This systematic review to identify randomized controlled trials (RCTs) and meta-analyses follows methods as specified by the Cochrane Collaboration [24] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (see Figure 1) [25]. A broad search to identify trial evidence for eHealth interventions to empower cancer patients to manage their symptoms, increase patient activation, and improve patient-professional interactions will be conducted. We posed the following specific research questions.

Are eHealth interventions (or programs) effective in reducing the physical or psychological effects of cancer and its treatment or improving other health outcomes (ie, function, health-related quality of life, health use, or costs) compared with usual care or other active treatment?

Does effectiveness (effect sizes [ESs]) of eHealth interventions (or programs) differ by patient or disease characteristics (age, race or ethnicity, education, cancer type, stage or phase in trajectory, treatment modality, or other antecedent personality variables such as optimism or trait anxiety), that is, effect modifiers?

Does effectiveness (ESs) of eHealth interventions (or programs) differ based on intervention design (delivery setting) or methods (eHealth-based self-management tools and platforms), training and qualities of the interventionist, intervention components, length of the intervention, or other potential mediators, that is, adherence to the intervention?

The search strategy was developed with assistance from a library information specialist. A computerized search of electronic databases will be conducted from January 2000 until January 2022 as follows: The Cochrane Central Registry of Controlled Trials (CENTRAL), Cochrane Library and Trials Registry and the Database of Abstracts of Reviews of Effectiveness (DARE), MEDLINE (2000 to January 2022), Embase (2000 to January 2022), CINAHL (2000 to January 2022), PSYCHINFO (2000 to January 2022), and CancerLit (2000 to January 2022). In addition, the gray literature databases, EAGLE (2000 to January 2022), openSIGLE (2000 to January 2022), and PsychEXTRA (2000 to January 2022) will be searched. The reasons for limiting the literature search from 2000 onwards are the development of internet technology and the use of internet-based support programs in the delivery of supportive care over the past 22 years [26].

The search for eligible studies will include search terms: self-manage* or “self-manage*” or self-car* or “self-care*”, behave* or cognitive* or train* or instruct* or patient education or “patient education” or “management plan*” or “management program* (AND) ehealth* or mHealth* or “mobile Health*” or Telehealth* (AND) terms for neoplasms, cancers, or cancer symptoms (fatigue, nausea or vomiting, pain, depression, anxiety, insomnia) and sensitive search terms for identifying randomized trials as subject headings specified by Cochrane [27]. The initial search strategy will be developed in MEDLINE (Multimedia Appendix 1) and will be adapted for all other databases.

Eligible studies will be identified based on the inclusion or exclusion criteria described below.

Studies will be selected using Covidence software based on a review of the title, keywords, and abstract and coded using the following criteria: (1) include: an RCT, with a focus on cancer patient activation or self-management; (2) exclude: no self-management focus. Selecting studies includes these steps: (1) using a reference management software to merge search results and remove duplicates; (2) examine all titles initially to remove articles that are clearly not eHealth, followed by an abstract review (if there is any uncertainty, the abstract is included for a full text review); and (3) retrieve the full study reports and assess compliance with eligibility criteria independently by 2 reviewers. Agreement will be examined using interrater agreement (<75 nonagreement); disagreements will be resolved by consensus or in consultation with a third reviewer. Authors| will clarify study eligibility criteria or missing data results if necessary. Interventions with more than 1 article will also be retrieved and reviewed to complement the data abstraction and quality assessment of the study (Multimedia Appendix 2).

Data will be abstracted using a data abstraction form developed for the review based on Cochrane methods. Data abstraction is independently assessed by 2 reviewers with reliability of coding assessed by computing Kappa, or percentage agreement, for categorical data and the intraclass correlation for continuous data. If any aspect of the study design and conduct is unclear, the study authors will be contacted to complete data abstraction. Two other review authors will check a random sample of the abstractions. Disagreements will be resolved by discussion, with arbitration by a third author if necessary, following an independent review of the study report in question. The data abstraction form will be pretested on a minimum of 5 studies. The abstracted data will include categories as per Cochrane: (1) source and setting; (2) methods; (3) participants; (4) experimental interventions (extent to which specific intervention components delivered as described [adherence]; number, length, and frequency of implementation of intervention components; and characteristics of the interventionists); (5) control treatment; (6) analysis; (7) adverse events; (8) outcome measures; (9) results; (10) conclusions of study authors; and (11) miscellaneous, that is, funding sources.

A quality assessment will be performed by 2 review authors and checked by another author. A methodological quality assessment of studies will be conducted based on an adapted version of the Cochrane Collaboration Back Review Group criteria [28], which were previously used in other systematic reviews of internet-based interventions [29,30]. The Cochrane criteria was modified to better suit the type of examined studies: specification of eligibility criteria, randomized groups, treatment allocation concealed, groups similar at baseline, explicit description of interventions, description of compliance, description of dropout and comparison with completers, long-term follow-up (>3 months after postintervention assessment), timing of outcome assessment comparable, sample size described with power calculation, intention-to-treat analyses, and point estimates and measures of variability. The quality score could range from 0 to 12 points. For each study, all criteria will be scored as yes, no, or unclear, resulting in a maximum quality score of 12. In line with other researchers [29-31], studies obtaining at least two-thirds of the total score (ie, ≥8 points) will be considered high quality. Studies scoring 4 to 7 points will be rated as moderate quality, and studies scoring lower than 4 points will be rated as low quality.

Authors will be contacted with 2 reminders to complete missing data. Reviewers will be blinded to the authors of study reports. For each of these potential sources of bias, a judgment of yes (low risk of bias), no (high risk of bias), or unclear is assigned to each study (number of yeses is the single score or study). A summary table of the risk of bias across studies will be developed for reporting purposes.

Outcomes will be analyzed as continuous or dichotomous variables depending on data reporting using standard statistical techniques. For continuous data (ie, symptom severity), a standardized mean difference with 95% CIs will be calculated as appropriate to facilitate comparison between intervention and controls with correction for differences in the direction of the scale. If reported as medians with ranges, means and SDs will be calculated [32]. For dichotomous outcomes, a relative risk ratio with 95% CIs is calculated.