Hematology-Medical Oncology Div. Dept. of Internal Meicine Hasan Sadikin General Hospital
What is basic oncology?
Learn to describe the pathophysiology of carcinogenesis, discuss prevention, screening and detection guidelines, review the process for diagnosing and staging, discussing current treatment modalities
Genetic change Heredity Chemica ls Radiatio n Viruses Clonal expansion Genetic change
Inflamation Endocrine factors Nutrition
Tumor suppressor genes
Number of cancer cells
diagnostic threshold (1cm) time
undetectabl detectable e cancer cancer
limit of clinicalHost death detection
The unique characteristics of cancer cells
• Immortality • Genetic instability • Increase in growth factor secretion • Increase in oncogene expression • Loss of tumor suppressor genes • Loss of contact inhibition • Progressive independence of proliferation from growth factors and nutrients • Metastasis
chemotherapy can not further reduce the cancer cell population • Kinetic models have suggested that one limitation to cytotoxic treatment is the rapid regrowth of the residual malignant cells. This might be explain why the results of HDCT in breast cancer have been so consistent. even though many different drugs combinations
. • This problem may not be overcome by the simple expedient of dose escalation.The limit of cytoreduction
• Once that critical number of cells is achieved.
5. 2.Some Major Types of Cancer
Cancer is categorized according to the tissue in which it arises: 1. 3. Sarcomas – connective tissues Carcinomas – epithelium Adenocarcinomas – glands or its ducts Lymphomas – lymphoid tissue Leukemia – blood
Cancer treatment modalities
• Goal(s): Cure. Control. Palliation • Treatment: > Chemotherapy > Radiation > Biologic Response Modifiers > Surgery
Classification of Chemotherapeutic Agents
ALKYLATING ANTIMITOTIC ANTIBIOTI OTHERS AGENTS METABOLITEINHIBITORS CS S
busulfan cytosine etoposide bleomycin l-sparaginase carmustine arabinoside teniposide dactinomycin hydroxyurea chlorambucil floxuridine vinblastine daunorubicin procarbazine cisplatin fluorouracil vincristine doxorubicin cyclophos.mercaptopurine vindesine mitomycin-c phamide methotrexate taxoids mitoxantrone ifosfamide melphalan
52h) Alkylating agents Vinca alkaloid s Mitotic inhibitors
G1 (2-∞ h)
.The cell cycle
Antimetabolites S (2-6h) Taxoids G2 (2-32h) M (0.
Growth factors and oncogenes
Paracrine (Adjacent cells) Growth Factor and Receptor Synthesis Gene Activation Oncogenes
Growth Factor Growth Factor Receptor
e n rin atio c l o ut imu A t s
Post receptor signal transduction pathways
RETROVIR US Oncoge ne Viral RNA Viral DNA NUCLEUS Oncogene REVERSE TRANSCRIPTAS RNA E messen INS ger E R T I O TRANSCRIPT N ION Oncogene Oncogene protein
TRANS CRIPTI ON
DNA Viral RNA
Viral genome CYTOPLAS M
Additive or synergistic mechanisms of action .Non-overlapping toxicity profiles
.Principles of Combination Chemotherapy
Rationale for combination chemotherapy is to: .Overcome drug resistance to individual agents .Improved remission rates and duration compared with single agent therapy .
• Given for patients after local control of tumor (surgery or radiation) to prevent metastatic or recurrence • Eliminating residual tumor and micrometastatic tumor deposits that are present at time of diagnosis • Should begin as soon as possible after local therapy • Delays to allow for recovery may compromise chance of cure
• Administration of chemotherapy before definitive local therapy • Avoids delays from surgery/radiation • May improve local control by shrinking the primary tumor and making it more amenable to surgical resection AC 4x
anaphylaxis Neurologic Tumor Lysis Renal Failure Fever Nausea and Vomiting Hemorrhagic Cystitis
. 2. phlebitis Rash. 4. 8. 6. 3.Chemotherapy toxicities
Immediate: hours to days 1. 5. Extravasation. 7.
Diarrhea 5. Paralytic ileus 1. Alopecia 3. Mucositis 4. anemia. Stomatitis.Chemotherapy toxicities
Early: days to weeks Myelosuppression infection. bleeding 2.
