.
96. Kintzel PE. Anticancer drug-induced kidney disorders. Drug Saf 2001;24:19.
97. de Jonge M et al. Renal toxicities of chemotherapy. Semin Oncol 2006;33:68.

Prevention and Management(1)
 Hydration: NS 2-3 L NS over 8 to 12 hours to maintain a urine output of 100 to
200 mL/hour for at least 6 hours after treatment with cisplatin(98,99,100)
 Mannitol (25–50 g) Pre-chemo (prevent cisplatin-induced renal artery
vasoconstriction, which can increase the concentration of platinum in the
renal tubules(100, 101)
 Prophylactic magnesium 16 mEq IV daily during a 5-day course of cisplatin
followed by 60 mEq orally (20 mEq three times daily) prefered>An oral
magnesium (diarrhea)
 A loop diuretic: furosemide in elderly patients to treat hypernatremia in
patients with compromised cardiac reserve(Ø routine use)
98. Ries F et al. Nephrotoxicity induced by cancer chemotherapy with special emphasis on cisplatin toxicity. Am J Kidney Dis 1986;8:368.
99. Finley RS et al. Cisplatin nephrotoxicity: a summary of preventative interventions. Agent Intell Clin Pharm 1985;19:362.
100. Pera MF et al. Effects of mannitol or furosemide diuresis on the nephrotoxicity and physiological disposition of cis-dichlorodiammineplatinum-(II). Cancer Res 1979;39:1269. Ries
101. F et al. Nephrotoxicity induced by cancer chemotherapy with special emphasis on cisplatin toxicity. Am J Kidney Dis 1986;8:368.

Prevention and Management(2)
 ASCO: Amifostine 910 mg/m2 OD, 15-minute IV infusion starting
30 minutes pre-chemo (free radical scavenger of cisplatin) for the
prevention of nephrotoxicity and neutropenia need to stop 24hrs
antihypertensives before chemo, coz significant
hypotension(Monitor BP/SBP)
 Recommended 50% dosage reduction when the GFR decreases to 30
to 60 mL/minute and discontinuation when the GFR falls to <10 to 30
mL/minute(102)
 Because the cisplatin dose ranges from 50 mg/m2 to 150 mg/m2, the
precise dose for a patient with a GFR of <60 mL/minute must be
individualized to the situation.
102. Patterson WP et al. Renal and electrolyte abnormalities due to chemotherapy. In: Perry MC, ed. The Chemotherapy Source Book. 3rd ed.

Dose Adjustment
103. Calvert AH et al. Carboplatin dosage: prospective evaluation of a simple formula
based on renal function. J Clin Oncol 1989;7:1748.
 If the tumor responds to
carboplatin, substitution
should be considered
because it does not cause
nephrotoxicity.
 The dose of carboplatin
when calculated by the
Calvert equation adjusts for
with decreased GFR.
 Carboplatin it is primarily
excreted by the kidneys.

Bladder Toxicity(oxazaphosphorine-induced
hemorrhagic cystitis)
 Ifosfamide~cyclophosphamide: oxazaphosphorine alkylating agents,
hydroxylated and activated by the liver enzymes, spontaneously
liberates acrolein, excreted in high concentrations in the urine
 Urotoxicity causing a direct irritation of the bladder mucosa.
 Cystitis is characterized by tissue edema and ulceration followed by
sloughing of mucosal epithelial cells, necrosis of smooth muscle fibers
and arteries, and culminating in focal hemorrhage.
 Because the metabolic activation of ifosfamide proceeds more
slowly than that of cyclophosphamide and the dosages of
ifosfamide are 3-4x>cyclophosphamide thus higher incidence of
urotoxicity is associated with ifosfamide.

Prevention of Urotoxicity(1)
 Hydration flushes the toxic metabolites reduce contact time
 Mesna-uroprotective agent, liberates free thiol groups in the bladder,
which can neutralize the oxazaphosphorine metabolite
 ASCO/NCCN: recommend a parenteral mesna dose of 20% of the
ifosfamide dose (<2.5 g/m2) given IV at zero/before the IFOS, 4/with
IFOS/cocktail, and 8 hours/after IFOS (for a total mesna dose of 60% of
the ifosfamide dose)(104)
 The goal is to maintain mesna levels within the urinary tract for some
time after treatment with ifosfamide to provide adequate uroprotection.
 Repeated administration is required because mesna has a short
elimination half-life (<1 hour), especially compared with the relatively
long half-life of ifosfamide.
104. Hensley ML et al. American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. J Clin Oncol
1999;17:3333.

