경희대학교 의과대학·의학전문대학원

(1)

Principles of Cancer Treatment

(암치료의 원리)

Multimodality Approach to Cancer Therapy

R di ti Surgeon Radiation oncologist Cancer cure Local modality Early stage Organ function Cytoreduction Local modality H&N cancer Hodgkin’s Systemic Tx Systemic Tx chemotherapy

(2)

Cancer Care

Moderate Normal epithelium Invasive cancer Mild dysplasia Moderate severe dysplasia Metastatic cancer End of life •Healthy diet •Physical exercise •Surgery •Chemoprevention •Surgery •Chemotherapy & Palliative Care •Discontinue tobacco •Reduce alcohol •Dietary intervention •Discontinue tobacco •Healthy lifestyle radiation therapy •Dietary intervention •Discontinue tobacco •Supportive care

Multimodality Approach to Cancer Care

방사선종양학 완화의료 전문의사 외과의사 방사선종양학 의사 Cancer Care Local modality Early stage Organ function Cytoreduction Local modality H&N cancer Hodgkin’s Systemic Tx chemotherapy 종양내과 의사 chemotherapy

molecular targeted therapy hormonal therapy biologic therapy Chemoprevention “일차진료의사” Prevention Early detection

(3)

Cancer surgery-

Surgical oncology

• Prophylaxis

– Colectomy for familial polyposis

– Mastectomy/oophorectomy for familial breast/ovarian cancer syndrome – Orchiectomy in undescended testis

Di i

• Diagnosis

• Staging

– Axillary lymph node sampling in breast cancer – Staging laparotomy in ovarian cancer

• Treatment

– Curative resection: 40% of patients – Debulking surgery: ovarian cancer – Curative metastatectomy

• Lung metastasis in osteosarcoma • Lung metastasis in osteosarcoma • Liver metastasis in colorectal cancer • Palliation

– Bypass surgery in GI obstruction

• Rehabilitation

– Plastic & reconstructive surgery

• Breast reconstruction

• Radiation oncology

M di

l

• Medical oncology

– Medical oncology is the subspecialty of internal medicine that caresfor and designs treatment approachesto patients with cancer, in conjunction with surgical and radiation oncologists. The core skills of the medical oncologist include the use of drugsthat may have a beneficial effect on the

drugsthat may have a beneficial effect on the natural history of the patient's illnessor favorably influence the patient's quality of life. (Harrison, 17th

(4)

Approach to Cancer Therapy

• Begin with an adequate data base

– Clinical trials ÆEvidence based treatment

• Proper histologicdiagnosis

– Histologic subtyping

– Biochemical, immunologic & biologic tissue

characterization characterization

• Adequate staging

• Appropriate plan of management

Staging

• Objectives

Determinant in planning appropriate

– Determinant in planning appropriate

therapy

– Prognostic information

– Compare treatment results

• T, N, M

,

– T: primary tumor

– N: regional lymph node

– M: distant metastasis

(5)

Gastric Cancer

T stage of Tongue Cancer

(6)

N stage of

Head &

N k

Neck

Cancer

Approach to Cancer Therapy

• Begin with an adequate data base

P hi t l i di i • Proper histologic diagnosis • Adequate staging

• Appropriate plan of management

– Biology and natural history of the tumor

A ailable treatment options

– Available treatment options

– Appropriateness to the patient's clinical situation – Wishes of the individual patient

(7)

Goal of Treatment Plan

• Curative

intent

– aggressive treatment with serious complication

• Treatment

for palliation

– relief of symptom

– prevention of complication – maximization of quality of life – Extend life

• Improve longevity without long-term disease free

survival

• consider risk-to-benifit ratio

benefit risk Toxicity benefit _risk Economy cure survival pain control QOL benefit risk QOL

(8)

Cancer Chemotherapy

• Maintreatment option for disseminatedmalignant disease

• Curativechemotherapy

– Metastatic cancer

– Adjuvant chemotherapy

O f th t i t t

• One of the most important

• Still evolving role for systemic chemotherapy

• Palliativechemotherapy

History of cancer chemotherapy

• Exposure to mustard gas led to bone marrow and lymph

node hypoplasia in World War II.

• The clinical use of nitrogen mustard was pioneered by • The clinical use of nitrogen mustard was pioneered by

Gilman at Yale in the 1940sin the treatment of lymphoma.

• Farber at Harvard, also in the 1940s, first induced

remission in childhood leukemia using aminopterin, a

folate antagonist.

• In 1955, chemotherapy was first used to curea solid

tumor, gestational trophoblastic carcinoma., g p

• In 1960s the development of multidrugregimens for

childhood acute leukemiaand Hodgkin'sdisease

demonstrated that chemotherapy could consistently cure a high percentage of patients with certain chemoresponsive diseases.

