Multidiscipline Treatment of Cancer Clinical oncologist Surgeon Radiation

Multidiscipline Treatment of Cancer • • • Clinical oncologist Surgeon Radiation oncologist Pathologist Radiologist

The Description of Cancer Patients 1. The pattern of presenting symptoms and signs. 2. The evidence of diagnosis. 3. The disease extent. 4. The treatment plan. 5. The effects and side effects of treatments. 6. The ongoing problems.

Pathophysiology of Cancer • Local effects: 1. Tumor necrosis, infection, bleeding. 2. Tumor invasion of adjacent structure.

Pathophysiology of Cancer • Remote effects: 1. Tumor production: hormones, growth factors, cytokines, other peptides. 2. Tumor-evoked production: a. Immune cells: antibodies, immune complex. b. Non-immune cells: other peptides.

Action sites of cytotoxic agents DNA synthesis DNA transcription Antimetabolites Alkylating agents DNA duplication Mitosis Cellular level Intercalating agents Spindle poisons

Action sites of cytotoxic agents PURINE SYNTHESIS 6 MERCAPTOPUR INE PYRIMIDINE SYNTHESIS RIBONUCLEOTIDES 6 -THIOGUANINE METHOTREXATE DEOXYRIBONUCLEOTIDES ALKYLATING AGENTS 5 -FLUOROURACIL HYDROXYUREA ANTIBIOTICS DNA ETOPOSIDE CYTARABINE RNA PROTEINS L-ASPARAGINASE VINCA ALKALOIDS ENZYMES MICROTUBULES TAXOIDS

化學治療可以 n 延長轉移患者的存活期 @ Primary chemotherapy n 減輕癌症引起的不適 @ Palliative chemotherapy n 增加手術或放射治療的療效 @ Neoadjuvant & adjuvant @ Concommitent radiosensitizer n 改善臨床的治療方式

化學藥物的給藥後 • 不同的藥物的給藥後注意事項根據其常 見毒性反應可能不同 • 注意嚴重的立即性毒性反應 ËCisplatin: hydration & urine output ËAdriamycin/ Epirubicin: heart failure ËHigh dose Methotrexate: renal failure ËCyclophosphamide: hemorrhagic cystitis

Side effects of chemotherapy Alopecia Mucositis Pulmonary fibrosis Cardiotoxicity Nausea/vomiting Diarrhea Cystitis Sterility Myalgia Neuropathy Local reaction Renal failure Myelosuppression Phlebitis

Aim of combination therapy INCREASED EFFICACY ACTIVITY Different mechanisms of action Different mechanisms of resistance SAFETY Compatible side effects

會引起組織壞死的藥物 • Vinka alkaloids: Vincristine(Oncovin), Vinblastine, Vinorelbine(Navelbine) • Anthracyclines: Epirubicin, Idarubicin • Mitomycin-C, BCNU, DTIC • Taxoids, Topotecan • Mithramycin, Nitrogen Mustard • VP-16, Cisplatin • Fludarabine, Gemcitabine, Irinotecan

Chemotherapy-associated Emesis

Type of Treatment-related Emesis • 1. Acute-phase symptoms: Correlated with serotonin (5 -HT) release from enterochromaffin cells. Emetic signals are propagated at local 5 -HT 3 receptors.

Type of Treatment-related Emesis • 2. Delayed-phase symptoms: Not to be related to serotonin. Severity and duration often correlate with drug dosage. Nausea severity reportedly is similar during both phases.

Type of Treatment-related Emesis • 3. Anticipatory emetic symptoms: An aversive conditioned response Develops after repeated antineoplastic treatments that are characterized by poor emetic control. Complete control throughout antineoplastic treatment remains the best preventive strategy.

Antiemetic Options 1. Serotonin (5 -HT 3) receptor antagonists: Granisetron (Kytril) Ondansetron (Zofran) • More effective and safer to use then other types of antiemetics.

Serotonin Antagonists 4. 接受腹部放射照射之癌症病人，得依下列規範 使用ondansetron及granisetron： (1)total body or half body irradiation (2)pelvis or upper abdominal region of single irradiation dose> 6 Gy (3)腹部放射治療中產生嘔吐，經使用 dexamethasone、metoclopramide或 prochlorperazine等傳統止吐劑無效，仍發生嚴 重嘔吐之患者。

Antiemetic Options 2. Steroids: Acute-phase symptoms: effective against mildly to moderately symptoms. Delayed-phase symptoms: most active agents. Dexamethasone (2 -20 mg) & methylprednisolone + 5 -HT 3 - and D 2 -receptor antagonists.