 Patients receiving CIV ifosfamide, ASCO guidelines recommend an IV
bolus mesna dose of 20% of the ifosphamide followed by a 40% mesna
dose by continuous infusion given over 12 to 24 hours after the end of
the ifosfamide infusion(104)
 Ensures mesna remains with max protection in the bladder for an
extensive amount of time following the end of the ifosfamide infusion.
 Mesna on occasion given as CIV to avoid the need for frequent bolus
dosing.
 Because ifosfamide and mesna are compatible in solution, combining
the ifosfamide and mesna in one IV bag and administering by
continuous infusion allows patients to conveniently receive
uroprotection.

 Forced hydration has been the mainstay for prevention of
cyclophosphamide-induced hemorrhagic cystitis, it is unnecessary and
potentially disadvantageous when mesna is used , can increase
urination and increase the evacuation of mesna from the bladder(105-
106)
 When patients receive cyclophosphamide for a BMT, they may receive
mesna in conjunction with saline diuresis because the higher
cyclophosphamide dosages produce more of the urotoxic metabolites
than conventional dosing.
 Hyperhydration and bladder irrigation (ASCO consensus
guidelines(104)
1999;17:3333.
105. Shaw IC, Graham MI. Mesna—a short review. Cancer Treat Rev 1987;14:67.

Pulmonary Toxicities: Bleomycin
 Cause interstitial pneumonitis->pulmonary fibrosis-> nonproductive
cough and dyspnea-> bibasilar rales + coarse rales(107-109)
 CXR early (normal), subsequently; bilateral alveolar and interstitial
infiltrates, hypoxia(105)
 Compromise PFX: forced vital capacity falls below 75%
 Observed in cumulative dose(450 to 500 mg) of bleomycin, CIV reduce
the incidence(110)
 Bleomycin halted in decompensated pulmonary function
 Oxygen: symptomatic support
107. Meadors M et al. Pulmonary toxicity of chemotherapy. Semin Oncol 2006;33:98.
108. Hinson JM et al. Chemotherapy-associated lung injury. In: Perry MC, ed. The Chemotherapy Source Book. 3rd ed. Philadelphia: Lippincott Williams &
Wilkins; 2001.
109. Stover DE et al. Pulmonary toxicity. In: De Vita VT et al, eds. Cancer: Principles and Practice of Oncology, 7th Ed. Philadelphia: Lippincott Williams &
Wilkins; 2005.
110, Sikic BI et al. Improved therapeutic index of bleomycin when administered by continuous infusion in mice. Cancer Treat Rep 1978;62:2011.

Hepatotoxicity
 S/S: jaundice, nausea, vomiting and abdominal pain
 Chemo induces: hepatotoxicity cytarabine, mercaptopurine,
methotrexate(daily dose> intermittent basis(111, 112)
 In metabolism, chemo damage the metabolic processes in the liver,
by(113)
(a) interfering with the mitochondrial function of the hepatocyte,
(b) depleting hepatic glutathione stores
(c) eliciting hypersensitivity reactions
(d) decreasing bile flow
(e) causing phlebitis of the central hepatic vein to produce veno-occlusive disease.
111. Dahl MGC et al. Methotrexate hepatotoxicity in psoriasis—comparison of different dosage regimens. BMJ 1972;1:654.
112. Podugiel BJ et al. Liver injury associated with methotrexate therapy for psoriasis. Mayo Clin Proc 1973;48:787.
113. Floyd J et al. Hepatotoxicity of chemotherapy. Semin Oncol 2006;33:50.

Common Causes of Elevated LFT in
Patients With Cancer
 Primary or metastatic tumor involvement of the liver
 Hepatotoxic drugs (e.g., cytotoxics, hormones [estrogens, androgens],
antimicrobials [trimethoprim-sulfamethoxazole, voriconazole])
Infections (e.g., hepatic candidiasis, viral hepatitis)
 Parenteral nutrition
 Portal vein thrombosis
 Paraneoplastic syndrome
 History of liver disease (including hepatitis B and C)

Types of Hepatotoxicity
Hepatocellular fatty metamorphosis
Veno-occlusive disease
Hepatocellular???
Cholestatic

Liver Functions Markers
 Serum transaminases, alkaline phosphatase, and bilirubin levels should
be monitored routinely in patients receiving hepatotoxic chemotherapy.
.
 Serum levels of proteins produced by the liver (e.g., ferritin, albumin,
prealbumin, or retinol-binding protein) also may be helpful in assessing
liver function.
 If the chemotherapy is the suspected cause hepatic dysfuctions, should
be withheld until LFT are within normal ranges.

