Diapositiva 1 - E
Principles of Cancer Treatment Authors: Edward A. Sausville, Dan L. Longo (Harrison’s) • • • 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 + + + + + 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 • • • • 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 • 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 • 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.