แนวทางการรักษาโรคมะเร็งในเด็ก-2557 (1)

Thai Pediatric Oncology Groupชมรมโรคมะเร็งเดก็Treatment protocol for rhabdomyosarcoma [ThaiPOG-RMS-13-SR]Protocol name ThaiPOG-RMS-13-SRProtocol for Intermediate risk, rhabdomyosarcomaReference Arndt C A et al. JCO 2009;27:5182-5188Open date January 2014Patient’s name..................................................................... Sex........................... HN...........................................Age (yy/mm)................................ BW............................. kg. Ht.............................cm BSA..............................m2Inclusion criteria Embryonal rhabdomyosarcoma, stage 2/3 group III, M0 Alveolar rhabdomyosarcoma, non-metastatic diseasePhase I: Induction phaseCycle 1 2 3 4 5 6 7 8 Week 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23Chemo V V V V V V V V V V V V V - - V - - V V V V V V AAAAA - - A CCCCCCCC E* Surgery + Radiotherapy‡Phase I: Induction phase Cycle 9 10 11 12 13 14 Week 24+ 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42Chemo V - - V - - V - - V V V V - - V - - - AAAAAA CCCCCC E** EE: evaluation of disease at week 12, 24 and the end of treatment*In group III patients, excision of the tumor with negative margins should be considered and the radiation dosewas adjusted according to the amount of residual**Selected patients who responded poorly to induction chemotherapy were recommended to proceed topreoperative RT followed by second-look surgery at week 24‡ RT began 2 to 3 days after completion of week 12 chemotherapy if no biopsy or second-look operation wasdone, or 2 to 3 weeks after surgery for patients who underwent second-look surgeryDrug Age(yrs) Dosage Total doseV: Vincristine 0.025 mg/kg IV push slowly (maximum dose, 2 mg) x 1 day <1 0.05 mg/kg IV push slowly (maximum dose, 2 mg) x 1 dayA: Dactinomycin* 1-3 1.5 mg/m2/day IV push slowly (maximum dose, 2.5 mg) x 1 day >3 0.025 mg/kg x 1 dayC: <1 0.045 mg/kg x 1 dayCyclophosphamide ≥1 36 mg/kg IV drip in 1 hr x 1 day(given with mesna) <1 73 mg/kg IV drip in 1 hr x 1 dayMesna 1-3 2.2 gm/m2/dose IV drip in 1 hr x 1 day >3 550 mg/m2/dose IV slowly push slowly at 0, 3, 6, 9 hr after cyclophosphamide infusionRhabdomyosarcoma: Treatment protocol for rhabdomyosarcoma [ThaiPOG-RMS-13-SR] 287

Thai Pediatric Oncology Group ชมรมโรคมะเร็งเด็กPatient’s name..................................................................... Sex........................... HN...........................................Age (yy/mm)................................ BW............................. kg. Ht.............................cm BSA..............................m2Cycle Date BSA Vincristine Dactinomycin Cyclophosphamide Note1 RADIOTHERAPY (parameningeal RMS with intracranial extension)* __________________2345 ** Re-evaluation and Radiotherapy‡ or Delayed surgery6*78*ในกลุ่มผู้ป่วย parameningeal RMS ที่มี intracranial extension (วินิจฉัยเม่ือพบว่ามีการแตะ กด ลุกลาม หรือทาให้เกิดความผดิ ปกตขิ อง dura mater จากภาพถา่ ยทางรังสชี นดิ ใดชนิดหนึ่ง) ควรเริ่มการรักษา VAC และได้รับรังสีรักษาอยา่ งรวดเรว็ (immediate radiotherapy) หลงั สัปดาห์ที่ 1 หรอื เรว็ ทสี่ ดุ หลังจากทไ่ี ด้รับ VAC**Vincristine is given only on day 1 (omit on day 8, 15)‡สาหรับผู้ป่วย group III ท่ีสัปดาห์ที่ 12 ท่ีมีตอบสนองดีต่อการรักษา ประเมินแล้วสามารถผ่าตัดได้อย่างสมบูรณ์(margin negative) ควรได้รับการผ่าตัดหลังสัปดาห์ท่ี 12 ทันที (second-look surgery) และเร่ิมรังสีรักษาภายหลังผ่าตัด 2-3 สปั ดาหซ์ ึ่งขนาดของรังสรี ักษาจะปรบั ตามผลการผ่าตัดSurgerySurgery date (………/………/………) Surgeon ……………..……………………………………….…………Type of surgery: ……………………………………………………………………………………………………………..Surgical margin  Adequate (> 5 cm)  Inadequate (not free margin, margin < 5 cm.)RadiotherapyRadiotherapy date (………/………/………) Total dose (Gy): ……………………………………………….Technique: ………………………………….. Involved field: ………………………………………………….- Embryonal/Alveolar RMS group IV: RT 50.4 Gy- Embryonal/Alveolar RMS group IV, second look surgery, margin negative: RT 36 Gy- Embryonal/Alveolar RMS group IV, second look surgery, margin negative: RT 41.4 GyEvaluation 7. CT/ MRI …………………………….(………/………/………) ……………..……………………………..……. 8. Bone scan (………/………/………) ………………………………...…………….…………………………….. 9. CXR/CT scan chest (………/………/………) ………………………..……………………………..………….Rhabdomyosarcoma: Treatment protocol for rhabdomyosarcoma [ThaiPOG-RMS-13-SR] 288

