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02 TUMORS AND STEM CELLS KINETIC PHARMACOTHERAPY

DR. JOY DE CASTRO, April 20, 2021

Elysian Trans by HelloitsMemiyuuuh
CLINPHARMA
Outline Cell Cycle

I. Tumor Cell Kinetics

II. Neoplastic Burden – Log-Kill Hypothesis
III. Cell Cycle
IV. Generalities
V. Major Classes of Anti-cancer Drugs
• Cell Cycle Specific Agents (CCS)
• Cell Cycle Non-specific Agents (CCNS)
VI. Hematologic Malignancies
• Leukemias
• Lymphomas
• Multiple Myeloma
VII. Solid Tumors
• Breast Cancer
• Prostate Cancer
• GIT Cancer
• Lung Cancer
• Ovarian Cancer
• Testicular Cancer
• Malignant Melanoma
• Brain Cancer Choriocarcinoma
VIII. Secondary Malignancies and Cancer Chemotherapy

Tumor Cell Kinetics

Ÿ Hematologic Malignancies
- Exponential cell kinetics
- Log cell-kill kinetics – a given agent would be predicted to kill a
constant fraction of cells as opposed to a constant number Ex.
10 7 5 2
10 to 10 , 10 to 10
- Cell kill is proportional regardless of tumor burden
- The cardinal rule of chemotherapy – inverse relation between cell
number and curability
Ÿ Solid tumors
- Gompertzian kinetics
- Growth fraction of the tumor is not constant but decreases
exponentially with time
- Growth fraction peaks when the tumor is approximately 37% of its
maximum size
- When the tumor mass is large, its growth fraction is low, and the
fraction of cells killed is therefore, small
- Important feature of Gompertzian growth is that response to
chemotherapy in drug-sensitive tumors depends on where the
tumor is in its particular growth curve
Neoplastic Burden – Log-Kill Hypothesis
Generalities
• The strategy for developing drug regimens requires a knowledge of the
particular characteristics of specific tumors (is it in G0 phase, is there
high growth fraction...)
• Knowledge of the pharmacology of specific drugs are also important (is
the drug CCS, does the drug require activation in the liver...)
• Knowledge of receptor expression is important (in breast CA patients, is
there estrogen receptor expression...)
• Recognition of true drug synergism or antagonism is important in the
design of combination chemotherapeutic programs (combination of
cytarabine and anthracycline in AML)
• It is preferable to use cytotoxic chemotherapeutic agents in intensive
pulse courses every 3-4 weeks rather than to use it continuously daily
because this allows maximum effects against cancer cells with
complete hematologic and immunologic recovery between courses
• Knowledge of specific pathway abnormalities (eg. EGFR pathway) for
intracellular signalling

Major Classes of Anti-cancer Drugs

Cell Cycle Specific Agents (CCS)
Antimetabolites Cladribine, Cytarabine, Capecitabine,
Fludarabine, Gemcitabine, 5-Fluorouracil
(5FU), Methotrexate (MTX), 6-
Mercaptopurine (6MP), 6-Thioguanine (6TG)
Taxanes Paclitaxel, Docetaxel
Vinca alkaloids Vincristine, Vinblastine, Vinorelbine
Antitumor Antibiotic Bleomycin
Epipodophyllotoxins Etoposide, Teniposide

Cell Cycle Non-s[ecific Agents (CCNS)

Alkylating agents Busulfan, Lomustine, Thiotepa, Melphalan,
Cyclophosphamide, Carmustine,
Mechlorethamine
Anthracyclines Doxorubicin, Daunorubicin, Mitoxantrone,
Epirubicin, Idarubicin
Platinum Analogs Cisplatin, Carboplatin, Oxaliplatin
Camptothecins Topotecan, Irinotecan
Antitumor Antibiotic Mitomycin, Dactinomycin
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- Rituximab (anti CD20 antibody) enhances antitumoreffects of

cytotoxic chemotherapy

LYMPHOMAS

1. Hodgkin’s Lymphoma
- B cell neoplasm; presence of Reed-Sternberg cells
- Epstein Barr virus is identified up to 80% of tumor specimens
- Complete staging is needed before treatment plan is made
- Stage I and IIA – due to late effects of radiation tx, combined modality
therapy with brief course of chemoTx and involved field radiation Tx
is now used
- For stage III and IV- MOPP regimen (mechlorethamine, vincristine,
procarbazine and prednisone); 80-90% Response Rates
- Newer regimen includes: ABVD regimen (doxorubicin, bleomycin,
vincristine, and dacarbazine); >80% go to complete remission; less
toxic than MOPP
- Stanford V – 12-week course of combination chemotherapy
(doxorubicin, vinblastine, mechlorethamine, vincristine,
bleomycin, etoposide, and prednisone) followed by involved
radiation therapy
- Over 80% of previously untreated advanced HL go into remission,
with disappearance of disease-related symptoms and objective
Hematologic Malignancies evidence of disease
LEUKEMIAS - Generally, 50-60% of HL patients are cured of their disease

