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

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.

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

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  1. Dr.zavarHematology resident Mofid pediatric hospital1392/08/12 JOURNAL CLUB

  2. 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

  3. 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.

  4. 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. ♣ Vincristineand 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.

  5. 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).

  6. 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.

  7. 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.

  8. Response to C/T was assessed according to the conventional International Neuroblastoma Response Criteria

  9. 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.

  10. 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.

  11. 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

  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.

  13. METHODS -TREATMENT • After completion of induction treatment, surgery, and myeloablation (if appropriate), patients were followed up according to the practice of the treating hospital.

  14. STATISTICAL ANALYSES • Primary endpoints were 3-year, 5-year, and10-year event-free survival (EFS). • EFSwas 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.

  15. ♣ 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

  16. Two patients, both male, developed second malignancies: ► One patient received ST and developed rhabdomyosarcoma27 months after diagnosis and subsequently died at 34 months. ► The other patient received RT and developed osteosarcoma125 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.

  17. DISCUSSION • Hypothesis >>>increasing dose-intensity of induction chemotherapy by rapid drug scheduling in patients aged over 1 year with stage 4 neuroblastoma improved EFS.

  18. 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).

  19. 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

  20. 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

  21. 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.

  22. DISCUSSION • In conclusion, arapid 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.

  23. END

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