Piccioli 2004b

Methods	Study design: randomised multicentre clinical trial. Source of funding: Associazone Italiana per le Ricerca sul Cancro.
Participants	Country: Italy. Setting: hospital. Number of centres: not stated. Number of participants: 201. Age (mean (SD)): screening group: 66.2 (13.1) years; no screening group: 66.6 (13.1) years. Sex: screening group: 54 M/45 F; no screening group: 46 M/56 F. Inclusion criteria: apparently cancer‐free people with a documented unprovoked first episode of symptomatic deep vein thrombosis of the lower extremity or pulmonary embolism. Exclusion criteria: recognised risk factor for VTE (malignant disease, trauma of the leg, surgical procedures or immobilisation within 6 months, confirmed spontaneous VTE in a first‐degree relative, deficiency of antithrombin, protein C or S, presence of circulating lupus anticoagulant, oestrogen use, pregnancy or childbirth), previously documented VTE, malignant disease identified at routine physical examination, history taking, laboratory assessment or chest X‐ray at referral, unable to attend follow‐up due to geographic inaccessibility and aged < 25 years.
Interventions	Screening procedure: combination of ultrasound and CT scan of abdomen and pelvis, gastroscopy or double‐contrast barium swallow, flexible sigmoidoscopy or rectoscopy followed by barium enema or colonoscopy, haemoccult, sputum cytology and tumour markers including carcinoembryonic antigen, α‐fetoprotein and CA125. In addition, women had gynaecological examination, Pap smear and mammography. Men had a transabdominal ultrasound of prostate and total PSA test. Control: tests at physician's discretion. Duration: 2‐year follow‐up. At these visits, special attention paid to recent medical history. To avoid diagnostic suspicion bias, medical history concerning general health, hospital admission, and occurrence of signs and symptoms of cancer obtained on a standardised form by a physician unaware of allocation of participant. If malignant disease had become apparent during follow‐up, information from the attending specialist sought after consent of participant.
Outcomes	Primary outcomes: cancer‐related mortality defined as death due to a malignant disease itself, or death due to complications of diagnostic or surgical procedures performed to diagnose or treat cancer. Secondary outcomes: cluster of cancer‐related mortality and presence of objectively documented residual malignancy or recurrent malignancy at 24 months and sensitivity of the diagnostic work‐up for occult malignancy.
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "According to the Zelen design, patients randomised to..."
Allocation concealment (selection bias)	Low risk	Quote: "Randomisation was performed centrally."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Patients randomised to extensive screening were informed about the study. As patients allocated to the control group were not informed about the study, patients and their physicians were not discouraged to search for malignant disease." Comment: blinding of participants in extensive screening group and study personnel not done but review authors judged that outcome and outcome measurement not likely to be influenced by lack of blinding.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "To avoid diagnostic suspicion bias, the medical history concerning general health, hospital admission and occurrence of signs and symptoms of cancer were obtained on a standardised form by a physician unaware of allocation of the patient." Comment: outcome assessors blinded to study allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: all participants completed the 2‐year follow‐up. No missing data.
Selective reporting (reporting bias)	Low risk	Comment: primary and secondary outcomes clearly prespecified and reported.
Other bias	High risk	Comment: study terminated early after inclusion of only 201 participants after 5 years for several reasons. First, only 5 of the more than 40 potential participating centres could contribute participants to the study. Second, some medical ethics committees rejected the protocol because of the absence of screening for occult cancer in the control group, other centres could not start because the proposed extensive screening was judged to be unethical. Finally, identification of cancer at an apparent early stage in the extensive screening group led to an increasing tendency among physicians in participating hospitals to initiate screening for cancer in control participants.