Diapositiva 1 - E

Principles of Cancer Treatment
Authors: Edward A. Sausville, Dan L. Longo
(Harrison’s)
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The goal of cancer treatment is first to eradicate the cancer. If this
primary goal cannot be accomplished, the goal of cancer treatment
shifts to palliation, the amelioration of symptoms, and preservation of
quality of life while striving to extend life.
The dictum primum non nocere is not the guiding principle of cancer
therapy. Every cancer treatment has the potential to cause harm, and
treatment may be given that produces toxicity with no benefit. The
therapeutic index of many interventions is quite narrow, and most
treatments are given to the point of toxicity.
Radical surgical procedures, large-field hyperfractionated radiation
therapy, high-dose chemotherapy, and maximum tolerable doses of
cytokines such as interleukin (IL) 2 are all used in certain settings
where 100% of the patients will experience toxicity and side effects
from the intervention, and only a fraction of the patients will
experience benefit. One of the challenges of cancer treatment is to use
the various treatment modalities alone and together in a fashion that
maximizes the chances for patient benefit.
Principles of Cancer Treatment
Authors: Edward A. Sausville, Dan L. Longo
(Harrison’s)
• Cancer treatments are divided into four
main groups: surgery, radiation therapy
(including photodynamic therapy),
chemotherapy (including hormonal
therapy), and biologic therapy (including
immunotherapy, differentiating agents, and
agents targeting cancer cell biology).
Treatment
Authors: Edward A. Sausville, Dan L. Longo
(Harrison’s)
• Surgery is perhaps the most effective means of treating cancer.
About 40% of cancer patients are cured today by surgery.
Unfortunately, a large fraction of patients with solid tumors (perhaps
60%) have metastatic disease that is not accessible for removal.
However, even when the disease is not curable by surgery alone,
the removal of tumor can obtain important benefits, including local
control of tumor, preservation of organ function, debulking that
permits subsequent therapy to work better, and staging information
on extent of involvement. Cancer surgery aiming for cure is usually
planned to excise the tumor completely with an adequate margin of
normal tissue (the margin varies with the tumor and the anatomy),
touching the tumor as little as possible to prevent vascular and
lymphatic spread, and minimizing operative risk. Extending the
procedure to resect draining lymph nodes obtains prognostic
information, but such resections alone generally do not improve
survival.
G0 = resting
S = sintetica (DNA)
G2=preparatoria
M =mitotica
G1=crescita
G0
G1
M
S
G2
Tumor growth.
Authors: Edward A. Sausville, Dan L. Longo (Harrison’s)
• The growth fraction of a tumor declines
exponentially over time (top). The growth rate
of a tumor peaks before it is clinically
detectable (middle). Tumor size increases
slowly, goes through an exponential phase,
and slows again as the tumor reaches the size
at which it is attempting to level off. The
maximum growth rate occurs at 1/e, the point
at which the tumor is about 37% of its
maximum size (marked with an X). Tumor
becomes detectable at a burden of about 109
(1 cm3) and kills the patient at a tumor burden
of about 1012 (1 kg). Efforts to treat the tumor
and reduce its size can result in an increase in
the growth fraction and an increase in growth
rate.
Fasi del ciclo cellulare e
chemioterapici antitumorali
Fase del ciclo cellulare
Farmaco
G1
S
G2
M
G1/G0
Alchilanti
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+
+
Cis-platino
+
+
+
+
+
Antracicline
+
+
+
+
+
Procarbazina
+
+
+
+
+
Idrossiurea
+
+
+
+
+
Antimetaboliti
Vinca,taxolo
+
+
Meccanismo d’azione
chemioterapici antitumorali
• Alchilanti
(ciclofosfamide,clorambucil)
• Antracicline
(doxorubicina, epirubicina,..)
