Chemotherapy in Breast Cancer

1. CHEMOTHERAPY IN BREAST
CANCER
Dr. Shaurya Mehra
2nd Year PG Resident
M.D. Radiation Oncology
Government Cancer
Hospital, MGMMC,
Indore

2. Rationale Behind Adjuvant Chemotherapy

16. Most Commonly Used Agents

17. ALKYLATING AGENTS

18. Cyclophosphamide
• Activated by Cty. P450 into cytotoxic metabolites phosphoramide mustard and acrolein.
• Cyclophosphamide metabolites form cross-links with DNA  inhibition of DNA synthesis and function.
• Cell cycle–nonspecific agent, active in all phases of the cell cycle.
• Encourage fluid intake of at least 2–3 L/day to reduce the risk of hemorrhagic cystitis.
• Increases effects of anticoagulants, may increase the risk of doxorubicin-induced cardiotoxicity.
• Drugs stimulating liver P450 enzymes increase the rate of metabolic activation of cyclophosphamide to its
cytotoxic metabolites.
• Dose limiting toxicity is Myelosuppression.
• Bladder toxicity in the form of hemorrhagic cystitis, dysuria, and increased urinary frequency occurs in 5%–
10% of patients. Uroprotection using Mesna and adequate hydration is a must.
• Breast cancer—When given orally, the usual dose is 100 mg/m2 PO on days 1–14 given every 28 days. When
administered IV, the usual dose is 600 mg/m2 given every 21 days as part of the AC or CMF regimens.

19. ANTIMETABOLITES

20. Methotrexate
• Cell cycle–specific antifolate analog, active in S-phase of the cell cycle.
• Enters cells through specific transport systems mediated by the reduced folate carrier and the folate receptor
protein.
• Requires polyglutamation by the enzyme folylpolyglutamate synthase (FPGS) for its cytotoxic activity.
• Inhibition of dihydrofolate reductase (DHFR)  depletion of critical reduced folates.
• Dose is 40mg/m2 on D1 and D8 (CMF Regimen)
• Renal excretion is the main route of elimination and is mediated by glomerular filtration and tubular secretion.
• Aspirin, penicillins, probenecid, NSAIDs, and cephalosporins—These drugs inhibit the renal excretion of
methotrexate, leading to enhanced drug effect and toxicity.
• Leucovorin—This rescues the toxic effects of methotrexate and may also impair the antitumor activity.
• Thymidine and Folic Acid—This rescues the toxic effects.
• Dose dependent toxicity is Myelosuppression and mucositis, others include renal toxicity, acute cerebral
dysfunction

21. • With high-dose therapy, methotrexate doses >1 g/m2, important to vigorously hydrate the patient with 2.5–3.5
liters/m2/day of IV 0.9% sodium chloride starting 12 hours before and for 24–48 hours after methotrexate
infusion. Sodium bicarbonate (1–2 amps/L solution) should be included in the IV fluid to ensure that the urine
pH is greater than 7.0 at the time of drug infusion and ideally for up to 48–72 hours after drug is given.
• Glucarpidase is indicated for the treatment of toxic plasma methotrexate concentrations (>1 mM) in patients
with delayed drug clearance due to impaired renal function.

22. 5FU (5 Fluorouracil)
• Fluoropyrimidine analog.
• Cell cycle–specific with activity in the S-phase.
• Incorporation of the 5-FU metabolite FUTP  RNA  alterations in RNA processing and/or mRNA
translation.
• Incorporation of the 5-FU metabolite FdUTP  DNA  (-) DNA synthesis and function.
• Inhibition of TS leads to accumulation of dUMP  misincorporated into DNA in the form of dUTP  (-)
DNA synthesis and function.
• After IV administration, 5-FU is widely distributed to tissues with highest concentration in GI mucosa, bone
marrow, and liver. Penetrates into third-space fluid collections such as ascites and pleural effusions. Crosses
the blood-brain barrier and distributes into CSF and brain tissue.
• Leucovorin enhances the antitumor activity and toxicity of 5-FU. Stabilizes the TS-FdUMP-reduced
folate ternary complex resulting in maximal inhibition of TS.

