Table 2.
Summary of the risk of bias for the assessment of severe adverse effects.
| Study | Method of assessment | Description | Exclusion of patients from the AE analysis | Presence of numerical data by intervention group |
|---|---|---|---|---|
| Amendola27 | 1 (Not specified) | No description of safety assessment provided; the only blood sampling was performed at baseline and at the end of the study. | Not applicable | No |
| Arnó28 | 3 (Prospective monitoring) | Patients were monitored throughout the study for safety; safety parameters included hematologic, renal, and hepatic routine tests. Based on a standardized and predefined grading scale | No | Yes |
| Artillo29 | 3 (Prospective monitoring) | The patients were studied every 4 weeks during treatment and 12 weeks post-treatment with a clinical examination and blood samples at each visit. | No | No |
| Bruch30 | 2 (Retrospective or possibly prospective monitoring) | Blood samples were taken at monthly intervals during treatment. Side effects are generically described. | No | No |
| Carr31 | 3 (Prospective monitoring) | Adverse events and laboratory tests were assessed during each treatment cycle, and two interim analyses to evaluate safety were specified in the study protocol, based on a standardized and predefined grading scale. | No | Yes |
| De Paoli32 | 2 (Retrospective or possibly prospective) | No predefined study visits is described, but grade toxicity of at least grade 2 guided dose reductions, suggesting some degree of prospective monitoring. Based on a standardized and predefined grading scale | No | Yes |
| Hartemann33 | 3 (Prospective monitoring) | Safety was assessed at predefined visits by a history taking and physical examination procedure described in detail, based on a standardized and predefined grading scale. | No | Yes |
| Johnson34 | 3 (Prospective monitoring) | Adverse events assessed at all study visits (thrice weekly) and injection sites twice daily; laboratory tests were assessed weekly during the study treatment. | No | Yes |
| Lalezari35 | 3 (Prospective monitoring) | Adverse events assessed at all study visits (10 out of 10), laboratory tests on predefined subset of study visits (5 out of 10); based on a standardized and predefined grading scale. | No | Yes |
| Li36 | 2 (Retrospective or possibly prospective monitoring) | Treatment with rIL-2 was performed post-modified radical mastectomy for primary breast cancer for 5 days and peripheral blood samples were collected on days 0, +1, +3, and +7. It is not explicitly stated whether patients were hospitalized during the whole treatment duration. | No | Yes |
| Losso37 | 2 (Retrospective or possibly prospective monitoring) | Control patient visits were performed and toxicity guided dose adjustments. However, no predefined study visits dates or intervals are specified; recipients of rIL-2 therapy underwent more frequent safety monitoring than control patients; and that grade IV toxicities and serious adverse events were recorded, while an overview of all toxicities was made retrospectively upon study completion. This suggests that monitoring was only in part prospective. Reporting was based on a standardized and predefined grading scale. | No | Yes |
| Mantovani38 | 2 (Retrospective or possibly prospective monitoring) | Patients received a full clinical and laboratory multi-specialist evaluation only at the beginning and the end of the study period, but monitoring of toxicity during chemotherapy cycles is mentioned. Based on a standardized and predefined grading scale. | No | Yes |
| Marchetti39 | 3 (Prospective monitoring) | Clinical evaluation including rIL-2 side effects and laboratory tests were assessed at predefined study visits; based on a standardized and predefined grading scale. | No | Yes |
| Nichols40 | 2 (Retrospective or possibly prospective monitoring) | Toxicity monitoring is not mentioned in the Methods. However, the treatment was perioperative, suggesting in-hospital monitoring, and a dedicated paragraph on toxicity was present in the Results. | No | Yes |
| Nicholson41 | 2 (Retrospective or possibly prospective monitoring) | Blood samples were drawn before and at the end of treatment; a number of patients received additional five treatment doses and were re-evaluated clinically and by imaging after the fifth dose. However, ‘flu-like’ symptoms on treatment days are mentioned, suggesting at least partial continuous monitoring. | No | No |
| Perillo42 | 2 (Retrospective or possibly prospective monitoring). | No description of safety assessment is provided, but patients were hospitalized during the whole study (both treatments lasted from day +1 to +12, while the range of hospital stay in days was 16–21 in the control arm, 15–23 in the rIL-2 arm). | No | Yes |
| Procopio43 | 2 (Retrospective or possibly prospective monitoring) | Based on a standardized and predefined grading scale. | No | Yes |
| Ridolfi44 | 3 (Prospective monitoring) | Clinical toxicity assessment was performed at baseline, before each chemotherapy course and every 3 months during follow-up based on a standardized and predefined grading scale. | No | Yes |
| Ruxrungtham45 | 2 (Retrospective or possibly prospective monitoring) | No predefined study visits are mentioned; however, it is specified that grade IV toxicities and serious adverse events were recorded. Based on a standardized and predefined grading scale. | No | No |
| Shen46 | 3 (Prospective monitoring) | Adverse events counted during treatment; and laboratory tests assessed monthly during treatment. | No | Yes |
| Smith47 | 2 (Retrospective or possibly prospective monitoring) | While no explicit mention is made of safety or adverse effects monitoring, in at least part of the study period visits were timed independently of treatment administration, suggesting that these visits were meant for safety evaluation rather than just treatment administration. Based on a standardized and predefined grading scale. | No | Yes |
| Vogler48 | 3 (Prospective monitoring) | Patients were trained to inject themselves, but they could report any toxicity they found intolerable to allow for dose reduction. The protocol specified an interim analysis of toxicity. Based on a standardized and predefined grading scale. | No | Yes |
| Woodson49 | 3 (Prospective monitoring) | Both adverse events and laboratory tests assessed weekly, the former also based on a daily symptom diary kept by patients. Based on a standardized grading scale. | No | Yes |
| Zanussi50 | 2 (Retrospective or possibly prospective monitoring) | No pre-defined study visits are mentioned other than tumor response assessment with maximal frequency of 8 weeks. However, dose adaptation and a protocol amendment based on toxicity are described in detail. Based on a standardized grading scale. | No | No |
Assessment of adverse events is classified in three categories: (1) Not specified: no mention of predefined study visits or intervals other than total duration of follow-up; no mention of a procedure for monitoring safety or adverse effects is made other than the possible use of a standardized grading; (2) Retrospective or possibly prospective monitoring: predefined study visits or their intervals are specified for laboratory and clinical assessment, although no explicit mention is made of regular monitoring of adverse effects or safety; patient checklist or diaries may be mentioned as a specific tool. (3) Prospective monitoring: it is explicitly stated that adverse events or safety were assessed during predefined study visits or interim analyses of which the timing is stated; physical examination may be mentioned as a specific tool. Adapted from Loke et al.61. AE: adverse event; rIL-2: recombinant interleukin 2.