• Antimetaboliti
(Metotressato, fluoruracile)
• Cis-platino
• Idrossiurea
• Procarbazina
• Vinca,taxolo
• Legame covalente con
DNA
• DNA-binding e ROS
• Blocco sintesi basi DNA
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Legame DNA e rottura
Inibizione sintesi DNA
Inibizione sintesi DNA
Alterazione micro-tuboli
fuso mitotico
Table 84-1: Curability of Cancers with
Chemotherapy
• A. Advanced cancers with possible cure
Acute lymphoid and acute myeloid leukemia
(pediatric/adult), Hodgkin's disease
(pediatric/adult), Lymphomas-certain types
(pediatric/adult), Germ cell neoplasms,
Embryonal carcinoma, Teratocarcinoma,
Seminoma or dysgerminoma, Choriocarcinoma,
Gestational trophoblastic neoplasia, Pediatric
neoplasms, Wilm's tumor, Embryonal
rhabdomyocarcinoma, Ewing's sarcoma,
Peripheral neuroepithelioma, Neuroblastoma,
Small cell lung carcinoma, Ovarian carcinoma
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Authors: Edward A. Sausville, Dan L. Longo (Harrison’s)
Table 84-1: Curability of Cancers with
Chemotherapy
• B. Advanced cancers possibly cured by chemotherapy and
radiation
Squamous carcinoma (head and neck),Squamous carcinoma
(anus), Breast carcinoma, Carcinoma of the uterine cervix, Nonsmall cell lung carcinoma (stage III), Small cell lung carcinoma
• C. Cancers possibly cured with chemotherapy as adjuvant to
surgery
Breast carcinoma, Colorectal carcinoma, Osteogenic sarcoma, Soft
tissue sarcoma
• D. Cancers possibly cured with 'high-dose' chemotherapy with
stem cell support
Relapsed leukemias, lymphoid and myeloid, Relapsed lymphomas,
Hodgkin's and non-Hodgkin's, Chronic myeloid leukemia, Multiple
myeloma
•
Authors: Edward A. Sausville, Dan L. Longo (Harrison’s)
Table 84-1: Curability of Cancers with
Chemotherapy
• E. Cancers responsive with useful palliation, but not
cure, by chemotherapy - Bladder carcinoma, Chronic
myeloid leukemia, Hairy cell leukemia, Chronic
lymphocytic leukemia, Lymphoma-certain types, Multiple
myeloma, Gastric carcinoma, Cervix carcinoma,
Endometrial carcinoma, Soft tissue sarcoma, Head and
neck cancer, Adrenocortical carcinoma, Islet-cell
neoplasms, Breast carcinoma
• F. Tumor poorly responsive in advanced stages to
chemotherapy - Pancreatic carcinoma, Biliary-tract
neoplasms, Renal carcinoma, Thyroid carcinoma,
Carcinoma of the vulva, Colorectal carcinoma, Non-small
cell lung carcinoma, Prostatecarcinoma, Melanoma,
Hepatocellular carcinoma
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Authors: Edward A. Sausville, Dan L. Longo (Harrison’s)
Meccanismi di resistenza delle cellule
tumorali ai più comune chemioterapici
• Ridotto “uptake” nella cellula del chemioterapico;
• Uso di vie metaboliche alternative e
superamento del processo “target”;
• Alterazione dei bersagli dei chemioterapico;
• Aumentato metabolismo inattivante del
chemioterapico;
• Ridotta formazione di chemioterapici attivi da
profarmaci;
• Aumento della rimozione del chemioterapico
dalla cellula per aumento della trascrizione di
geni (P-glicoproteine).
Effetti collaterali
• Tossicità generale e specialmente per quei
tessuti ad alto turn-over
• Vomito
New perspectives in the treatments
of cancer
Authors: Edward A. Sausville, Dan L. Longo
(Harrison’s)
• The capacity to invade and metastasize is
conveyed by elaboration of matrix
metalloproteases and plasminogen
activators and the capacity to recruit host
stromal cells at the site of invasion through
tumor-induced angiogenesis.