23. • Bolus monthly schedule: 425–450 mg/m2 IV on days 1–5 every 28 days. Main S/E is Metallic Taste in mouth.
• Bolus weekly schedule: 500–600 mg/m2 IV every week for 6 weeks every 8 weeks. Main S/E which is also
the dose limiting S/E is Myelosuppression – Neutropenia and Thrombocytopenia.
• Long Term Infusion Therapy : Major S/E is Diarrhoea and/or Mucositis and Hand-Foot Syndrome
• Thymidine—Rescues against the TS- and DNA-mediated toxic effects of 5-FU.
• Vistonuridine (Uridine Triacetate), at a dose of 10 g PO every 6 hours, may be used in patients overdosed with
5-FU or in those who experience severe toxicity.
• Vitamin B6 (pyridoxine 50 mg PO bid) may be used to prevent and/or reduce the incidence and severity of
hand-foot syndrome

24. Capecitabine
• Fluoropyrimidine carbamate prodrug form of 5-FU. Capecitabine itself is inactive.
• Metabolized in liver to 5’-deoxy-5-fluorocytidine (5’-DFCR) by the carboxylesterase enzyme  5’-DFUR by
cytidine deaminase (found in liver and in tumor tissues)  5-FU by the thymidine phosphorylase, which is
expressed in higher levels in tumor versus normal tissue.
• Metastatic breast cancer—FDA-approved when used in combination with docetaxel for the treatment of
patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.
• Metastatic breast cancer—FDA-approved as monotherapy in patients refractory to both paclitaxel- and
anthracycline-based chemotherapy or when anthracycline therapy is contraindicated.
• Recommended dose is 1000-1250 mg/m2 PO bid (morning and evening) for 2 weeks with 1 week rest.
• Capecitabine-warfarin interaction - coagulation parameters (PT and INR) to be monitored frequently.
• Leucovorin enhances the antitumor activity and toxicity of capecitabine.
• Capecitabine should be taken with a glass of water within 30 minutes after a meal.
• No dose adjustment in liver dysfunction, advised in moderate renal dysfunction.
• Dose limiting toxicity is diarrhoea, important S/E is Hand-Foot Syndrome (Palmar-Plantar-
Erythrodysesthesia) can be reduced with supplementing Vit. B6/Pyridoxine supplementation.

25. • Concomitant use of aluminum hydroxide– or magnesium hydroxide–containing antacids may increase the
bioavailability of capecitabine by 16%–35%.
• Celecoxib at a dose of 200 mg PO bid may be effective in preventing and/ or reducing the incidence and
severity of hand-foot syndrome.

26. Gemcitabine
• Fluorine-substituted deoxycytidine analog.
• Cell cycle–specific with activity in the S-phase.
• Intracellular activation by deoxycytidine kinase  monophosphate form  eventual metabolism to the
cytotoxic triphosphate nucleotide metabolite (dFdCTP)  Triphosphate metabolite inhibits DNA
polymerases α, β, and γ  interferes with DNA synthesis, DNA repair, and DNA chain elongation.
• FDA-approved in combination with paclitaxel for first-line treatment of metastatic breast cancer after failure
of prior anthracycline containing adjuvant chemotherapy.
• Dose is 1000mg/m2 on D1 and D8.
• Gemcitabine is a potent radiosensitizer.
• Myelosuppression is dose-limiting toxicity.
• Dose modification should be considered in liver/renal dysfunction.
• Gemcitabine enhances the cytotoxicity of cisplatin by increasing the formation of cytotoxic platinum-DNA
adducts

27. ANTHRACYCLINE ANTIBIOTICS

28. Doxorubicin (Adriamycin)
• Anthracycline antibiotic isolated from Streptomyces species.
• Intercalates into DNA  inhibition of DNA synthesis and function.
• Inhibits transcription through inhibition of DNA-dependent RNA polymerase.
• Inhibits topoisomerase II by forming a cleavable complex with DNA and topoisomerase II to create
uncompensated DNA helix torsional tension, leading to eventual DNA breaks.
• Doxorubicin is incompatible with dexamethasone, 5-FU, and heparin, as concurrent use will lead to
precipitate formation.
• Dose : 60mg/m2 (AC Regimen)
• Increased risk of hemorrhagic cystitis and cardiotoxicity when doxorubicin is given with
cyclophosphamide.
• Increased risk of hepatotoxicity when doxorubicin is given with 6-mercaptopurine.
• Use with caution in patients previously treated with radiation therapy as doxorubicin can cause
radiation-recall skin reaction.
• Myelosuppression is dose limiting toxicity, Leukopenia > Thrombocytopenia.