Antiemetic Options 3. Metoclopramide: A weak competitive 5 -HT 3 -receptor antagonist at high dosages. 4. Benzodiazepines: Lorazepam (Ativan). 5. Dopaminergic (D 2)-receptor antagonists: Phenothiazines—Prochlorperazine. Butyrophenones—Haloperidol.

Neutropenic Fever

Neutropenic Fever • Fever: 1 oral temperature > 38. 3 o. C. 2 oral temperatures > 38 o. C, an hour apart. • Neutropenia: ANC (Band + Neutrophil) < 500/mm 3. ANC 500/mm 3 ~ 1, 000/mm 3, with a predicted decline to < 500/mm 3 within 48 hours.

Neutropenic Fever In the absence of white cells: 1. Signs and symptoms of invasive infections may be absent. 2. Infections can invade and spread quickly. 3. Fever may be the only manifestation of a potentially life-threatening infection.

Neutropenic Fever • Bacteremia: 10% to 20% • Gram-positive bacteremia: 70% Coagulase-negative staphylococcus S. aureus. • Gram-negative bacteremia: 30% Escherichia coli, Klebsiella sp. , Enterobacter sp. , and rarely, Pseudomonas aeruginosa.

Neutropenic Fever • Common sites of local infection: The respiratory tract. Sinuses. Skin, soft tissue. Venous catheter entry/exit sites. Urinary tract. Gastrointestinal tract: oral cavity, anus.

Neutropenic Fever • Laboratory evaluation: CBC/DC, Platelet. Chemistries (hepatic and renal function). Blood cultures. U/A and U/C. CXR. Any accessible sites of possible infection.

IDSA 2002 Guidelines CID 2002; 730 -51

Vancomycin • In initial empirical therapy: 1. Clinically suspected serious catheter related infections. 2. Known colonization with penicillin- and cephalosporin-resistant pneumococci or MRSA. 3. B/C gram-(+) bacteria before final identification and susceptibility testing. 4. Hypotension or other evidence of CV impairment.

癌症疼痛 Cancer Pain

晚期癌症患者常見症狀 • • Pain Fatigue Weakness Lack of energy Dry mouth Constipation Dyspnea Sleep Dis. 89% 66% 61% 57% 51% 50% 49% • • Depression 41% Cough 38% Nausea 36% Edema 28% Taste 28% Hoarseness 24% Anxiety 24% Vomiting 23%

癌症疼痛可由一些簡單的治療方 式在 90%的患者得到有效的處置 Cancer pain can be managed effectively through relatively simple means in up to 90% of Patients. Unfortunately, pain associated with cancer is frequently undertreated.

治療的基本原則 • 1. Dose "by mouth" whenever possible. • 2. Around the clock (ATC): Basal analgesic administration should not be based on an "as needed" (prn) basis. • 3. Dose by the WHO three-step ladder.

WHO Analgesic Ladder Step 3 Co-analgesics Strong Opioids ± Non-Opioids Morphine, Oxycodone, Hydromorphone, TTS-Fentanyl, Methadon Step 1 Step 2 , Weak Opioids ± Non-Opioids Codein, Dihydrocodein, Tramadol, Tilidin/Naloxon Non-Opioids Ibuprofen, Diclofenac, „Cox 2“ Paracetamol, Metamizol, Flupirtin 47

Strong Opioids Relation Morphine 1 Oxycodone 2 Hydromorphone 7. 5 Fentanyl-TTS 100 Duration 8 - 12 48 - 72

Strong Opioids • Morphine 10 mg IV, IM = 20 mg SC = 30 mg PO

Morphine SR Dosage 2 x 30 mg If pain continues: A. 2 x 60 mg B. 3 x 30 mg never < 8 hrs 12 hrs 8 hrs Fentanyl-TTS Dosage 25 mg/h If pain continues: A. 50 mg/h B. 25 mg/h never < 2 days Every 3. day Every 2. day

Rapid Calculation of Duragesic for Cancer Pain q Divide morphine equivalent dose (mg/day) PO by 2, round off to closest Duragesic patch in mcg/hr q EXAMPLE: Pt is on morphine (PO) 180 mg/day -> 180 /2 = 90, round off to Duragesic 100 mcg/hr

