Principles of Cancer Treatment Authors: Edward A. Sausville

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Principles of Cancer TreatmentAuthors Edward A.
Sausville, Dan L. Longo (Harrisons)

• 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.

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Principles of Cancer TreatmentAuthors Edward A.
Sausville, Dan L. Longo (Harrisons)

• 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).

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TreatmentAuthors Edward A. Sausville, Dan L.
Longo (Harrisons)

• 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.

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G0 resting S sintetica (DNA) G2preparatoria
M mitotica G1crescita
G0
G1
M
S
G2
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Tumor growth.
Authors Edward A. Sausville, Dan L. Longo
(Harrisons)
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• 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.

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Fasi del ciclo cellulare e chemioterapici
antitumorali Fase del ciclo cellulare
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Meccanismo dazione chemioterapici antitumorali

• Legame covalente con DNA
• DNA-binding e ROS
• Blocco sintesi basi DNA
• Legame DNA e rottura
• Inibizione sintesi DNA
• Inibizione sintesi DNA
• Alterazione micro-tuboli fuso mitotico

• Alchilanti
• (ciclofosfamide,clorambucil)
• Antracicline
• (doxorubicina, epirubicina,..)
• Antimetaboliti
• (Metotressato, fluoruracile)
• Cis-platino
• Idrossiurea
• Procarbazina
• Vinca,taxolo

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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
• Authors Edward A. Sausville, Dan L. Longo
  (Harrisons)

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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, Non-small 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
  (Harrisons)

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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
• Authors Edward A. Sausville, Dan L. Longo
  (Harrisons)

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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).

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Effetti collaterali

• Tossicità generale e specialmente per quei
  tessuti ad alto turn-over
• Vomito

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New perspectives in the treatments of
cancerAuthors Edward A. Sausville, Dan L.
Longo (Harrisons)

• 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.