29. • Cardiotoxicity. Acute form presents within the first 2–3 days as arrhythmias and/ or conduction abnormalities,
ECG changes, pericarditis, and/or myocarditis. Chronic form results in dilated cardiomyopathy associated
with congestive heart failure. Risk increases when cumulative doses are >450 mg/m2.
Monitor cardiac function before (baseline) and periodically during therapy with either MUGA radionuclide
scan or echocardiogram to assess LVEF
• Doxorubicin is a strong vesicant, administer slowly with a rapidly flowing IV. Avoid using veins over joints or
in extremities with compromised venous and/or lymphatic drainage. Use of a central venous catheter is
recommended for patients with difficult venous access and mandatory for prolonged infusions.
If extravasation is suspected, immediately stop infusion, withdraw fluid, elevate extremity, and apply
ice to involved site.
• Lipodox is liposomal encapsulation of doxorubicin, Liposomal doxorubicin should NOT be substituted for
doxorubicin and should be used only where indicated. Dose is 50mg/m2.
• Infusions of liposomal doxorubicin should be given at an initial rate of 1 mg/min over a period of at least 30
minutes to avoid the risk of infusion-associated reactions. This reaction is thought to be related to the lipid
component of liposomal doxorubicin.

31. Epirubicin
• Anthracycline derivative of doxorubicin.
• Intercalates into DNA  inhibition of DNA synthesis and function.
• Inhibits topoisomerase II by forming a cleavable complex with topoisomerase II and DNA.
• Formation of cytotoxic oxygen free radicals, which can cause single- and double-stranded DNA breaks.
• FDA-approved as part of adjuvant therapy in women with axillary node involvement following resection of
primary breast cancer. Dose is 100mg/m2 (EC Regimen).
• Epirubicin is incompatible with Heparin as a precipitate will form.
• Increased risk of myelosuppression when epirubicin is used in combination with 5-FU and
cyclophosphamide.
• Dose modification needed with Hepatic dysfunction and renal impairement.
• Dose limiting side effect is Myelosuppression. Leukopenia > Thrombocytopenia.
• Chronic form of cardiotoxicity presents as a dilated cardiomyopathy with congestive heart failure. Risk of
congestive heart failure increases significantly with cumulative doses >900 mg/m2.

32. A prospective randomized comparison of epirubicin and doxorubicin in
patients with advanced breast cancer (1985).
K K Jain , E S Casper , N L Geller , T B Hakes , R J Kaufman , V Currie W Schwartz , C Cassidy , G R Petroni , C W Young
• Fifty-four patients with advanced breast cancer who had failed prior non-anthracycline combination chemotherapy were
randomized to treatment with either epirubicin 85 mg/m2 or doxorubicin 60 mg/m2 intravenously every three weeks. Of 52
evaluable patients, 25% (six of 24) treated with epirubicin, and 25% (seven of 28) treated with doxorubicin experienced major
therapeutic responses.
• The median duration of response to epirubicin was 11.9 months compared to 7.1 months with doxorubicin. Cardiotoxicity was
monitored by serial multigated radionuclide cineangiocardiography performed at rest and after exercise.
• Fifteen patients treated with epirubicin and 18 patients treated with doxorubicin had at least two determinations of left
ventricular ejection fraction and were evaluable for laboratory cardiotoxicity.
• Using methods of survival analysis, the median doses to the development of laboratory cardiotoxicity were estimated to be 935
mg/m2 of epirubicin and 468 mg/m2 of doxorubicin.
• Four patients treated with epirubicin and five treated with doxorubicin developed symptomatic congestive heart failure. The
median cumulative dose at which congestive heart failure occurred was 1,134 mg/m2 of epirubicin compared with 492 mg/m2
of doxorubicin.
• Fewer episodes of nausea and vomiting were observed in patients receiving epirubicin. Epirubicin is a new anthracycline with
reduced cardiac toxicity, but preserved efficacy in the treatment of patients with advanced breast cancer.