Thai Pediatric Oncology Group ชมรมโรคมะเร็งเด็กPatient’s name..................................................................... Sex........................... HN...........................................Age (yy/mm)................................ BW............................. kg. Ht.............................cm BSA..............................m2Cycle Date BSA Vincristine Dactinomycin Cyclophosphamide Note9* Re-evaluation** and Radiotherapy‡ or Delayed surgery10 *11 *1213 *14 * Re-evaluation*Vincristine is given only on day 1 (omit on day 8, 15)**Selected patients who responded poorly to induction chemotherapy were recommended to proceed topreoperative RT followed by second-look surgery at week 24SurgerySurgery date (………/………/………) Surgeon ……………..……………………………………….…………Type of surgery: ……………………………………………………………………………………………………………..Surgical margin  Adequate (> 5 cm)  Inadequate (not free margin, margin < 5 cm.)RadiotherapyRadiotherapy date (………/………/………) Total dose (Gy): ……………………………………………….Technique: ………………………………….. Involved field: ………………………………………………….- Embryonal/Alveolar RMS group IV: RT 50.4 Gy- Embryonal/Alveolar RMS group IV, second look surgery, margin negative: RT 36 Gy- Embryonal/Alveolar RMS group IV, second look surgery, margin negative: RT 41.4 GyEvaluation 1. CT/ MRI …………………………….(………/………/………) ……………..……………………………..……. 2. Bone scan (………/………/………) ………………………………...…………….…………………………….. 3. CXR/CT scan chest (………/………/………) ………………………..……………………………..………….Rhabdomyosarcoma: Treatment protocol for rhabdomyosarcoma [ThaiPOG-RMS-13-SR] 289

Thai Pediatric Oncology Groupชมรมโรคมะเร็งเดก็ Treatment protocol for rhabdomyosarcoma [ThaiPOG-RMS-13-HR]Protocol name ThaiPOG-RMS-13-HRProtocol for High risk, rhabdomyosarcomaReference Oberlin O et al. JCO 2012;30:2457-65Open date January 2014Patient’s name..................................................................... Sex........................... HN...........................................Age (yy/mm)................................ BW............................. kg. Ht.............................cm BSA..............................m2Inclusion criteria Metastatic diseasePhase I: Induction PhaseCycle 1 2 3 456 78 9Week 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27Chemo I V V Cb V V I I Cb I I Cb IVEV VEV VE VAVE AVE AV E E* E* E* Radiotherapy** Re-surgery or Radiotherapy‡Phase II: Maintenance PhaseCycle 10 11 12 13 14 15 16 17 18Week 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52Chemo V V V V V V V V V AAAAAAAAA CCCCCCCCC E* E*For children less than 1 year of age or weighing less than 10 kg, the full combination of drugs are introduced at66% of the calculated meter-squared dose and increased gradually toward the full meter-squared dose forsubsequent courses of treatment as tolerated.*E: evaluation**Radiation to all patients age ≥ 3 years with parameningeal disease and to all patients who achieved partialresponse < 50%‡Radiation to all patients who not received radiation at 9th week of chemotherapyDrug Dosage Total doseI: Ifosfamide 3.0 gm/m2/dose IV drip in 1 hr x 3 daysMesna 600 mg/m2/dose IV slowly push slowly at 0, 3, 6, 9, 12 hr after ifosfamide infusionV: Vincristine 1.5 mg/m2/day IV push slowly (maxinum dose, 2 mg) x 1 dayA: Dactinomycin* 1.5 mg/m2/day IV push slowly (maxinum dose, 2 mg) x 1 dayCb: Carboplatin 500 mg/m2/day IV drip in 1 hr x 1 dayE: Etoposide 150 mg/m2/day IV drip in 2 hr x 1 dayC: Cyclophosphamide 1.0 gm/m2/dose IV drip in 1 hr x 1 dayRhabdomyosarcoma: Treatment protocol for rhabdomyosarcoma [ThaiPOG-RMS-13-HR] 290