1. Acute Lymphocytic Leukemia (ALL) – childhood leukemia 2. Non-Hodgkin’s Lymphoma

- Most common form of cancer in children - Heterogenous disease, clinical characteristics of subsets are related
- Folic acid antagonists, asparaginase, vincristine, 6- MP - active to the underlying histopathologic features and extent of disease
against the cancer involvement
- Combination of vincristine and prednisone induces remission in - Nodular or follicular type- better prognosis compared with diffuse type
90% of cases with median survival of 2 months
- However cancer cells migrate into sanctuary sites (brain and testes) - Combination chemotherapy –standard of treatment
thus intrathecal therapy with methotrexate is considered as a - CHOP ( Cyclophosphamide, Doxorubicin, Vincristine,
standard therapy Prednisone) ± Rituximab (anti-CD- 20 monoclonal antibody)

MULTIPLE MYELOMA
2. Acute Myelogenous Leukemia (AML) – adult leukemia
• Plasma cell malignancy
- Most common in adults
• Produces a marker protein (myeloma immunoglobulin) that allows the
- Complete remissions occur in 70% of patients on combination
total body burden of tumor cells to be quantified
cytarabine and anthracycline
- Patient may need platelet transfusion, granulocyte colony- • Principally involves the bone marrow and bone causing bone pain,
lytic lesions, bone fractures and anemia
stimulating factor (GCSF) to shorten periods of neutropenia,
antibiotics to combat infection • MP protocol remains the standard regimen (Melphalan and
- Younger patients(age<55) may be candidate for BMT; older patients Prednisone) with 40% successful response (2-2.5 years remission)
less responsive Thalidomide – for refractory or relapsed disease (65% response
rates together with dexamethasone)
• Lenalidomide + Dexamethasone
3. Chronic Myelogenous Leukemia (CML)
• Bortezomib recently approved for relapse; inhibits NF-kB signalling
- Arise from chromosomally abnormal hematopoietic stem cell- t(9:22) pathway
in 90-95% of cases
- There is expression of Bcr-Abl fusion oncoprotein leading to BREAST CANCER
increase WBC (>50,000/uL)
1. Stage I and II
- Goals of treatment – to reduce the granulocytes to normal levels, to
• For stage I – surgery alone; 80% chance of cure (negative axillary
raise the hemoglobin to normal, and to relieve disease-related
lymph node dissection)
symptoms
• For + node- high incidence of recurrence thus post-op use of
- Imatinib – standard first-line treatment; exhibits a complete
CMF protocol (cyclo, methotrexate and fluorouracil of 6 cycles)
hematologic response, and up to 40- 50% complete cytogenetic
or FAC protocol (fluorouracil, doxorubicin & cyclophosphamide)
response
has reduced relapse
- Dasatinib and Nilotinib – for Imatinib resistant
- Interferon α, Busulfan, Hydroxyurea, and other alkylating agents • FEC protocol is another regimen
(4 cycles of doxorubicin and cyclophosphamide and 6 cycles of
fluorouracil, epirubicin and cyclophosphamide)
4. Chronic Lymphocytic Leukemia (CLL) • Above regimen benefited women with 1-3 lymph node involvement
- Early stage has good prognosis • For 4 or more have limited benefit
- Chlorambucil (0.1 mkday with close monitoring of CBC per week • First cancer that is responsive to hormonal manipulation
+/- prednisone) and Cyclophosphamide (1- 2g/m2 every 3-4 • Tamoxifen – postmenopausal women when used alone or in
weeks) are used combination chemotherapy
- Other drug regimen: COP – cyclophosphamide, vincristine and • Present recommendation- use tamoxifen for 5 years after surgery
prednisone thereafter followed by aromatase inhibitor for at least 2.5 years
- CHOP – above + doxorubicin
• Trastuzumab – for HER-2 overexpressing breast cancer
- Fludarabine ±cyclophosphamide, or + mitoxantrone and prednisone,
or combination with anti-CD20 antibody Rituximab
- Alemtuzumab (humanized monoclonal antibody directed against
CD-52 antigen) used in those refractory to fludarabine; 30-35% RR