33. Doxorubicin vs Epirubicin
• There are no phase III studies comparing epirubicin with doxorubicin as adjuvant therapy at optimal doses of
each anthracycline.
• However, phase III comparisons of FEC and FAC at the same doses 50 mg/m2 per course in metastatic
disease confirm similar efficacy, but consistently demonstrate improved safety for epirubicin*
• This low toxicity suggests that higher doses of epirubicin may produce more optimal clinical outcomes.
• Escalation of doxorubicin dose does not seem to improve survival** (in CALGB9344 , doses from 60 mg/m2
to 90 mg/m2 administered as adjuvant therapy to women with node-positive primary disease had nearly
identical 5-year rates of DFS),
• French Adjuvant Study Group 05 (FASG-05) started randomized trial on epirubicin dose escalation.
*French Epirubicin Study Group: A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide,
fluorouracil, and either doxorubicin or epirubicin. J Clin Oncol 6::679,1988-688,
** Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose
in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21::976,2003-983

34. TAXANES

35. Docetaxel
• Semisynthetic taxane. Derived from the needles of the European yew tree.
• High-affinity binding to microtubules enhances tubulin polymerization.
• Normal dynamic process of microtubule network is inhibited  inhibition of mitosis and cell division.
• Cell cycle–specific agent with activity in the mitotic (M) phase.
• Dose : 75mg/m2.
• Extensively metabolized by the hepatic P450 microsomal system.
• FDA-approved for the treatment of locally advanced or metastatic breast cancer after failure of prior
chemotherapy.
• FDA-approved in combination with doxorubicin and cyclophosphamide for adjuvant treatment of patients
with node-positive breast cancer.
• Docetaxel acts as a radiosensitizing agent.
• Use with caution in patients with abnormal liver function and Closely monitor CBCs; docetaxel therapy
should not be given to patients with neutrophil counts of <1500 cells/mm3.
• Neutropenia is dose limiting side effect. Others include HSR and Fluid Retention Syndrome seen when
cumulative dose exceeds 400mg/m2.

37. Phase III Randomized Trial Comparing Doxorubicin and Cyclophosphamide
Followed by Docetaxel (AC→T) with Doxorubicin and Cyclophosphamide
Followed by Docetaxel and Trastuzumab (AC→TH) with Docetaxel,
Carboplatin and Trastuzumab (TCH) in Her2neu Positive Early Breast
Cancer Patients: BCIRG 006 Study (2009).
D. Slamon, W. Eiermann, N. Robert, T. Pienkowski, M. Martin, J. Rolski, A. Chan, J. Mackey, M. Liu, T. Pinter, V. Valero, C. Falkson,
T. Fornander, T. Shiftan, S. Olsen, M. Buyse, T. Kiskartalyi, V. Landreau, V. Wilson, M. Press and J. Crown
• The primary endpoint was disease-free survival (DFS) with 80% power (0.05 significance level) to
detect an absolute difference of 7%.
• Synergistic cardiac toxicity (symptomatic events and asymptomatic LVEF decline) was significant in
Arm 2.

38. Paclitaxel
• Cell cycle–specific, active in the mitosis (M) phase of the cell cycle.
• High-affinity binding to microtubules enhances tubulin polymerization.
• Normal dynamic process of microtubule network is inhibited  inhibition of mitosis and cell division.
• Dose : 175mg/m2 in 3 weekly cycle and 80mg/m2 in weekly cycles.
• Radiation therapy—Paclitaxel is a radiosensitizing agent.
• Myelosuppression is greater when Cisplatin, Carboplatin and Cyclophosphamide administered before
paclitaxel.
• Paclitaxel reduces the plasma clearance of doxorubicin by about 30%, resulting in increased severity of
myelosuppression.
• Dose reduction in liver impairment.
• Dose limiting toxicity is Myelosuppression (Neutropenia), others include HSR, Neurotoxicity, Aymptomatic
sinus bradycardia.
• Peripheral Neuropathy is a common toxicity presents as symmetric glove and stocking distribution
which is transient first and later permanent.

39. • Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a solvent-free colloidal suspension made by
homogenizing paclitaxel with 3% to 4% albumin under high pressure to form nanoparticles of approximately
130 nm that disperse in plasma to approximately 10 nm.
• Dose is 260mg/m2 for 3 weekly and 90mg/m2 on weekly regimen.
• The main dose-limiting toxicities are neutropenia and sensory neuropathy.

42. 5 Yr OS/DFS were observed to be
superior with a 3 weekly Docetaxel
and weekly Paclitaxel Regimen.