Thai Pediatric Oncology Group ชมรมโรคมะเร็งเดก็Patient’s name..................................................................... Sex........................... HN...........................................Age (yy/mm)................................ BW............................. kg. Ht.............................cm BSA..............................m2Phase I: Induction PhaseCycle Date BSA Ifosfamide Vincristine Dactinomycin Carboplatin Etoposide Note123* Evaluation (1) and Radiotherapy**4*5*6* Evaluation (2), Delayed surgery and/or Radiotherapy‡7*8*9* Evaluation (3)*Vincristine is given only on day 1 (omit on day 8, 15)**Radiation to all patients age ≥ 3 years with parameningeal disease and to all patients who achieved partialresponse < 50%‡Radiation to all patients who not received radiation at 9th week of chemotherapyEvaluation (1) 1. CT/ MRI …………………………….(………/………/………) ……………..……………………………..……. 2. Bone scan (………/………/………) ………………………………...…………….…………………………….. 3. CXR/CT scan chest (………/………/………) ………………………..……………………………..………….RadiotherapyRadiotherapy date (………/………/………) Total dose (Gy): ……………………………………………….Technique: ………………………………….. Involved field: ………………………………………………….- Embryonal/Alveolar RMS group IV: RT 50.4 Gy- Embryonal/Alveolar RMS group IV, second look surgery, margin negative: RT 36 Gy- Embryonal/Alveolar RMS group IV, second look surgery, margin negative: RT 41.4 GyRhabdomyosarcoma: Treatment protocol for rhabdomyosarcoma [ThaiPOG-RMS-13-HR] 291

Thai Pediatric Oncology Group ชมรมโรคมะเร็งเด็กPatient’s name..................................................................... Sex........................... HN...........................................Age (yy/mm)................................ BW............................. kg. Ht.............................cm BSA..............................m2Evaluation (2)1. CT/ MRI …………………………….(………/………/………) ……………..……………………………..…….2. Bone scan (………/………/………) ………………………………...…………….……………………………..3. CXR/CT scan chest (………/………/………) ………………………..……………………………..………….SurgerySurgery date (………/………/………) Surgeon ……………..……………………………………….…………Type of surgery: ….………………………………………………………………………………………………………….Surgical margin  Adequate (> 5 cm)  Inadequate (not free margin, margin < 5 cm.)RadiotherapyRadiotherapy date (………/………/………) Total dose (Gy): ……………………………………………….Technique: ………………………………….. Involved field: ………………………………………………….- Embryonal/Alveolar RMS group IV: RT 50.4 Gy- Embryonal/Alveolar RMS group IV, second-look surgery, margin negative: RT 36 Gy- Embryonal/Alveolar RMS group IV, second-look surgery, margin negative: RT 41.4 GyEvaluation (3) 1. CT/ MRI …………………………….(………/………/………) ……………..……………………………..……. 2. Bone scan (………/………/………) ………………………………...…………….…………………………….. 3. CXR/CT scan chest (………/………/………) ………………………..……………………………..………….Phase II: Maintenance Phase Vincristine Dactinomycin Cyclophosphamide NoteCycle Date BSA 1 2 3 4 5 6 7 8 9Rhabdomyosarcoma: Treatment protocol for rhabdomyosarcoma [ThaiPOG-RMS-13-HR] 292

Thai Pediatric Oncology Group ชมรมโรคมะเร็งเด็กGerm Cell Tumor Staging of germ cell tumor (gonadal and extragonadal)Germ Cell Tumor: Staging of germ cell tumor (gonadal and extragonadal) 293

Thai Pediatric Oncology Groupชมรมโรคมะเร็งเด็กการวินิจฉยั และการรกั ษา gonadal and extragonadal germ cell tumor Patients suspect germ cell tumor (GCT) Tumor marker evaluation (-HCG, AFP) Diagnostic surgery (if possible) Pathology confirm diagnosisMature and Low risk Intermediate risk High risk*immature teratoma GCT GCT GCTat any sitesObservation and Observation and Standard PEB regimen monitoring monitoring 4 courses EvaluationComplete Partialresponse response Off Secondtreatment look surgery Pathology positive for Pathology negative malignant GCT for malignant GCT Standard PEB regimen Off 2 courses and follow up treatmentGerm Cell Tumor: การวนิ จิ ฉยั และการรักษา gonadal and extragonadal germ cell tumor 294

Thai Pediatric Oncology Group ชมรมโรคมะเร็งเด็ก Type of germ cell tumor by staging and by risk groupStaging Ovarian Testicular ExtragonadalStaging 1 Low Low IntermediateStaging 2 Intermediate Intermediate IntermediateStaging 3 Intermediate IntermediateStaging 4 Intermediate Intermediate High Highแผนการรักษาผู้ป่วย germ cell tumor ตามตาแหน่งของกอ้ น histology และ staging Histology Primary site Stage Treatment Mature teratoma All sitesImmature teratoma* All sites Localized Surgery +observation Testicular Localized Surgery +observation Malignant germ cell Stage 1 Surgery +observationtumor and germinoma Ovary Stage 2-4 Surgery+ standard PEB Stage 1** Surgery +observation Extragonadal Stage 2-4 Surgery+ standard PEB Stage 1-2 Surgery+ standard PEB Stage 3-4 Surgery+ standard PEB* Immature teratoma ถ้า rupture cyst ระหวา่ งผา่ ตัด หรอื ผ่าตัดไมห่ มด พิจาณาใหย้ าเคมีบาบัด PEB Immature teratoma grade III ทต่ี าแหน่ง sacrococcygeal พิจารณาให้ยาเคมีบาบัด PEB หลงั ผา่ ตดั** Malignant GCT ที่ ovary stage I พจิ ารณาให้ยาเคมีบาบดั PEB หลังผา่ ตัด ในกรณที ีต่ ิดตามอาการใกลช้ ิดหลงัผ่าตัดไม่ได้ เพราะโอกาส recurrence ได้ ขนาดของยาเคมบี าบัด PEB และ JEB Regimen Bleomycin Etoposide Cisplatin CarboplatinStandard-PEB 15 units/m2, 100 mg/ m2, 20 mg/ m2, 600 mg/ m2,(every 21days) day 1 day 1-5 day 1-5 day 2 JEB 15 units/m2, 120 mg/ m2,(every 21-28 days)* day 1 day 1-3*พจิ ารณาให้ JEB แทน PEB ในกรณที ่ผี ปู้ ว่ ยมีปัญหาทางไต และไมส่ ามารถให้ cisplatinum ได้Germ Cell Tumor: Type of germ cell tumor by staging and by risk group 295