6. 7. 5. 2.Chemotherapy toxicities
Delayed: weeks to months 1. Peripheral neuropathy Aspermia Nephrotoxicity Ototoxicity Hepatocellular damage Hyperpigmentation Pulmonary fibrosis
. 4. 3. 8. Anemia Constipation.
grade 2. Ib (consider chemotherapy) • Stage Ic (chemotherapy regimen not specified) SOR.3.
EORTC. 2001 • Stage Ia. Ib. Ic.Adjuvant therapy for women with early stage ovarian cancer. 2000 Did not specify which patients should receive adjuvant therapy
. IIa (no standard treatment. options include platinum-based chemotherapy. 2003 should Did not specify which patients receive adjuvant therapy
ESMO. or no adjuvant therapy SOGC. 2001 • Poorly differentiated stage Ia. external beam radiation.
.Adjuvant chemotherapy versus no chemotherapy
There is no benefit from adjuvant chemotherapy in women with stage I epithelial ovarian cancer who have undergone optimal surgical staging as EORTC Women with surgically staged stage I ovarian cancer and good prognostic factors (grade 1. non-clear cell histology) could be managed with or without adjuvant chemotherapy Women who have not undergone optimal surgical staging can be offered two options: .platinum-based chemotherapy to decrease the risk of recurrence and improve survival.undergo re-operation and then be offered adjuvant therapy.
. and the magnitude of the survival benefit is unclear.Adjuvant chemotherapy option
Intravenous carboplatin with or without paclitaxel or docetaxel is the recommended postoperative chemotherapy regimen for newly diagnosed stage II-IV epithelial ovarian cancer. the incorporation of anthracyclines as part of first-line therapy is not recommended at the present time. Because the addition of doxorubicin to chemotherapy increases toxicity.
.cyclophosphamide 500 + doxorubicin 50 + cisplatin 50 36.carboplatin alone OR .paclitaxel 175 + carboplatin N=2074 AUC=6 vs .Summary of available trials
Study GOG-111 1996 Patients Regimen Median survival (months)
Stage III & -paclitaxel 135 + cisplatin 75 vs 38 vs 24 IV .001 suboptimal N=386
Intergroup Stages IIb-IV .paclitaxel 135 + cisplatin 75 vs 26 vs 26 vs 2000 suboptimal .cisplatin 100 ICON3.cyclophosphamide + cisplatin p=0016 2000 GOG-132.paclitaxel 175 + cisplatin 75 vs 36 vs 26 .31 . Stage III-IV .4 p=0.1 vs 35. N=680 .cyclophosphamide + cisplatin 30 vs N=614 p=0. 2000 Stages I-IV .cyclophosphamide + cisplatin p<0.
3 vs 17. 2004
41 vs 45.Summary of available trials
Study SCOTROC.1 p>0.paclitaxel 175 + cisplatin 75 h2000 N=208 .docetaxel 75 + carboplatin AUC=5 Stage IIb-IV .8 p=0.05
Stage IC-IV .05
.paclitaxel 175 + carboplatin N=887 AUC= .paclitaxel 175 + carboplatin AUC=5 + epirubicin 75 Stage IIb-IV -paclitaxel 175 + carboplatin N=1282 AUC= .paclitaxel 175 + carboplatin AUC=5
35 vs 37 p>0.paclitaxel 175 + carboplatin N=1077 AUC=5 .71
Dutch/Danis Stage IIb-IV . 2003 Patients Regimen
(cont’d) Median survival (months) 15.2 p>0.05
Du Bois.4 vs 15.paclitaxel 175 + carboplatin AUC=5 + epirubicin 60
Low risk Size ER/PR Grading Age Comment <2cm positive 1 >35 All factors must be present
High risk >2cm negative 2-3 <35 At least 1 factor present
Multidisciplinary treatment planning should be used to integrate local and systemic therapies as well as their sequence.
