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. 2012 Jan 18;2012(1):CD007678. doi: 10.1002/14651858.CD007678.pub2

GELA/GELF‐94.

Methods

  • Randomised controlled trial with two arms: chemotherapy arm and HDT + ASCT arm.

  • Conducted by the Groupe d`Etude des Lymphomes de L`Adulte (GELA), 402 patients from 71 centres in France and Belgium were enrolled.

  • Recruitment period from July 1994 to March 2001.

  • 402 patients were enrolled, 401 patients were included in the final analysis and randomised 1:1, 209 in the CHVP‐I arm and 192 in the CHOP‐HDT arm; one patient was found to have a benign disease on revision and was rapidly withdrawn from the study.Staging: The extent of the disease was determined by a standardised evaluation including computed tomography of the chest, abdomen, and pelvis; bone marrow biopsy; bone marrow aspiration with complete blood counts; LDH level; and 2‐microglobulin assay. PS was graded with the ECOG scale. A panel of 5 haemato‐pathologists conducted a central pathology review.

  • Baseline patient characteristics described.

  • Median follow‐up time: 51 months.

  • ITT analysis.
Participants

  • Inclusion criteria: Patients had to be younger than 61years with untreated FL at bulky stage II disease or stage III or IV and require therapy because of high tumour burden. High tumour burden was defined by at least one of the following parameters using GELF criteria: systemic symptoms (> 10% weight loss, temperature > 38°C for more than 5 days, abundant night sweats); PS greater than 1 according to the ECOG scale; elevated LDH level; ß2‐microglobulin level greater than 25.5 nM/L (3 µg/mL); a single lymph node larger than 7 cm; marked splenomegaly; organ failure; pleural effusion or ascites; orbital or epidural involvement; blood infiltration or cytopenia.

  • Exclusion criteria: Previous treatment for lymphoma; diagnosis more than 3 months before; blood creatinine level above 150 µM; history of another cancer except in situ breast cancer or uterine cancer; contraindication to doxorubicin, interferon or intensive therapy; positive serologic test for the HIV; or histologic transformation into a more aggressive lymphoma

  • Mean age: chemotherapy arm: 49 years; HDT + ASCT arm: 49 years.

  • Gender: chemotherapy arm: 114 males (55%), 95 females; HDT + ASCT: 107 males (56%), 85 females.

  • Disease Stage, No. (%): CT‐arm: stage II 16 (8), stage III 26 (13), stage IV 160 (79); HDT + ASCT arm: stage II 11 (6), stage III 23 (12), stage IV 153 (82); Data were missing for 12 patients

  • FLIPI score, No.(%): chemotherapy arm: low risk 63 (32), intermediate risk 67 (34), high risk 69 (34); HDT + ASCT arm: low risk 55 (30), intermediate risk 79 (43), high risk 51 (27); data were missing for 17 patients.

  • Similar baseline patients' characteristics in comparison arms.
Interventions

  • Conventional chemotherapy arm:

    • Patients received 6‐monthly courses of CHVP, with cyclophosphamide 600 mg/m2, doxorubicin 25 mg/m2, and teniposide 60 mg/m2 on day 1 and prednisolone 40 mg/m2 on days 1 to 5. Interferon alpha was given s.c. at a dosage of 5 Mio units (MU) 3 times a week. Patients then achieving a CR or PR received 6 courses of CHVP plus interferon every 2 months for 1 year. In the event of haematologic toxicity, the next chemotherapy cycle was postponed for 1 week and the dose of interferon was decreased to 3 MU. In the event of chronic grade 3 or 4 interferon‐related toxicity, the dose of interferon was reduced to 3 MU. If grade 4 toxicity occurred despite this decreased dosage, interferon was stopped and chemotherapy was continued as scheduled.

  • HDT + ASCT arm:

    • 4 cycles of CHOP every 3 weeks, with cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (max. 2mg) on day 1 and prednisolone 40mg/m2 on days 1 to 5. Two weeks after the 4th course of CHOP, the response was assessed and patients with stable or progressive disease were considered to be non‐responders and were treated according to the individual centre's policy. Responding patients (CR or PR) received a single course of cyclophosphamide 4500 mg/m2, etoposide 450 mg/m2 in 3 infusions, and G‐CSF 300 µg from days 4 to 12 followed by PBSC harvest. PBSCs were harvested until 4x108 mononuclear cells/kg were obtained. HDT was instated 4 weeks later and compromised cyclophosphamide 60 mg/kg/d, mesna 60mg/kg/d, and etoposide 150mg/m2 from day ‐6 to ‐5. Split TBI was then performed delivering 10 Gy in 5 fractions from day ‐3 to ‐1 followed by PBSC reinfusion on day 0. A change in the dose or a delay between 2 courses of CHOP was not recommended except in the case of grade 3 or 4 haematologic toxicity.

  • Important treatment information: As the marketing of teniposide was stopped during this study, it was replaced by etoposide 100mg/m2 on day 1.
Outcomes

  • Primary objective: EFS

  • Secondary objectives: OS, RR, secondary malignancies, PFS
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk "randomised study"
Allocation concealment (selection bias) Low risk "After stratification according to Center, eligible patients were assigned by the study coordinating Center"
Blinding (performance bias and detection bias) 
 patients High risk Usually trials evaluating stem cell transplantation are not blinded
Blinding (performance bias and detection bias) 
 physicians High risk Usually trials evaluating stem cell transplantation are not blinded
Blinding (performance bias and detection bias) 
 assessors Unclear risk No information about blinding of the assessors.
Incomplete outcome data (attrition bias) 
 All outcomes Low risk According to the ITT principle
Selective reporting (reporting bias) Unclear risk For primary outcome, event‐free survival was chosen. It is unclear why event‐free survival was chosen and not overall survival. No protocol is available.
Other bias Low risk no indication for other sources of bias