Thai Pediatric Oncology Group ชมรมโรคมะเร็งเด็ก Data entry formPatient’s name......................................................... HN............................ Sex  male femaleAddress..............................................................................................................................................................................................................................................Contact person....................................Tel......................................Father’s name........................................................ Age...........yr Occupation…………….......................................Mother’s name........................................................ Age...........yr Occupation……………......................................Date of Birth (dd/mm/yy)............................................. Date of Diagnosis (dd/mm/yy) .......................................... BSA...............m2Age ............... yr...............m. BW...............kg Ht...............cm.สทิ ธิการรักษา บัตรประกันสขุ ภาพ จา่ ยตรง อื่นๆ (ระบ)ุ .............................................HistoryPhysical examination Metastatic SitePrimary Site and SizePre- treatment investigations.A. Blood date (………/………/………)CBC …………..……………………… β-hCG ……..……………………….…. AFP……………..…………………..…B. Imaging studyCT chest (………/………/………) ……………..……….……………………..……………………………………………Chest X-Ray (………/………/………) ..……………..……….……………………..……………………………………..MRI/CT primary lesion (………/………/………) ..……………………….……………………..…………………………Bone scan (in high risk only) (………/………/………) ..……………...………..………………………………………..C. Bone marrow for metastatic work upBone marrow aspiration (abnormal CBC only) (………/………/………)…………………...…………………..……..D. OtherOther (………/………/………) ……………………………………………………………………………………………...Initial surgery (………/………/………) surgeon………………………….....…………………………………………...Operation  biopsy  partial removal  total removal  wide excision  Other…..………………………section # ………………………….. result ………………………………………………………………………………….Histology ……………………………………………………………………………………………………………………...Diagnosis ………………………………………………… Stage …………………………………………………Germ Cell Tumor: Data entry form 296

Thai Pediatric Oncology Group ชมรมโรคมะเร็งเด็ก Treatment protocol for germ cell tumor [ThaiPOG-GCT-13]Protocol name ThaiPOG-GCT-13Protocol for Germ Cell TumorReference Cushing B, Giller R, Cullen JW, et al. J Clin Oncol 2004;22(13):2691-700. Mann JR, Raafat F, Robinson K, et al. J Clin Oncol 2000; 18(22):3809-18.Open Date January 2014Patient’s name..................................................................... Sex........................... HN...........................................Age (yy/mm)................................ BW............................. kg. Ht.............................cm BSA..............................m2Inclusion criteria: Extracranial Germ cell tumor PEB regimen Drug Dosage Given dose/day Cisplatin 20 mg/m2IV Day 1-5 Etoposide 100 mg/m2 IV on Day 1-5 Bleomycin 15 unit/m2 IV on Days 1 JEB regimen Drug Dosage Given dose/day 600 mg/m2IV Day 2 Carboplatin 120 mg/m2 IV on Day 1-3 Etoposide 15 unit/m2 IV on Days 1 Bleomycin Repeat chemotherapy q 3 weeks x 4 courses ANC > 1,000 and platelet count > 100,000 before start chemotherapy Blood for LFT, AFP and/or HCG before start chemotherapy BW < 12 kg, calculate chemotherapeutic agent dose per kgStandard-PEB Date AFP -hCG Hearing RemarksIIIIIIIVsurgeryVVIพจิ ารณาให้ G-CSF 5 µg / kg SC OD Start Day 7 ในกรณที ีผ่ ู้ปว่ ยเคยมี febrile neutropenia มากอ่ นเทา่ นั้นGerm Cell Tumor: Treatment protocol for germ cell tumor [ThaiPOG-GCT-13] 297

