Frequently Asked Questions
How was the PRO-CTCAE measurement system developed?
Visit the Development, Testing, and Implementation page for more information.
Do I need a separate permission to use PRO-CTCAE?
What are the costs and timelines in obtaining permission to use PRO-CTCAE?
There are no costs to use PRO-CTCAE. Interested users register their study, select the PRO-CTCAE items they wish to use in that study, and are immediately supplied with the items in English and/or Spanish. If you have interests in modifying PRO-CTCAE, testing language translations, or developing new PRO-CTCAE items please be in touch with us to discuss your interest and your planned approach.
I am only interested in measuring the severity of symptoms. Do I have to also use the ‘frequency’ or ‘interference’ PRO-CTCAE items?
Yes. Since PRO-CTCAE was developed to provide information that is complementary to CTCAE reporting, all of the relevant attributes, including frequency and/or interference must be included. Safety assessment in cancer clinical trials has been standardized through the use of the CTCAE. PRO-CTCAE was developed as a companion to the CTCAE to improve the validity, reliability, and precision with which symptomatic adverse effects of treatment are evaluated in patients on cancer clinical trials.
Each of the 78 symptom terms included in the PRO-CTCAE item library is assessed relative to one or more distinct attributes, including presence/absence, frequency, severity, and/or interference with usual or daily activities. Responses are provided on a 5-point Likert scale. The generic PRO-CTCAE item structures for the frequency, severity and interference attributes are listed below:
- Frequency item: How OFTEN did you have __________?
(Never / Rarely / Occasionally / Frequently / Almost constantly)
- Severity item: What was the SEVERITY of your __________ at its WORST?
(None / Mild / Moderate / Severe / Very severe)
- Interference item: How much did __________ INTERFERE with your usual or daily activities?
(Not at all / A little bit / Somewhat / Quite a bit / Very much)
The items in the PRO-CTCAE item library were developed to measure the relevant attributes of a symptom, for the purposes of symptomatic toxicity reporting. Increasing CTCAE grades typically reflect greater frequency and/or interference with usual daily activities, as well as the need for clinical intervention.
For more information about what attributes are included for a given symptom term, please see the PRO-CTCAE Item library (PDF, 138 KB) .
When PRO-CTCAE is going to be included in a trial how should I decide which symptomatic adverse events to measure and at what time points?
Selecting which symptomatic adverse events to assess and determining the time points for measurement are critical trial design decisions. In trials developed to date, items from the PRO-CTCAE and time points of measurement have generally been specified using an approach similar to that used to define the adverse event surveillance plan for the trial more broadly. That is, the study team reviews published data, as well as data from earlier phase trials or animal models, if available, and incorporates information about the known or anticipated on- and off-target effects of agents in a similar mechanistic class, to identify those symptomatic adverse events likely to be associated with the regimens in the trial.
After establishing a pre-treatment baseline, more frequent PRO-CTCAE administration is generally warranted during the first few cycles of therapy (e.g., weekly reporting during the initial several months of therapy). Thereafter, the assessment intervals may be extended (e.g., monthly or quarterly, depending on the regimen under study), particularly in trial contexts where the duration of investigational treatment is prolonged or where toxicities are anticipated to have stabilized. In summary, the time points of measurement should reflect the anticipated pattern of toxicity, and the scientific objectives of the trial.
Can I change the recall period from ‘over the past 7 days’ to ‘in the past month’?
At this time, we cannot recommend use of longer or shorter PRO-CTCAE recall periods. The standard PRO-CTCAE recall period is “the past 7 days”. A recent study suggests that longer recall periods (2-, 3- or 4- week recall) are associated with small but successively increasing measurement error. This must be considered if recall periods longer than 1 week are going to be used in a trial for logistical reasons.
On average, how long does it take a respondent to complete PRO-CTCAE?
Based on our findings, PRO-CTCAE items are completed rapidly. We estimate that a 20-item PRO-CTCAE survey would take on average 3.4 minutes by paper, 3.7 minutes by web, and 5.4 minutes by interactive voice response system (IVRS).
Our research also indicates that there is no evidence of clinically meaningful variation in completion times by participant characteristics, including impairments in physical or cognitive functioning (Mode equivalence and acceptability of tablet computer-, interactive voice response system-, and paper-based administration of the U.S. National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).). These findings suggest that completion of PRO-CTCAE items is generally not laborious, even for those respondents who may have some degree of functional limitation.