癌病代謝性急症 (Metabolic Emergencies in Oncology)

高血鈣症: 病程之變化 • Early signs : fatique, lethargy, constipation, nausea and polyuria. • Polyuria and nocturia secondary to renal tubular defect in water conservation. ==> Dehydration • Stupor and coma are signs of severe hypercalcemia

高血鈣症的鑑別診斷 • • Endocrine/metabolic disorders Cancer Infectious disease Renal insufficiency Granulomatous diseases Dietary/drug related Milk_alkali syndrome • 高血鈣症最常見原因為癌症及副甲狀腺功能亢進

高血鈣症的治療 • Saline hydration and diuretics • Steroids: inhibit bone resorption and decrease GI tract calcium absorption. Òmost helpful in myeloma, leukemia and breast cancer • Calcitonin: increase renal excretion and reduce bone resorption

高血鈣症的治療(II) • Diphosphonates : reduce calcium flux from bone. osteoclast inhibitor. • Gallium nitrate : inhibit bone resorption • Mithramycin : kill osteoclasts.

腫瘤融解症候群 Tumor Lysis Syndrome

腫瘤細胞內含物及其代謝產物 大量釋出於血液中所引發的全 身性反應 Rapid release of intracellular contents into the blood stream

主要代謝異常及其引致之病變 • Hyperuricemia: acute urate nephropahy --> obstruction and renal failure • Hyperkalemia: cardiac arrhythmias • Hyperphosphatemia : acute renal failure • Hypocalcemia: muscle cramp, cardiac arrhythmias and tetany

Tumor Lysis常見於下列腫瘤 • Large tumor burdens, rapid proliferative fraction and sensitive to chemotherapy. • High grade lymphoma , such as Burkit's lymphoma. Leukemia with high leucocyte counts, CML in blastic crisis • Rarely seen in solid tumors: small cell lung ca, breast cancer • Few hours to few days after initiation of treatment

Tumor Lysis臨床症狀 • Oliguria-azotemia • Hyperkalemia, hyperphosphatemia, hyperuricemia • Tetany • Cardiac arrhythmia • Hypotension-shock • Cardiac arrest

如何早期發現 Tumor Lysis • 密切檢測 • Chemistry screen : K+, Ca++, uric acid, PO 4, LDH, BUN, creatinine

Tumor Lysis的治療方式 • Prevention for high risk patients • Hydration 2500 -3000 ml/sqm/day • Sodium bicarbonate for alkalinization to urine PH >7 (50100 meq / L) • Allopurinol 10 mg/kg/day , , 300 mg/day (12 hrs before C/T), reduces to 100 mg/day if creatinine > 2 mg%

Tumor Lysis的治療方式 • Monitor elctrolytes, uric acid, phosphorus, calcium and creatinine daily for 1 week • once tumor lysis developed, monitor the lytes every few hours. • Hypocalcemia : calcium gluconate • Hyperkalemia : Kayexalate (15 gm q 6 h), 20% dextrose with 10 -20 U of insulin /liter. • Hyperphosphatemia : aluminum gel 30 cc q 3 -4 hrs

Tumor Lysis的治療方式 • 早期使用血液透析 • • potassium >6 m. Eq/l uric acid > 10 mg/dl phospharus > 10 mg/dl, symptomatic hypocalcemia and fluid overload.

脊索壓迫症候群 Spinal Cord Compression

Highlight of Leukemia Management Bleeding diasthesis Risks of life-threatening hemorrhage -- ICH, DIC, pulmonary hemorrhage Fever, neutropenic fever Hyperleucocytosis Severe anemia Organomegaly

Cytochemical staining Myeloperoxidase (MPO): AML M 1, 2, 3, 4, 5 Chloroacetate esterase (CAE): M 1, 2, 3, 4 Alpha-naphthyl butyrate (ANBE): M 4, M 5 PAS: ALL, AML (15%) Tdt: ALL LAP score: leukocyte ALK P stain (80 -100) LAP < 20 in CML, PNH

Approach of Acute Leukemia Blasts≧ 30% Peroxidase stain Positive Negative CAE PAS Positive Negative POS Neg AML ANBE ALL AML Mo M 1 -M 4 M 4, M 5 AML M 6, 7 CD 13, 33, 65 CD 41, 61 ALL Glycophyrin CD 2, 7, 10, 19 CD 13, 14, 33, 65