Thai Pediatric Oncology Group ชมรมโรคมะเร็งเดก็Patient’s name..................................................................... Sex........................... HN...........................................Age (yy/mm)................................ BW............................. kg. Ht.............................cm BSA..............................m2 การให้ cisplatinum (CDDP)1. ก่อนให้ CDDP ต้องตรวจ electrolytes, Ca, Mg, BUN creatinine, U/A คานวณ GFR จากสูตร GFR ml/ min/ 1.73 sqm  0.55 x Ht cm Scr mg/ dL ใหย้ าเม่ือ GFR > 25 ml /min /1.73 sqm2. 4 ชม. ก่อนเริม่ ยา Hydration ดว้ ย 5%D NSS/ ……………… (Vol ………………….ml/bottle)+ KCl (10 mEq/L) ……………… ml + MgSO4 (8 mEq/L) ………………….mlIV drip at rate ……………… /hr (125 ml/m2/hr) x 4 hr Hour 0 วัดความดนั ชง่ั นา้ หนัก record I/O ใหย้ าแกอ้ าเจยี น ตามความเหมาะสม ซ้าได้ทกุ 4-6 ชม.เรม่ิ ใหย้ า ดว้ ย 5%D NSS/ ……………… Vol ………………….ml ……………… mg (20 mg/m2)+ CDDP+ mannitol ……………… gm (500 mg/kg)+ KCl ……………… ml (1 mEq/kg)IV at rate ………………ml /hr (150 ml/m2/h) x 6 hr(ระหวา่ งการให้ CDDP ตอ้ งมปี สั สาวะออก 3-4 ml/kg/hrถ้านอ้ ยกว่าน้ใี ห้ mannitol ได้อีก 200 mg/kg in 25 ml NSS IV over 15 minถ้าไม่ดขี ้นึ ใน 1 ชม. ให้ฉดี lasix 0.5 mg/kg ได้) Hour 24 หยุด CDDP และเปล่ยี น IV fluid เปน็ด้วย 5%D NSS/ ……………… (Vol ………………….ml/bottle)+ KCl (10 mEq/L) ……………… ml + MgSO4 (8 mEq/L) ………………….mlIV drip at rate ……………… /hr (125 ml/m2/h) x 18 hrหลังจากนนั้ ลด rate IV เป็น ……………… ml /hr (65 ml/m2/h)3. Oral Mg supplement: Minimal daily requirement = 0.3 mEq/kg/d (12 mg Mg = 1 mEq)Mag oral tab = 7 mEq Mg/tabMilk of Magnesia = 13 mEq Mg/ 5 mlMg sulfate solution 50% = 20 mEq/ 5 ml แนวทางตดิ ตามการรักษาหลงั หยุดยาเคมีบาบดั หรอื หลังผ่าตดั แล้วไมไ่ ด้ใหย้ าเคมบี าบดั Tumor marker: AFP and / or HCG ทุก 1-2 เดือน ใน 6 เดอื นแรก หลงั จากนัน้ ทกุ 3 เดอื น CT or MRI ท่ี tumor primary site ทุก 4 เดือนในปีแรก หลังจากน้ัน ทุก 6 เดือน พิจารณาตรวจการไดย้ นิ ในกรณที ่ีได้ cisplatin ก่อนใหย้ า และหลังให้ยาครบ 4-6 ครงั้Germ Cell Tumor: การให้ cisplatinum (CDDP) 298

Thai Pediatric Oncology Group ชมรมโรคมะเร็งเดก็Histiocytosis Langerhans cell histiocytosis Disease stratificationLow Risk group-Single or Multiple organ involvement, but WITHOUT involvement of “Risk” organsHigh Risk group-Multisystem patients with involvement of one or more “Risk” organs i.e. hematopoietic system, liver,spleen Definition of organ involvementRISK Organs DefinitionsHematopoietic involvement (With orwithout bone marrow involvement) Anemia (exclusion of iron deficiency) -Hb < 10 g/dlSpleen involvement -infants, Hb < 9 g/dlLiver involvement Leukocytopenia -WBC < 4,000 /mm3 Thrombocytopenia -platelets < 100,000 /mm3 enlargement > 2 cm below costal margin (proven by sonography) -enlargement > 3 cm below costal margin (proven by sonography) and/or -liver dysfunction (hyperbilirubinemia, hypoproteinemia, hypalbuminemia, elevated  GT, alkaline phosphatase, elevated transaminases, ascites, edema) and/or -histopathological diagnosisHistiocytosis: Langerhans cell histiocytosis 299

Thai Pediatric Oncology Group ชมรมโรคมะเร็งเดก็ LCH treatment guideline Induction-I GR PR/NR PD GR/PR Induction-II Off protocol NR/PD Paliative vs HSCT GR/PR NR/PDContinuation SalvageDefinition of clinical responseGood Response (GR) Resolution of all signs or symptomsPartial Response (PR) Regression of sign or symptoms, no new lesionsNot Resposponse (NR) Persistence of signs or symptoms, no new lesionsProgressive Disease (PD) Progression of signs or Symptoms and/or appearance of new lesionsNote: Lytic bone lesions can take months to year for resolution. Stable or any resolution of lytic bone lesion is considered Good Response (GR) Start PCP prophylaxis as soon as possible and continue until 6 months after end of therapyHistiocytosis: LCH treatment guideline 300