Infections in People with Cancer

Risk factors for infection
• Neutropenia(immunity weaken): chemotherapy, radiation
therapy, stem cell transplant, or bone marrow transplant
• Medications: steroids, mAbs
• Cancers type: affect/met bone marrow, performance status and
stages
• Mucositis: Irritation or soreness of the digestive tract lining
• Other medical conditions: diabetes, COPD, autoimmune disease
• Other factors: poor nutrition, stress, or lack of sleep
114. American cancer society; cancer.org | 1.800.227.2345

Common sites of infection in people with cancer
 The skin and mucous membranes (soft linings-mouth,
vagina, and intestines)
 The digestive system (mouth, esophagus, stomach, and
intestines)
 The lungs and breathing passages (sinuses and throat)
 The urinary system (bladder and kidneys)
 The nervous system (brain and spinal cord)
 The skin and tissue around a central venous catheter2
(CVC).

Causes of Infection
 Compromised immunity: malignant disease and chemotherapy
 Fever: most constant and an indicator of infection(neutropenia/lack of
inflammatory mediators0)
 Infections is more serious and harder to treat> non cancer patients
 Specific microbiological diagnosis: sputum and bronchoalveolar lavage
samples lack of clear distinction between colonization and infection
 Tissue biopsy: reliable but is rarely available(haemorrhagic
complication)
 Immunocompromised patients do not raise adequate antibody titres in
response to infections: Ab detection is not useful for early diagnosis

Signs of infection in people with cancer
 Fever(higher than normal body temperature)
 Shaking chills or sweats (often goes along with fever)
 Sore throat Sores or white coating on your tongue or in your mouth
 Cough or shortness of breath
 Nasal congestion
 Burning or pain when urinating; bloody or cloudy urine
 Redness, swelling, drainage, or warmth at the site of an injury, surgical
wound, or IV such as a central venous catheter (VAD), or anywhere on the
skin including the genital and rectal areas
 Pain or tenderness in the stomach or abdomen (the belly)
 Stiff neck
 Sinus pain, ear pain, or headache

Opportunistic Infections
Haematogenous
Pulmonary
Central nervous system (CNS) infection

Drugs used for treating infections in
people with cancer
Anti-biotics
Anti-fungals
Anti-virals
Anti-protozoal
Anti-helminthics

115. J. Klastersky & M. Aoun, 2017; Opportunistic infections in patients with cancer
The use of Antibiotics based on AWaRE categorization, antibiodiagrams, STG/NEMLT, 2021, pharmacoeconomics

The prophylactic and therapeutics use: STG/NELT, nation guidelines

The prophylactic and therapeutics use: STG/NELT, national guidelines

Biomarkers for Sepsis
 Useful for monitoring the infectious process.
 Procalcitonin (PCT) and C-reactive protein (CRP)
 Compromised with other inflammatory conditions or to predict
outcome.
 PCT and CRP: guide empirical therapy and prognostic
assessments
 Other biomarkers: soluble triggering receptor expressed on
myeloid cells-1 (sTREM-1), soluble urokinase-type plasminogen
receptor (suPAR), proadrenomedullin (ProADM), and presepsin.
117. Cesar Henriquez-Camacho and Juan Losa; Biomarkers for Sepsis:
2014

Role of biomarkers of sepsis.
117. Cesar Henriquez-Camacho and Juan Losa; Biomarkers for Sepsis: 2014