CHROMOSOME ANALYSIS For diagnosis t(9, 22) : CML t(2, 5) : Ki-1 lymphoma ALCL t(4, 11) : biphenotypic leukemia For prognosis Favorable : t(8, 21), t(15, 17), inv(16) Unfavorable : -5/del, -7/del, +8 For detection of minimal residual disease

AML-Treatment Remission induction: Ara-c 100 mg/m 2/d X 7, Idarubicin 12 mg / m 2/d X 3 Consolidation: Standard Ara-c 100 mg/m 2 X 5, Ida X 2 High dose Ara-c 1 -3 gm/m 2 Bid X 4 days Maintenance: not helpful Stem cell transplant — Allo-BMT, Allo-PBSCT — ABMT, autologous PBSCT — MUD, no better than Hi. DAC — Allo-minitransplant (mixed chimerism) Acute GVHD, VOD, interstitial pneumonia, TRM 30%

COMMON CHEMOTHERAPY REGIMEN AML A) 7 + 3 • Ara - C 100 mg/m 2 + N/S or D 5 W 500 ml CIV qd or bid • Idarubicin 10 -12 mg/m 2×d + N/S 100 ml IV infusion for 1 hr (Mitoxantrone same as Idarubicin) B) HDAC • Ara-C 1 gm-3 gm/m 2×bid + N/S 500 ml IV infusion for 3 -4 hours

Acute Promyelocytic Leukemia ( M 3 ) Remission induction : ATRA 45/m 2/d WBC > 3000/cumm : ATRA + Idarubicin 12 mg/m 2 WBC > 10000/cumm : ATRA + Ida × 3 + Ara – C Consolidation : 7+3 then HIDAC + DNR or IDA Maintenance : 1 yr ATRA or observation ( APL 93 trial ) 5 yr DFS = 70 % Retinoid acid syndrome : weight gain , hyperleucocytosis , interstitial pulmonary infiltrate , pleural or pericardial effusion , hypoxemia , hypotension Treatment : dexamethasone 10 mg bid × 3 day

Treatment of ALL Remission induction : - standard risk : vincristin , prednisolone - high risk : vincristin , PDN , doxorubicin Early intensification : L – asparaginase, MTX CNS prophylaxis : MTX , dexamethasone Consolidation : Ara – C , cyclophosphamide Maintenance : 6 MP/MTX , VCR/PDN , VP-16 ALLO-BMT, PBSCT ( auto, MUD )

Clinical Practice in Ward 1 st WK: FAB subtype (confirm DX), Karyotype, set IV line, cyto-reduction , initiate C/T, blood component, control infection, risk factors 2 nd WK: C/T, infection, hemorrhage 3 rd WK: d 15 BM exam, folic acid, G-CSF fungal infection, HSV, diarrhea 4 th WK: recovery of CBC, fever should subside otherwise consider partial remission or fungal infection Always check skin, oral cavity, bowel, anus, venipuncture site, UA, CXR

MANAGEMENT OF ACUTE LEUKEMIAS SET IV line, CVP, PICC or port-A Blood component transfusion supportive care for bleeding and infection – blood culture in febrile patients – empirical antibiotics Reverse isolation, single room or HEPA Gut decontamination Bone marrow aspiration & biopsy Flow cytometry for leukemia markers – lymphoid and myeloid Chromosome, cytogenetic study Cytochemical stain PCR, ISH

NOTICE OF PLATELET TRANSFUSION Hazards of low platelet count – platelet　 70 - 80 K guarantee safety for operation – platelet　 ＜ 50 K bleeding in minor trauma – platelet　 ＜ 20 K spontaneous bleeding Bleeding diathesis – – – DIC, sepsis, aplastic anemia acute leukemias high dose chemotherapy stem cell transplantation thrombocytopenia of any cause

Fever in Acute Leukemia Before admission: pneumonia, leukemia 1 st 7 days: infection, G(-) bacilli, Ara-c 2 nd 7 days: infection, G(+) cocci, blood transfusion 3 rd 7 days: G-CSF, blood transfusion, G(+)/G(-) fungi, herpes simplex HSV NEC: necrotizing neutropenic enterocolitis Common site of infection: mucositis, dental, perianal infection, IV catheter, skin, ENT, lung, G-I.

Thanks for attention