Thai Pediatric Oncology Group ชมรมโรคมะเร็งเดก็ Data entry formPatient’s name Age Sex HN m2Address Contact Person Tel:BW  yes kg Ht cm BSA  yes  yesHistory  >2yr  <2yr. PE  no  yes  no  yes  no  yesAge  no  yes Exopthalmos  no  yesFever  no  yes Dental anomalies  no  yesRecurrent infection  no  yes Otitis media  no  yesWeight loss  no  yes Lymphadenopathy  no  yesLarge abdomen  no  yes Hepatomegaly  no  yesMass  no  yes Splenomegaly  no  yesBone pain  no  yes Skin lesion  noRash  no  yes Abnormal mass  noDyspnea/Tachypnea  no  yes Growth retardation  noPolyurea Delayed sexual maturationOther OtherInvestigation CBC: Hb _____ g/dl, Hct ______ %, WBC __________ /mm3, Platelet ____________ / mm3 LFT _________________________________________________________________________________  Coagulogram: PT _____________ sec., aPTT _____________ sec., Fibrinogen ____________ Bone marrow  abnormal  normal Endocrine work up Diabetes insipidus  yes  no Other endocrine disorders  yes  no specified: __________________________ CXR  positive  negative Bone survey  positive  negativeOptional:  Bone scan  positive  negative  Lung function test  abnormal  normal  CT/MRI brain  abnormal  normal Surgery & PathologySurgery Date ___/___/___ surgeon________________________Operation  biopsy  curette  partial removal  total removal  wide excision other_____________________________________________________Pathology section # ______________ result ________________________________ Histology ___________________________________________________Histiocytosis: Data entry form 301

Patient’s name Thai Pediatric Oncology Group Sex HN m2Address Tel:BW ชมรมโรคมะเร็งเดก็ Age Contact Person kg Ht cm BSAFinal diagnosis ____________________________________________________Risk Group _______________________________________________________Indication for systemic chemotherapy for LCH 1. Low risk LCH (Single-system or multisystem) Skull lesions in mastoid, temporal, or orbital bones (CNS-risk lesion) Vertebral or femoral bone lesions (lesion at risk for collapse) Multiple bone lesions Combinations of skin or lymph node or pituitary gland with or without bone lesions 2. High risk multisystem LCH Spleen involvement may or may not include skin, bone, lymph node, lung or pituitary gland Liver involvement may or may not include skin, bone, lymph node, lung or pituitary gland Hematologic involvement may or may not include skin, bone, lymph node, lung or pituitary glandHistiocytosis: Data entry form 302

Thai Pediatric Oncology Group ชมรมโรคมะเร็งเด็กReference Treatment protocol for Langerhan cell histiocytosis m2Open date Treatment protocol for low risk LCH; from LCH III study protocol January 2014Patient’s nameDiagnosis Age Sex HNBW kg Ht cm BSAPhase I INDUCTION 1 Date Start ___________________ 1 Week 23456 Day  8 15 22 29 36 Date given Prednisolone __________ ← taper off → Vinblastine ____________ mg Drug Dosage SchedulePrednisolone 40 mg/m2/day oral bid-qid then taper off in 2 wk Day 1-28Vinblastine 6 mg/m2 IV push (max 10 mg) Day 1, 8, 15, 22, 29, 36Modify dose in infant with BW < 10 kg Age < 6 months  give 50% dosage calculated from BSA Age 6-12 months  give 75% dosage calculated from BSAEvaluation after week 6 of treatmentimaging of primary lesion ____________________________________________imaging of metastasis sites ___________________________________________Bone survey ________________________________________________________BMA/biopsy or clotted marrow __________________________________________ GR  Proceed to continuation therapy PR/NR and all High risk patient  Go on phase II (induction II) PD  Consider salvage regimenHistiocytosis: Treatment protocol for Langerhan cell histiocytosis 303

Thai Pediatric Oncology Group ชมรมโรคมะเร็งเดก็Patient’s name Age HN m2BW kg Ht cm BSA 6 36Phase II INDUCTION II Date Start ___________________ III (For PR/NR and all high risk patients)Week 1 2 3 4 5Day 1 8 15 22 29Date givenPrednisolone __________ III III III III IIIVinblastine ____________ mg     Drug Dosage SchedulePrednisolone 40 mg/m2/day oral bid-qid Day 1-3 weeklyVinblastine 6 mg/m2 IV push (max 10 mg) Day 1, 8, 15, 22, 29, 36Evaluation after week 6 of treatmentimaging of primary lesion ____________________________________________imaging of metastasis sites ___________________________________________Bone survey ________________________________________________________BMA/biopsy or clotted marrow __________________________________________ GR and PR  Proceed to phase III (Continuation treatment) NR and PD  Consider salvage regimenHistiocytosis: Treatment protocol for Langerhan cell histiocytosis 304