Estimates of the total time to complete a survey by each mode depend upon the number of items presented to the respondent. As an additional consideration, because paper surveys do not incorporate conditional branching patterns, as do web-based and IVRS surveys, a participant completing a paper survey would likely have to complete more PRO-CTCAE items, compared to the same participant completing PRO-CTCAE using an electronic version of the questions.
As an example of an estimate of respondent burden for human subjects research applications, 75% of respondents would be able to complete twenty items in 3.8 minutes by web, in 6.1 minutes by IVRS, and in 4.3 minutes by paper.
How is PRO-CTCAE scored?
At the present time, PRO-CTCAE responses are scored from 0 to 4, and there are no guidelines yet established for how to combine attributes into a single score or how best to analyse PRO-CTCAE data longitudinally. These are topics of ongoing studies. PRO-CTCAE scores for each attribute (frequency, severity and/or interference) should be presented descriptively (eg. summary statistics or graphical presentations). CTCAE grades for the corresponding time period should be presented alongside PRO-CTCAE scores. The proportion of missing data should also be summarized to aid interpretation.
Is there, and should there be, a perfect correspondence between PRO-CTCAE scores and clinicians’ CTCAE grades?
No there is not, nor should there be. One should expect this for many reasons, including:
- Clinicians and patients providing their reports at differing time points
- Clinicians and patients reporting on slightly different phenomena (eg. sadness vs. depression)
- Frequent management of severe toxicity by clinicians may skew clinician perceptions of symptom severity
- Patients may under-report symptoms to their clinicians due to time constraints, a desire to avoid an appearance that they are complaining or bothering their clinician, as well as concerns about not qualifying for continued treatment, and/or being removed from a study protocol or receiving a lower dose of treatment, if they report toxicities.
Disagreement between patient-reported and clinician-reported symptomatic toxicity has been extensively described. Research has shown a varying relationship between self-report of symptoms and clinician-based CTCAE grades (See: Xiao C, Polomano R, Bruner DW. Comparison between patient-reported and clinician-observed symptoms in oncology. Cancer Nurs 2013 Nov-Dec;36(6):E1-E16. Review).
Several additional key points:
- Criteria for grading on the CTCAE scale vary by toxicity, however by convention, grade 1 typically refers to asymptomatic or mild symptoms not requiring intervention, grade 2 refers to moderate symptoms that interfere somewhat with daily function and where some intervention may be indicated, and grade 3 refers to severe symptoms that interfere with daily activities or require more significant intervention. Grade 4 toxicity (life-threatening, with urgent intervention indicated) and Grade 5 (death) are indicative of significantly higher levels of toxicity, and are rarely applied for symptomatic toxicities such as fatigue, tinnitus, hoarseness or xerostomia. Thus, a patient-reported symptom of 'severe' or 'very severe' may not therefore correspond to CTCAE grade 4 or 5 toxicity. In addition many of the symptomatic toxicities in the CTCAE do not permit assignment of a grade higher than grade 3.
- PRO-CTCAE scores range from 0-4, with corresponding response choices for frequency (Never / Rarely / Occasionally / Frequently / Almost constantly), for severity (None / Mild / Moderate / Severe / Very severe) and interference (Not at all / A little bit / Somewhat / Quite a bit / Very much).
- While there is apparent similarity between grading scales for PRO-CTCAE and CTCAE, differences between CTCAE grades and PRO-CTCAE scores should not be over-interpreted. Disagreement between PRO-CTCAE scores and CTCAE grades may not represent 'under-ascertainment' by clinicians or 'over-reporting' by patients. For example, a patient may meet CTCAE criteria for grade 1 vomiting (1-2 episodes separated by 5 minutes in a 24 hour period), but to the patient, two daily episodes of vomiting constitutes a severe symptom.
- There are unique challenges when attempting to directly compare CTCAE grades and PRO-CTCAE scores. These toxicity scoring instruments were not developed for direct comparison but rather were designed to be complementary strategies for capturing symptomatic adverse events. The NCI is leading an effort to determine the best approaches to scoring PRO-CTCAE and ultimately to using the PRO-CTCAE scores to assign a CTCAE grade
What is the conditional branching logic that should be employed when PRO-CTCAE is used on an electronic platform?