OR Chemotherapy → tamoxifen. OR Ovarian ablation – postmenopausal Tamoxifen. endocrine responsive – premenopausal Chemotherapy. OR Chemotherapy → tamoxifen Higher risk. endocrine non-responsive – premenopausal Chemotherapy – postmenopausal Chemotherapy
.Node negative (N0) patient
Low risk (=endocrine responsive) Tamoxifen OR nil
Higher risk. Ovarian ablation → tamoxifen.
Node positive (N+) patient
Endocrine responsive – premenopausal Chemotherapy → tamoxifen ±ovarian ablation – postmenopausal Chemotherapy → tamoxifen. OR Tamoxifen Endocrine non-responsive – premenopausal Chemotherapy – postmenopausal Chemotherapy
adjuvant AI is an option Ovarian ablation Ablation of ovarian function is effective adjuvant treatment for premenopausal patients with endocrine responsive tumors [I. A] Chemotherapy
. Aromatase For postmenopausal patients with intolerance or inhibitor contraindications to tamoxifen.Adjuvant systemic therapy
Tamoxifen Patients with ER and/or PR positive tumors should receive tamoxifen 20mg/d for 5 years Tamoxifen should be started when chemotherapy is completed.
Adjuvant systemic therapy
Chemotherapy Adjuvant chemotherapy should use a combination regimen.
. 4 cycles of AC equal to 6 cycles of CMF. In node positive and node-negative disease anthracyclinecontaining therapy has superior in efficacy to CMF. while ER and PR negative tumors were considered candidates for more prolonged chemotherapy. 4 cycles of AC or 6 cycles of CMF were considered adequate treatment for ER and/or PR positive patients. Gallen consensus conference 2003. Adding 4 cycles of paclitaxel to 4 cycles of AC improves outcome in nodepositive patients
At the St.
Factors associated with favourable prognosis in metastatic breast cancer
ER/PR positive tumor Long disease free interval (>1–2 year) No visceral involvement Limited metastatic sites. no bulky disease HER2 negative tumor
Goals of treatment include improving quality of life and prolongation of survival [I. Bisphosphonates are effective in
. Treatment for systemic disease is palliative. A]. Treatment of metastatic breast cancer usually involves hormone therapy and/or chemotherapy with or without trastuzumab.Treatment plan
Isolated local-regional recurrence should be treated like a new primary with a curative intent including adjuvant treatment modalities. Radiation therapy is an integral part of palliative treatment.
Patients with hormone-receptor positive tumor
Premenopausal patients If no prior adjuvant tamoxifen or discontinued for more than 12 months: Tamoxifen with ovarian ablation (LHRH analogs or surgery) [I. Postmenopausal patients Tamoxifen or aromatase inhibitors. Third generation aromatase inhibitors are marginally superior to tamoxifen in first line therapy regarding response and time to
. B]. Otherwise: Third generation aromatase inhibitors can be considered after or concomitantly with ovarian ablation.
The optimal treatment duration for patients with responsive or stable disease is unknown.Patients with hormone-receptor negative tumo
Hormone-receptor negative and/or have progressed on hormone therapy are candidates for cytotoxic chemotherapy (II. rate of disease progression. there are no data supporting the superiority of any particular regimen. previous adjuvant systemic therapy) and patient/physician preferences. presence or absence of comorbid medical conditions. At this time. It is not clear whether single agent chemotherapy or combination chemotherapy is preferable for first-line treatment..
.g.B) The selection of the regimen should be based on tumor and patients characteristics (e.
Selection of commonly used chemotherapy regimen
Non-anthracycline containing Cyclophosphamide / methotrexate / fluorouracil (CMF) Antracycline containing Adriamycin / cyclophosphamide (AC) Fluorouracil / adriamycin / cyclophosphamide (FAC) Fluoroucil / epirubicin / cyclophoshamide (FEC) Taxane containing Adriamycin / taxane (AT) (paclitaxel or docetaxel) Epirubicin / taxane (ET) (paclitaxel or docetaxel)
HDCT + BMT/PBSCT
Xie … xie …
3 4 Time (years)
Early Breast Cancer Trialists’ Collaborative Group (unpublished data)
.Choice of adjuvant chemotherapy: impact on survival 100
Estimated percentage still alive
90 80 70 60 50 40 Combination regimen Single agent 70.