(9)

Cancer Cell Kinetics

Chemosensitive period: small tumor burden maximal growth fraction

Gompertzian Tumor Growth

Action of Chemotherapeutic Agents

S

G0 G1 G2

Cell-cycle-active drug

Cell Cycle

(10)

Cancer Cell Kinetics

Maximum tolerated dose Dose-limiting toxicity

Bone marrow GI mucosa

Dose-Response Effect of Cytotoxic Drug

Criteria for response to therapy

• Complete response(remission)

– Disappearance of alldetectable disease

• Partial responsep

– Decrease by more than 50%in the sum of the products

of the perpendicular diameters of all measurable lesions

– No increase in size of any lesion – No appearance of new lesion

• Stable disease

– No change in measurable disease

• Progressive disease

– Increase by at least 25%in the sum of the products of

the perpendicular diameters of the lesions

(11)

Duration of Response

• Progression-free survival/Time to progression

– Palliative chemotherapy

• Disease-free survival

– Adjuvant chemotherapyj py

• Overall survival

Clinical Application of Chemotherapy

• Primary chemotherapy

• Adjuvant chemotherapy

– Post-operative

– Breast cancer, colon cancer

• Neoadjuvant chemotherapy

– Pre-operativep

– Head & neck cancer, breast cancer

(12)

Primary Chemotherapy

• Advanced/metastatic cancer patients

• Objective

– Cure – Palliation • Symptom control • Improve QOL • Prolong survival

Advanced cancers with possible

Cure

• Acute lymphoid & myeloid leukemia

• Hodgkin’s disease lymphoma(certain types) • Hodgkin’s disease, lymphoma(certain types) • Germ cell neoplasm

– Embryonal

carcinoma, teratocarcinoma, seminoma, dysgerminoma , choriocarcinoma

• Gestational trophoblastic neoplasia • Pediatric neoplasms

– Wilm’s tumor, embryonal rhabdomyosarcoma, Ewing’s

sarcoma, peripheral neuroepithelioma, neuroblastoma • Small cell lung carcinoma

(13)

Cancers possibly cured with

‘high-dose’

chemotherapy with stem cell support

• Relapsed leukemia

– lymphoid & myeloid

• Relapsed lymphomas

– Hodgkin’s & non-Hodgkin’s

• Chronic myeloid leukemia • Chronic myeloid leukemia • Multiple myeloma

Concept of Dose Intensity

Dose Intensity(DI): mg/m2_/wk Dose Intensity(DI): mg/m /wk 100 E ffect Breast cancer Tumor response 50 totoxic E Therapeutic Index

(14)

Sequence of PBSCT

Stem cell Mobilization Stem cell Collection Stem cell Infusion High Dose ChemoTx Chemotherapy G(M)-CSF Apheresis

Advanced cancers possibly

cures

by

chemotherapy

and

radiation

• Head and neck squamous carcinoma • Anal squamous carcinoma

• Breast carcinoma

• Carcinoma of the uterine cervix

• Non-small cell lung carcinoma (stage III) • Small cell lung carcinoma

(15)

Chemotherapy+RT in Laryngeal Cancer

Treatment No. 3yr

surv.

VA Laryngeal DDP,5FU+RT 166 53%

cancer trial Surg+RT 166 56%

At two years, the proportion of patients who had an intact larynx after

Radiotherapy with concurrent cisplatin (88 percent)differed significantly from the

percent) differed significantly from the proportions in the groups given Induction chemotherapy followed by

(16)

hazard ratio, 0.68; P = 0.005

hazard ratio, 0.74; P = 0.03

N Engl J Med 2006;354:567-78.

Adjuvant Chemotherapy

• Rationale

– tumor volume is minimum: higher cure rateg

– reduce drug dosage: decrease toxicity

• End point

– not the response rate

– prolong relapse-free/overall survivalp g p

• Selection of treatment program

(17)

Cancer Cell Kinetics

Chemosensitive period: small tumor burden maximal growth fraction

Gompertzian Tumor Growth

Cancers possibly

cured

with chemotherapy

as

adjuvant

to surgery

• Breast carcinoma • Colorectal carcinoma • Osteogenic sarcoma • Soft tissue sarcoma

(18)

Neoadjuvant Chemotherapy

• Preceed definitive local surgical or radiation

treatment treatment

• Organ preservation surgery • Increase resectability

• Kill micrometastasis Æ prolong survival

I f ti b t t ti t t t

• Information about postoperative treatment • Delay effective local disease control

• Perioperative complication

Neoadjuvant Chemotherapy

Organ Preservation

• Laryngeal cancer • Anal cancer • Bladder cancer • Osteogenic sarcoma • Breast cancer

(19)

Cancers responsive with useful

palliation

, but

not cure

, by chemotherapy

• Multiple myeloma • Chronic lymphocytic leukemia • Lymphoma-certain type • Bladder carcinoma • Cervix carcinoma • Endometrial carcinoma • Soft tissue sarcoma

• Head and neck cancer type

• Hairy cell leukemia • Head and neck cancer

• Breast carcinoma • Gastric carcinoma

Responses of Chemotherapy in Cancer

Tumor CR RR Survival (%) (%) 5yr(%) median (month) ( ) Diffuse lymphoma 70-84 51-76 Testicular cancer 63-78 70-92 Ovarian cancer 17-34 50-79 16-31

Small cell lung cancer 31 70 5-11

Breast cancer 5-25 45-80 15-33

H&N cancer 5-10 30-63 5-6

(20)

Tumors

poorly

responsive in advanced

stages to chemotherapy

• Pancreatic carcinoma – Gemcitabine

• Improve QOL

• Biliary tract neoplasms • Renal carcinoma • Prostate carcinoma – Hormonal therapy • Melanoma – Biologic therapy • Hepatocellular carcinoma L l d li – Biologic therapy – Targeted therapy • Thyroid carcinoma – Local modality – Sorafenib • Carcinoma of vulva