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2. Stage III and IV TESTICULAR CANCER

• Currently- palliative • BEP protocol (cisplatin, etoposide and bleomycin) three cycles
• Combination chemo, endocrine therapy or both results in response • Over 90% respond and 70-80% have complete remission
rates of 40-50% with 10-20% complete response rates
• Aromatase inhibitors are now first line therapy of advanced breast MALIGNANT MELANOMA
cancer whose tumors are hormone receptor positive • Most difficult to treat
• Those with advanced involvement of other organs rarely benefit • Drug-resistant cancer
from these hormonal treatments; initial systemic chemotherapy is • Dacarbazine, cisplatin and temozolomide are most active against
indicated with 50-60% respond to initial chemotx (doxorubicin and this disease
taxanes) • Interferon α and IL-2 also led to response rate in some patients
• Anthracycline containing regimen- first line therapy (10-20%
achieve complete remission) BRAIN CANCER
• Addition of Tamoxifen yields modest improvement
• Nitrosoureas- crosses the BBB
• 50-60% with metastatic disease respond to initial chemotherapy
• BCNU carmustine or CCNU lomustine is used with combination of
• Anthracyclines, taxanes, navelbine, capecitabine, gemcitabine, procarbazine and vincristine (PCV protocol)
cisplatin, cyclophosphamide, methotrexate
• For recurrent disease- temozolomide
• Anthracycline-based chemotherapy- more durable remission up to
50-80%
CHORIOCARCINOMA
• Bevacizumab-confer benefit together with paclitaxel
• Arises from fetal trophoblastic tissue is the first metastatic cancer that
can be cured with chemotherapy
PROSTATE CANCER
nd • For low risk - single agent methotrexate or dactinomycin
• 2 type of cancer with response to hormonal manipulation
• For high risk-methotrexate and leucovorin, etoposide, dactinomycin
• Elimination of testosterone production by the testes either thru surgery
or chemical castration
SECONDARY MALIGNANCIES AND CANCER CHEMOTHERPAPY
• Use of LHRH agonists (Leuprolide and Goserelin) reduces bone
• Complication of some types of cancer
pain in 70-80% and reduced PSA levels (marker of response to Tx)
• AML- most frequent
• Unfortunately, nearly all are refractory to hormone therapy
• Alkylating agents, etoposide, ionizing radiation are causes; melphalan
• Mitoxantrone and Prednisone for hormone refractory prostate
Tx in ovarian, malignant melanoma
cancer
• Develops 2-4 years after chemoTx and peaks at 5-9 years
• Estramustine plus taxanes or etoposide offers a response rate of
40-50%

GIT CANCER
Colorectal Cancer
• Most common type of GI malignancy
• At time of presentation, only 40-45% are curable with surgery
• For Stage II and III high risk disease, adjuvant chemoTx with
oxaliplatin based regimen with 5-FU plus leucovorin (FOLFOX)
given 6-8 months after surgery; 35% reduction of recurrence rate
• Rectal CA- surgical adjuvant therapy with IV 5- FU along with pelvic
irradiation
• Other regimen include:
- IFL protocol (Irinotecan, 5-FU and leucovorin) weekly or
biweekly – now first line
- FOLFOX plus Bevacizumab or Cetuximab is being considered
Gastric, Esophageal and Pancreatic CA
• More aggressive malignancies
• 5-FU - based chemotx has been the usual approach for gastro-
esophageal CA
• Erlotinib plus gemcitabine for pancreatic cancer

LUNG CANCER
Non-Small Cell Lung CA (NSCLSC)
• 75-85%of cases (adeno, squamous cell and large cell) while
remaining 20-25% are small cell lung CA
• If diagnosed in advanced stage- prognosis is poor (8 months)
• Palliative systemic chemo for advanced disease
(bevacizumab with carboplatin and paclitaxel) or platinum based
chemoTx)
Small Cell Lung CA (SCLC)
• Most aggressive form but extremely sensitive to platinum-based
combination regimen (cisplatin and etoposide or irinotecan)
• When diagnosed as limited stage- potentially curable with combined
chemo and radioTx

OVARIAN CANCER
• Remains occult; presents with ascites
• Combination chemotx for stage III and IV
• Carboplatin plus paclitaxel - Tx of choice
• For recurrent disease- topotecan or altretamine

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