dr.zavar hematology resident mofid pediatric hospital 1392/08/12

33

Upload: clio

Post on 23-Feb-2016

62 views

Category:

Documents


0 download

DESCRIPTION

Dr.zavar Hematology resident Mofid pediatric hospital 1392/08/12. JOURNAL CLUB. TITLE. HIGH-DOSE RAPID AND STANDARD INDUCTION CHEMOTHERAPY FOR PATIENTS AGED OVER 1 YEAR WITH STAGE 4 NEUROBLASTOMA : A RANDOMISED TRIAL † Lancet Oncol 2008; 9: 247–56. INTRODUCTION. - PowerPoint PPT Presentation

TRANSCRIPT

Page 1: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12
Page 2: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

DR.ZAVARHEMATOLOGY RESIDENT

MOFID PEDIATRIC HOSPITAL1392/08/12

JOURNAL CLUB

Page 3: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

TITLE HIGH-DOSE RAPID AND STANDARD

INDUCTION CHEMOTHERAPY FOR PATIENTS AGED OVER 1 YEAR WITH STAGE 4 NEUROBLASTOMA: A RANDOMISED TRIAL

† Lancet Oncol 2008; 9: 247–56

Page 4: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

INTRODUCTION Neuroblastoma is one of the most common

childhood cancers. > 1 y/o + stage 4 disease→poor prognosis. Current standard treatment for HR

neuroblastoma: ♦ Initial induction chemotherapy, ♦ Attempted surgical resection of the primary

tumour, ♦ Myeloablation: consolidation tx ♦ local radiation to the primary tumour-site ♦ differentiation treatment with 13-cis retinoic

acid.

Page 5: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12
Page 6: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

INTRODUCTION Rapid administration of max. tolerated doses of

drugs >>> more rapid cell death, ↓drug resistance. >>> some drugs will be given when the bone

marrow has been suppressed by a previous dose of chemotherapy.

♣ Vincristine and cisplatin (ie, 80 mg/m2) are the least myelotoxic.

♣ An intensive chemotherapy protocol was designed that had a 10-day interval between treatments, rather than the conventional 21-day interval, and that used relatively non-myelotoxic drugs alternated with myelotoxic drugs.

Page 7: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

BRIEF rapid

treatment (cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C], known as COJEC)

standard treatment (vincristine [O], cisplatin [P], etoposide [E], and cyclophosphamide [C], ie, OPEC, alternated with vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C], ie, OJEC).

Page 8: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12
Page 9: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

METHODS -PATIENTS Oct 30, 1990 ↔ March 18, 1999. Patients >1 y/o and adults who fulfilled

the International Neuroblastoma Staging System (INSS) criteria for stage 4 neuroblastoma and who had not received previous C/T for their disease were eligible.

Patients with stage 4S neuroblastoma were not eligible.

Page 10: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

METHODS -TREATMENT

Eligible patients were randomly assigned to receive standard(ST) or rapid treatment(RT).

C/T was planned if neutrophils were >1.0×10⁹/L and platelets >100×10⁹/L in patients assigned to ST, or irrespective of these counts as long as any infection was controlled in patients assigned to RT.

For both groups of patients, if GFR<80 mL/min / 1.73 m2 BSA, the subsequent course of cisplatin should be omitted.

Page 11: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

RESPONSE TO C/T WAS ASSESSED ACCORDING TO THE CONVENTIONAL INTERNATIONAL NEUROBLASTOMA RESPONSE CRITERIA

Page 12: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

METHODS -TREATMENT Day 154 for ST >>> if there was CR,

VGPR, PR or mixed

response Day 100 for RT >>> (MR) with a CR of

any BM involvement >>> total surgical resection of the

primary tumour Gross total resection of the primary

tumour was assessed by CT or ultrasonography.

Page 13: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

METHODS -TREATMENT All patients who had undergone resection were scheduled to receive myeloablation as consolidation treatment. consisted of single-agent melphalan (200 mg/m2) with haemopoieticstem-cell rescue.

After patients recovered from myeloablation, they were randomised to receive 13-cis retinoic acid (0.75 mg/kg daily or 22.5 mg/m2 daily) or no 13-cis retinoic acid.

better event-free survival with 13-cis retinoic acid changed the protocol in November, 1999, so that all patients received 6 months of treatment with 13-cis retinoic acid (160 mg/m2

daily for 2 weeks in each month). Radiotherapy was not given.

Page 14: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

METHODS -STUDY ASSESSMENTS Clinical assessments: history and physical assessment, measurements

of BW, BH, BP, CBC, BUN and electrolytes, serum proteins, Mg, Ca and P, liver function tests, and urine microscopy.