43. PLATINUM COMPOUNDS

44. Carboplatin
• Covalently binds to DNA with preferential binding to the N-7 position of guanine and adenine.
• Reacts with two different sites on DNA to produce cross-links, either intrastrand (>90%) or interstrand (<5%).
Formation of DNA adducts  inhibition of DNA synthesis and function as well as inhibition of transcription.
• Dose of carboplatin is usually calculated to a target area under the curve (AUC) based on the
glomerular filtration rate (GFR)  Calvert formula is used to calculate dose—Total dose (mg) = (target
AUC) × (GFR + 25)
• Target AUC is usually between 5 and 7 mg/mL/min for previously untreated patients. In previously treated
patients, lower AUCs (between 4 and 6 mg/mL/min) are recommended.
• Platinum agents are Indicated in TNBC and BRCA1/2 Germline mutations. Dose is AUC 2 I/V in
combination with Gemcitabine and AUC 6 in combination with Paclitaxel.
• Carboplatin should be administered after paclitaxel when carboplatin and paclitaxel are used in combination
cuz sequence prevents delayed paclitaxel excretion  increased paclitaxel drug levels and potentially
increased host toxicity.
• Dose reduction is required in the setting of renal dysfunction.
• Myelosuppression is significant and dose-limiting. Thrombocytopenia > leukopenia.

45. Cisplatin
• M.O.A is same as carboplatin.
• The nephrotoxic effect of cisplatin is inactivated by amifostine and mesna.
• Within the cytoplasm of the cell, low concentrations of chloride (4 mM) favor the aquation reaction whereby
the chloride atom is replaced by a water molecule, resulting in a highly reactive species. 10%–40% of a given
dose of cisplatin is excreted in the urine in 24 hours.
• Dose : 75mg/m2
• Cisplatin may enhance the antitumor activity of etoposide.
• Acts as a Radiosensitizing agent.
• Hydration : give at least 1 liter before and 1 liter post-drug treatment of 0.9% sodium chloride with 20 mEq of
KCl. With higher doses of drug, more aggressive hydration should be considered, with at least 2 liters of fluid
administered before drug. In this setting, urine output should be greater than 100 mL/hr.
• Dose-limiting toxicity is Nephrotoxicity mainly hypomagnesemia, other toxicities like myelosuppression,
stocking-glove paraesthesia, neurotoxicity, ototoxicity.

46. ANTIMICROTUBULE AGENT

47. Vinorelbin
• Semisynthetic alkaloid derived from vinblastine.
• Cell-cycle specific with activity in mitosis (M) phase.
• Inhibits tubulin polymerization, disrupting formation of microtubule assembly during mitosis. This results in
an arrest in cell division, ultimately leading to cell death.
• Widely and rapidly distributed into most body tissues with a large apparent volume of distribution (>30 L/kg).
Extensive binding to plasma proteins (about 80%).
• Dose : 25mg/m2 Weekly, 20-35 mg/m2 on D1 and D8 every 21 days, 25-30 mg/m2 on D1, D8 and D15 every
28 days.
• Risk of myelosuppression increases when vinorelbine is used in combination with cisplatin.
• Vinorelbine should be infused as a rapid push in a free-flowing IV line to avoid extravasation. If extravasation
occurs, the infusion should be discontinued immediately. Flushing with sterile water, elevation of the
extremity, and local application of ice are recommended.
• Myelosuppression is Dose-limiting toxicity. Readily reversible once treatment is stopped. Neutropenia is most
commonly observed.

48. Eribulin
• Cell cycle–specific as it leads to a block in the G2-M phase of the cell cycle.
• Inhibits microtubule growth by sequestering tubulin in nonproductive aggregates with no effect on
microtubule shortening.
• FDA-approved for the treatment of patients with metastatic breast cancer who have previously received at
least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have
included an anthracycline and a taxane in either the adjuvant or metastatic setting.
• Dose : 1.4 mg/m2 on D1 and D8 cycled 21 days.
• Dose adjustment required in Hepatic and Mod. Renal Dysfunction CrCl is 30-50ml/min.
• Dose limited S/E is Myelosuppression. Another Imp. S/E is QTc Prolongation, Use with caution in patients
with a history of CHF, bradyarrhythmias, concomitant use of drugs that prolong QT interval, congenital QT
syndrome, and electrolyte abnormalities (hypokalemia and hypomagnesemia).

49. THANK YOU