JOURNAL CLUB

 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

 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.

 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. ♣ V incristine and cisplatin (ie, 80 mg/m2) are the least myelotoxic. 10-day conventional 21-day interval ♣ A n 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.

 rapid COJEC  rapid treatment (cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C], known as COJEC )  standard OPEC OJEC  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 ).

 Oct 30, 1990 ↔ March 18,  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.

STRT  Eligible patients were randomly assigned to receive standard(ST) or rapid treatment(RT).  C/T was planned if neutrophils were >1.0×10 ⁹ /L and platelets >100×10 ⁹ /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.

S  Day 154 for ST >>> if there was CR, VGPR, PR or mixed response R  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.

 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.

 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

 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.

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

 Primary endpoints were 3-year, 5-year, and10-year event-free survival (EFS).  EFS  EFS was calculated from the date of randomisation to date of relapse or progression or death from any cause. OS  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.

♣ 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

 Two patients, both male, developed second malignancies: rhabdomyosarcoma ► One patient received ST and developed rhabdomyosarcoma 27 months after diagnosis and subsequently died at 34 months. osteosarcoma ► 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.

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

 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).

the standard regimen was given every 21 days if patients had haematological recovery rapid regimen was given every 10 days, irrespective of blood counts  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. 1.8 times higher  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

 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. rapid treatment  Patients assigned rapid treatment had a median neutrophil count of below 1.0×10 ⁹ /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

 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  GI toxic effects were not significantly different between the two treatment regimens. renal toxicity and ototoxicity  Two potential concerns of the rapid regimen were renal toxicity and ototoxicity that were induced by platinum compounds.  rapid scheduling did not increase toxicity no treatment-related myelodysplasia or leukaemia.  In this trial, we noted second malignancies, but no treatment-related myelodysplasia or leukaemia.

a rapid induction regimen increases dose intensity in the treatment of patients with high risk neuroblastoma  In conclusion, a rapid induction regimen increases dose intensity in the treatment of patients with high risk neuroblastoma. EFS and OS seem to be better only EFS at 5 years reached significance.  Although EFS and OS seem to be better with the rapid than with the standard regimen, only EFS at 5 years reached significance. enables myeloablation to be given much earlier  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.