Thai Pediatric Oncology Group ชมรมโรคมะเร็งเด็กPatient’s name Age HN m2BW kg Ht cm BSAPhase III Continuation treatmentDate Start Regimen ________________ / Date Start Maintenance__________________End of therapy date _______________ Drug DosePulse Treatment every 3 week______________ -Vinblastine 6 mg /m2 IV push (max 10 mg) 1______________ -Prednisolone (5 mg) 40 mg /m2 /day POMaintenance Therapy 1-5______________ -6-MP (50 mg) 50 mg /m2/dose PO hs, daily daily Total duration of treatment 12 months including induction phase Continue PCP prophylaxis throughout treatment period and 6 months off therapy Lab each visit: CBC, BUN, Cr, AST, ALT, Bili, E’lyte, ESR Lab every other visit: UA, Urine osmolCycle Date Note Cycle Date Note BSA:_______VBL: _______Pred: _______6-MP: _______ BSA:_______VBL: _______Pred: _______6-MP: _______1 11 BSA:_______VBL: _______Pred: _______6-MP: _______ BSA:_______VBL: _______Pred: _______6-MP: _______2 12 BSA:_______VBL: _______Pred: _______6-MP: _______ BSA:_______VBL: _______Pred: _______6-MP: _______3 13 BSA:_______VBL: _______Pred: _______6-MP: _______ BSA:_______VBL: _______Pred: _______6-MP: _______4 14 BSA:_______VBL: _______Pred: _______6-MP: _______ BSA:_______VBL: _______Pred: _______6-MP: _______5 15 BSA:_______VBL: _______Pred: _______6-MP: _______ BSA:_______VBL: _______Pred: _______6-MP: _______6 16 BSA:_______VBL: _______Pred: _______6-MP: _______ BSA:_______VBL: _______Pred: _______6-MP: _______7 17 BSA:_______VBL: _______Pred: _______6-MP: _______ BSA:_______VBL: _______Pred: _______6-MP: _______8 18 BSA:_______VBL: _______Pred: _______6-MP: _______ BSA:_______VBL: _______Pred: _______6-MP: _______9 19 BSA:_______VBL: _______Pred: _______6-MP: _______ BSA:_______VBL: _______Pred: _______6-MP: _______10 20Histiocytosis: Treatment protocol for Langerhan cell histiocytosis 305

Patient’s name Thai Pediatric Oncology Group HN m2BW Date Start ___________________Phase IV ชมรมโรคมะเร็งเดก็ Age kg Ht cm BSA Salvage Regimen(For patient with progressive disease)Reference: Apollonsky et al, J Pediatri Hemato Oncol, Vol 31, Jan 2009Course Date Note1 Ara-C ______ mg2 Ara-C ______ mg3 Ara-C ______ mg 4 Ara-C ______ mg*Repeat every 3-4 weeksDrug Dosage ScheduleAra-C 1,000 mg/m2/day IV over 2 hours Day 1-5G-CSF Day 6 until ANC > 1,000 x 2 daysDecadron eye drop 5 mcg/kg SQ/IV daily Day 1-6 1 drop both eyes BID Evaluation after cycle 2 and 4 of treatment imaging of primary lesion _________________________________________________________________ imaging of metastasis sites _________________________________________________________________ Bone survey _________________________________________________________________ BMA/ biopsy + clotted marrow _________________________________________________________________ GR after cycle 2  Proceed to phase III (Continuation treatment) PR/NR after cycle 2  Give 2 more cycle of High dose Ara-C GR/PR after cycle 4  Proceed to phase III (Continuation treatment) PD at any point in salvage regimen  Off protocolNote:  For patient with only progressive osteolytic lesion consider -Low dose ARA-C (100 mg/m2) x 5 days for 2-4 cycle or -Bisphosphonate 200mg/m2/day PO daily for 14 days Q 3 monthsHistiocytosis: Treatment protocol for Langerhan cell histiocytosis 306

Thai Pediatric Oncology Group ชมรมโรคมะเร็งเด็ก Hemophagocytic lymphohistiocytosisPatient’s name Data entry form Sex HNAddress AgeBW kg Ht Contact Person m2 cm BSAHistory  Abdominal mass  Other specified:………………………. Fever  CNS symptoms  Anemia BleedingPhysical Examination  Anemia  Other specified:………………………. Fever  CNS abnormalities  Splenomegaly Hepatomegaly  Bleeding evidences LymphadenopathyInvestigations CBC (___/___/___) Hct _____% Hb _____g/dL, MCV _____fl, MCHC _____g/dl, Plt ____________/mm3,WBC ________/mm3 (N ____, L ____, Mo ____, Eo ____, Ba ____, blast ____), Retic count _____% Viral study HIV  neg  pos, Hepatitis profile ___________________________________ CMV  neg  pos, EBV  neg  pos Other culture:  neg  pos; specified: _________________________________________ Cancer:  No  Yes; specified: _________________________________________ Collagen profile:  neg  pos; specified: _________________________________________ Blood Chemistry (___/___/___) Fibrinogen ______________, Coagulogram : PT ________________ , APTT __________________ LFT ______________________________________________________ , Triglyceride ___________ Ferritin _________________, LDH ___________________, Uric acid ________________________ Immunoglobulin level (___/___/___) : IgG ___________, IgA ___________ , IgM ____________ Molecular study: HLH gene mutation: __________________NK cell acitivity:________________________ BM aspiration (___/___/___) ______________________________________________________________ CXR (___/___/___) _____________________________________________________________________ CSF profile (___/___/___) ________________________________________________________________ MRI/CT primary lesion _____________________  Ultra sound/CT abdomen _____________________Histiocytosis: Hemophagocytic lymphohistiocytosis 307