Long-Term Complications of Chemotherapy

Acute Myeloid Leukemia (AML)
 AML (1-3 yrs post therapy) may occur in hematologic malignancies,
solid tumors, and nonmalignant diseases(118)
 Topoisomerase inhibitors (etoposide) and anthracyclines (doxorubicinn
& epirubicin), solo/combo(119) used is more associated with AML
 Chromosome mutation 11q23 are involved in many of the cases with
cytogenetic abnormalities from topoisomerase inhibitors(120)
 AML observed in previous exposure to alkylating agents(melphalan) (5-
7 yrs) after the patient finishes chemotherapy(121)
 Risk factor: Large, continuous, dose, age >40 years, and chemoradio
118. Boyce JD. Second malignancies after chemotherapy. In: Perry MC, ed. The Chemotherapy Source Book. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001.
119. Pedersen-Bjergaard J et al. Increased risk of myelodysplasia and leukaemia after etoposide, cisplatin, and bleomycin for germ-cell tumors. Lancet 1991;338:359.
120. Smith RE et al. Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National
Surgical Adjuvant Breast and Bowel Project Experience. J Clin Oncol 2003;21:1195.
121. Casciato DA et al. Acute leukemia following prolonged cytotoxic agent therapy. Medicine (Baltimore) 1979;58:32.

OTHER MALIGANCIES
 Lymphoid Malignancies(Non-hodgkin's Lymphoma)-
Immunosuppression
 Solid tumors: superficial bladder cancer (oral cyclophosphamide), and
bone sarcoma (alkylating agents)(122).
 The best “treatment” of therapy-associated AML is prevention
 Use current and reliable guidelines in cancer treament-NCCN, ASCO
122. Tucker MA et al. Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med 1987;317:588.

Fertility and Teratogenicity: Effects on Oogenesis
 Chemo is potentially gonadotropic in pre and pubertal, loss of ova and follicular
elements(123-125)
 Cyclophosphamide, vinblastine, etoposide, and cisplatin have strong evidence on the
development of gonadotoxcity(126, 127)
 The damage of follicular elements (FSH and LH) is extensive and irreversible, fertility is
impaired even if the ova are spared also chemo reduces ovarian estrogen and progesterone
secretion in menstruating women.
 Severe/prolonged, chemo use: irregular/delayed menses to permanent ovarian failure and
depletion of ova and follicles.
 !!!Prepubertal girls have a greater reserve of primary follicles (ovaries are not producing
OH/PH, increases in FSH and LH with resultant recruitment of follicular elements do not
occur hence can tolerate large doses(125, 128)
123. Belohorsky B et al. Comments on the development of amenorrhea caused by Myleran in cases of chronic myelosis. Neoplasma 1960;7:397.
124. Sobrinho LG et al. Amenorrhea in patients with Hodgkin's disease treated with chemotherapy agents. Am J Obstet Gynecol 1971;109:135.
125. Nicosia SV et al. Gonadal effects of cancer therapy in girls. Cancer 1985;55:2364.
126. Klein CE. Gonadal complications and teratogenicity of cancer therapy. In: Perry MC, ed. The Chemotherapy Source Book. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001.
127. Myers SE et al. Prospects for fertility after cancer. Semin Oncol 1992;19:597.
128. Maltaris T et al. The effect of cancer treatment on female fertility and strategies for preserving fertility. Eur J Obstet Gynecol Reprod Biol 2007;130:148.

Effects on Spermatogenesis
 Progressive dose-related depletion of the germinal epithelium
lining the seminiferous tubule, reduction in testicular volume and
azoospermia-> loss of reproductive capacity(129).
 On Rx Libido and sexual activity may decline, but most men report
a return to pretreatment sexual function after chemotherapy.
 The Leydig cells responsible for testosterone production remain
morphologically intact, although mild functional impairment occurs
rarely.
 Non phase specific mostly associated with azoospermia>Phase-
specific agents
129. Meistrich ML. Critical components of testicular function and sensitivity to disruption. Biol Reprod 1986;34:17.

Summary
1. Oncologists/clinicians: close, precise and adequate assessment,
management and prevention of antineoplastics ADEs
2. Pharmacists: availability of affordable, quality, safe and efficacious
antineoplastics medicines, medicines to manage ADEs, and be part of
cancer patients care team to advice on anticancers rational
prescribing and dispensing and other medication used to treat
antineoplastic ADEs respectively
3. Nurses: right anticancers administration by considering the peculiar
nature of each drug and inform clinicians and pharmacists on
presence of ADEs
4. Patients: educated on importance of earlier communicating of ADEs
during cancer treatment for best prevention and treatments

“NO single evaluation can
substitute for the
therapeutic accuracy of the
experienced, motivated,
knowledgeable and life long
learner health personnel”
5/9/2021

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