CUP trial.

Methods	Randomised controlled trial with three arms: chemotherapy arm, unpurged HDT + ASCT arm and purged HDT + ASCT arm. Conducted by the Univerity Hospital Maastricht, 140 patients from 36 centres in 11 countries in Europe and Australia were registered. Recruitment period from August 1993 to April 1997. 89 patients were randomly assigned. 70 patients were randomised 1:1:1; 24 patients in chemotherapy arm; 22 patients in unpurged HDT + ASCT arm and 24 patients in purged HDT + ASCT arm. The remaining 19 patients were randomly assigned with a 1:1 ratio between HDT with or without purging only, because the protocol was amended in March 1996 to enable centres that felt uncomfortable treating relapsed patients without HDT and transplantation. 51 patients not evaluated due to death (4), persistent marrow infiltration (4), refusal (6), no response or progressive disease (28), CNS involvement (2), histologic pathology (2) and unknown reasons (5). Baseline patient characteristics described. Median follow‐up time: 69 months.
Participants	Inclusion criteria: Patients with relapsed or progressive follicular NHL, aged between 15 and 65 years, with a WHO performance status of 0, 1 or 2. Exclusion criteria: Patients were excluded if they had previous radiotherapy (precluding TBI) or bone marrow harvest, CNS localisation; cumulative doxorubicin dose of more than 300 mg/m2; prior malignancies with the exception of those originating in the skin (non‐melanoma) or cervical carcinoma stage 1; cardiopulmonary, neurological, liver (liver enzymes more than 3x the upper limit of normal) or renal / creatinine > 150 µmol/L) dysfunction; evidence of histologically proven transformation; or HIV positivity. No. of relapses: in purged HDT + ASCT arm 57% (1 relapse), 38% (2 relapses), 5% (3 relapses); in unpurged HDT + ASCT arm 75% (1 relapse), 20% (2 relapses), 5% (other); in chemotherapy arm 76% (1 relapse), 19% (2 relapses), 5% (3 relapses. Mean age (range): chemotherapy arm: 47 (30 to 64) years; unpurged HDT + ASCT arm: 47 (30 to 60) years; purged HDT + ASCT arm: 48 (32 to 63). Gender: chemotherapy arm: 12 males (50%), 12 females; unpurged HDT + ASCT arm: 15 males (68%), 7 females; purged HDT arm + ASCT: 10 males (42%), 14 females. Similar baseline patients' characteristics in comparison arms. Initial investigations: physical examination, WBC and differential, biochemistry, urine analysis, ECG, chest x‐ray, computer tomography scan of the chest and abdomen, bone marrow histology and immunophenotyping, and peripheral blood cytology and immunophenotyping.
Interventions	Induction therapy: Following registration, all patients were treated with three cycles of chemotherapy. CHOP chemotherapy (3‐week cycle; cyclophosphamide 750 mg/m² IV, doxorubicin 50mg/m² IV and vincristine 1.4 mg/m² IV. on day 1; prednisone 100mg orally on days 1 to 5 was the recommended regimen, but any other suitable regimen was acceptable. Patients who achieved a CR or PR to induction therapy, had a WHO performance status of 0 to 2, had limited bone marrow infiltration (< 20%) and gave informed consent were eligible for random assignment . Intervention after randomisation: Chemotherapy arm: These patients had 3 additional cycles of chemotherapy; Unpurged and purged HDT + ASCT arm: Within 4 weeks after harvesting, the patients had to be treated with cyclophosphamide 60 mg/kg on 2 days, in combination with fractionated or unfractionated TBI. Cryopreserved stem cells were thawed and infused by the IV route within 20 to 40 minutes. Supportive treatment: With regard to post‐chemotherapy treatment with radiotherapy, areas of prior bulky disease (> 5 cm) as assessed at time of entry in the trial, and/or areas that still showed residual masses 2 months after transplantation or after the completion of the chemotherapy could be irradiated, if this was considered feasible.
Outcomes	Primary end point: PFS Secondary end point: OS
Notes	Data included for the patients randomly assigned between the three planned arms, before protocol amendment
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomised controlled phase III trial
Allocation concealment (selection bias)	Low risk	"Random assignment, using the method of minimization, was performed at the MRC CTU in London by telephone or fax"
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	Low risk	Assessors: "during the trial the investigators were blinded to the results". This is judged not to be a source of bias for OS and PFS
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT analysis
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	The protocol was amended in March 1996 to enable centres, that felt uncomfortable treating relapsed patients without HDT and transplantation.