GFR was measured : ◘ ST: before the courses 1, 3, and 6, and 4 wks

after completion of C/T, ◘ RT: days 1, 39, and 100 High-tone audiometry : ♥ ST: at diagnosis, before course 6 and at the end

of C/T♥ RT: at diagnosis, on days 39 and 100

Page 15: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

METHODS -TREATMENT At diagnosis and during treatment: -measurement of urinary catecholamines, -assessment of primary tumour(by CT or US), -bone marrow assay -bone metastases (by technetium-90 bone scan), -CXR, and radiological visualisation of other

imageable disease were undertaken. -MIBG: recommanded -Assessment of tumours ◙ ST: before courses 3 and 6; at 4 weeks after

completion of C/T; and also immediately after surgery.

◙ RT: on days 40 and 100, and after surgery.

Page 16: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

METHODS -TREATMENT After completion of induction treatment,

surgery, and myeloablation (if appropriate), patients were followed up according to the practice of the treating hospital.

Page 17: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

STATISTICAL ANALYSES Primary endpoints were 3-year, 5-year,

and10-year event-free survival (EFS). EFS was calculated from the date of

randomisation to date of relapse or progression or death from any cause.

Overall survival (OS)was calculated from the date of randomisation to date of death from any cause or to date of the last follow-up for those who were alive.

Page 18: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12
Page 19: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12
Page 20: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

♣ Reasons for not attempting surgery after induction treatment were:

no detectable primary tumour surgical resection at diagnosis early death disease progression poor or no response complete response inoperable primary tumour

Page 21: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12
Page 22: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

Two patients, both male, developed second malignancies:

► One patient received ST and developed rhabdomyosarcoma 27 months after diagnosis and subsequently died at 34 months.

► The other patient received RT and developed osteosarcoma 125 months after diagnosis; he is currently alive a 10.9 years from diagnosis.

♫ High-tone hearing loss was his major long-term side-effect, which did not progress.

Page 23: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12
Page 24: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12
Page 25: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12
Page 26: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

DISCUSSION Hypothesis >>> increasing dose-

intensity of induction chemotherapy by rapid drug scheduling in patients aged over 1 year with stage 4 neuroblastoma improved EFS.

Page 27: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

DISCUSSION. Current treatment for HR Only myeloablation and the addition of

differentiation treatment with 13-cis retinoic acid for 6 months have been shown to be effective.

Although many different induction regimens for HR neuroblastoma have been described, no regimen has been shown to be better than the rest.

Comparison of EFS and OS is difficult between different induction regimens.

EFS might be improved if induction treatment is rapidly completed and followed by early myeloablation (prevent drug resistance).

Page 28: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

DISCUSSION In our randomised trial, the standard regimen was

given every 21 days if patients had haematological recovery and the rapid regimen was given every 10 days, irrespective of blood counts.

dose intensity of the rapid regimen was 1.8 times higher than the standard regimen.

The total amount of C/T given compared with that prescribed in the protocol was less in the rapid regimen (67% vs79%), but was more often given on time.

10-year OS of the rapid regimen was 28.3%. The patients in our trial were assigned only single-

agent melphalan for myeloablation, local treatment was not intensive and most did not receive 13-cis retinoic acid at a therapeutic dose ; 5-year EFS was lower

Page 29: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

DISCUSSION A higher proportion of patients achieved overall CR

or VGPR (74%) compared with the SG (53%). EFS and OS were consistent with these findings

support to the higher efficacy of the rapid regimen Deaths due to toxicity were not different from

previously published regimens. Patients assigned rapid treatment had a median

neutrophil count of below 1.0×10⁹/L for the duration of treatment.

had more episodes of febrile neutropenia and septicaemia, with more patients receiving antibiotics and antifungal treatment.

only two (2%) fungal infections were recorded in the RG

Page 30: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

DISCUSSION The addition G-CSF »»» ↓ episodes of and

numbers of patients with febrile neutropenia, and resulted in fewer days in hospital, fewer days with fever, and shorter antibiotic use.

GI toxic effects were not significantly different between the two treatment regimens.

Two potential concerns of the rapid regimen were renal toxicity and ototoxicity that were induced by platinum compounds.

rapid scheduling did not increase toxicity In this trial, we noted second malignancies, but

no treatment-related myelodysplasia or leukaemia.

Page 31: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

DISCUSSION In conclusion, a rapid induction regimen

increases dose intensity in the treatment of patients with high risk neuroblastoma.

Although EFS and OS seem to be better with the rapid than with the standard regimen, only EFS at 5 years reached significance.

Additionally, the rapid regimen produces a rapid response in patients with high-risk neuroblastoma and enables myeloablation to be given much earlier, which could improve long term survival.

Page 32: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12
Page 33: Dr.zavar Hematology resident  Mofid  pediatric hospital 1392/08/12

END