Patient’s name Thai Pediatric Oncology Group Sex HN ชมรมโรคมะเร็งเด็ก AgeBW kg Ht cm BSA m2Patients eligibility Familial Hemophagocytic Lymphohistiocytosis Infectious-associated hemophagocytosis (IAHS) Malignant-associated hemophagocytosis (MAHS) Macrophage Activation Syndrome (MAS) refractory to steroidThe diagnosis HLH can be established if one of either 1 or 2 below is fufilled (1) A molecular diagnosis consistent with HLH (2) Diagnostic criteria for HLH fulflled (five out of the eight criteria below) (A) Initial diagnostic criteria (to be evaluated in all patients with HLH)  Fever  Splenomegaly  Cytopenias (affecting  2 of 3 lineages in the peripheral blood)  Hemoglobin < 9 g/L (in infants <4 wks, Hb <10 g/L)  Platelets < 100,000  ANC < 1,000  Hypertriglyceridemia and/or hypofibrinogenemia  Fasting triglycerides  300 mg/dl)  Fibrinogen  150  Hemophagocytosis in bone marrow or spleen or lymph nodes  No evidence of malignancy (B) New diagnostic criteria  Low or absent NK-cell activity  Ferritin  500 mg/L  Soluble CD25 (i.e., soluble IL-2 receptor)  2,400 U/mlHistiocytosis: Data entry form 308

Protocol for Thai Pediatric Oncology GroupModified from ชมรมโรคมะเร็งเด็กOpen date Treatment protocol for hemophagocytic lymphohistiocytosis Hemophagocytic lymphohistiocytosis Hemophagocytic lymphohistiocytosis study group 2004 January 2014Patient’s name Age Sex HNBW kg Ht cm BSA m2Phase I Initial therapy (Week 1-8) Date start ______/______/______ Week 1 2 3456 7 8 Day 1 8 15 22 29 36 43 50Etoposide ________mg*         5 mg/m2 2.5 mg/m2 1.25mg/m2 taper offDexa ________ mg 10 mg/m2IVIG ____________ mg  CSA________ml** q12hr ____ ml ____ ml ____ ml ____ ml ___ ml ____ ml ____ ml ____ ml IT# T# T# T# T#Drug Dosage ScheduleEtoposide* 150 mg/m2 IV drip in 2 hr 1, 4, 8, 11, 15, 22, 29, 36, 43, 50 Twice weekly for first 2 weeks, then weeklyDexamethasone 10 mg/m2/day for 2 weeks 1-14 5 mg/m2/day for 2 weeks 15-28 2.5 mg/m2/day for 2 weeks 29-42 1.25 mg/m2/day for 2 weeks then taper off 43-56Cyclosporine** 3-5 mg/kg/day q 12hr IV or daily 6-10 mg/kg/day q 12hr orallyIVIG (for IAHS only) 0.5 g /kg/dose q 4 wk 1, 29, 57*The first two doses may be omitted if ANC < 500/ mm3 AND hypocellular marrow**Keep trough level 150-200 ng/ml#Given IT chemotherapy if progressive neurological symptom or abnormal cell persist in CSF only#age adjusted dose intrathecal chemotherapy <1 yr 1-2 yr 2-3 yr >3 yr Methotrexate 6 8 10 12 Hydrocortisone 4 6 8 10Histiocytosis: Treatment protocol for hemophagocytic lymphohistiocytosis 309

Thai Pediatric Oncology Group ชมรมโรคมะเร็งเดก็Patient’s name Age Sex HNBW kg Ht cm BSA m2Phase II Continuation therapy (Week 9-40) Date start ____/____/____Given dose Drug Dosage Day___________ mg Etoposide 150 mg/m2 IV every 2 weeks 1___________ mg Dexamethasone 10 mg/m2 day PO x 3 days every 2 weeks 8-10___________ mg Cyclosporin A 6-10 mg/kg /day PO q 12hr daily___________ mg Cotrimoxazole 5 mg of TMZ/kg/day PO bid 3 day/wk (Fri-Sat-Sun)Record date given Note Week Note Weekwk 9 (____/____/____) wk 25 (____/____/____)wk 11 (____/____/____) wk 27 (____/____/____)wk 13 (____/____/____) wk 29 (____/____/____)wk 15 (____/____/____) wk 31 (____/____/____)wk 17 (____/____/____) wk 33 (____/____/____)wk 19 (____/____/____) wk 35 (____/____/____)wk 21 (____/____/____) wk 37 (____/____/____)wk 23 (____/____/____) wk 39 (____/____/____) F/U CBC, LFT q 2wk F/U BUN/Cr, Serum ferritin monthly Keep Cyclosporine level 150-200 ng/ml End of therapy _______/________/________Histiocytosis: Treatment protocol for hemophagocytic lymphohistiocytosis 310

Thai Pediatric Oncology Groupชมรมโรคมะเร็งเดก็Histiocytosis: Treatment protocol for hemophagocytic lymphohistiocytosis 311