PRO-CTCAE has been developed and tested with a conditional branching logic that helps to reduce respondent burden. Conditional branching should be employed for electronic administration of PRO-CTCAE symptom terms that have two or more items. The logic branches from frequency, then to severity, then to interference. For example, if frequency is > (greater than) never, you next pose the severity question, and if severity>none, you pose the interference question.
Is there any other guidance that a developer of an electronic PRO administration instance should consider when using PRO-CTCAE?
PRO-CTCAE questions were developed and tested using a ‘wide’ layout (see below for an example), and have been shown to be equivalent when administered on tablet computer, interactive voice response system (IVRS), or paper. Equivalence using other layouts (eg. vertical response choices) or other devices (eg. smartphone) has not been studied.
PRO-CTCAE questions should be grouped in bundles (eg. frequency, severity and interference) so as to preserve the sequencing of the cognitive task patients are completing when answering (ie. reflecting on the different attributes of a single symptom). For an example, please see below.
Mouth and Throat Sores
What was the severity of your mouth and throat sores at their worst?
- Ο None
- Ο Mild
- Ο Moderate
- Ο Severe
- Ο Very severe
How much did mouth and throat sores interfere with your usual or daily activities?
- Ο Not at all
- Ο A little bit
- Ο Somewhat
- Ο Quite a bit
- Ο Very much
In our studies, the whole group of questions about a particular symptom has been presented on a single screen, although because of conditional branching, questions only appear on the screen if the answer to the first question is greater than never (frequency) or none (severity).
A PRO-CTCAE mode equivalence study has been performed examining psychometric equivalence of responses gathered using web-enabled tablets (screen size ranging from 10-12 inches), IVRS and paper. Participants were drawn from one of 6 clinical sites, and included older respondents and those with poor performance status. All respondents were currently undergoing cancer treatment.
There is psychometric evidence to justify comparison of results and pooled analyses across studies that employ different PRO-CTCAE modes of administration (Mode equivalence and acceptability of tablet computer-, interactive voice response system-, and paper-based administration of the U.S. National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).). Administration of PRO-CTCAE via different modes including desk top computers, web-enabled tablet computers, IVRS, and paper offers flexibility for patients and for study operations personnel.
Can I reprint PRO-CTCAE items in a publication?
PRO-CTCAE items should not be reprinted in a publication. Instead, please cite the appropriate reference to our PRO-CTCAE Web site (https://healthcaredelivery.cancer.gov/pro-ctcae/) in the reference list.
I am interested to develop and test additional PRO-CTCAE items reflecting symptom terms not currently included in the PRO-CTCAE Item Library version 1. Who should I contact to discuss that further?
We have several early adopters testing additional or revised PRO-CTCAE items that may one day be included in the PRO-CTCAE item library.
To protect the integrity of PRO-CTCAE, the US National Cancer Institute holds the trademark for PRO-CTCAE, all translations, and all related documents. To assure standardization, PRO-CTCAE users are not permitted to adapt the PRO-CTCAE instrument (including symptom terms, item phrasing, response choices and recall period) as specified on the PRO-CTCAE Instrument page without prior written consent of the National Cancer Institute.
If you have interest in developing and testing additional or revised PRO-CTCAE items, please be in touch with us by e-mail to discuss this interest and your planned approach.
Has PRO-CTCAE been translated for use in other languages?
Visit the Language Translation page for more information.
I am interested to develop a PRO-CTCAE language translation. What permission is required to do that?
PRO-CTCAE is currently available in 23 languages including English, Chinese (Simplified), Chinese (Traditional), Czech, Danish, Dutch (for Belgium and the Netherlands), French (for Canada), French (for France, Belgium, Switzerland), German, Greek, Hungarian, Italian, Japanese, Korean, Malay, Polish, Portuguese (for Brazil), Portuguese (for Portugal), Romanian, Russian, Spanish, Turkish, and Ukrainian. Additional translations are in development (including Afrikaans, Arabic, Punjabi, Slovak, Swedish, Tamil, Thai, and Urdu), and will be posted upon completion.
To assure consistency, all translations are on file with NCI, and should be obtained from NCI. Each translated version includes certification of the procedures used to assure conceptual equivalence.
To assure standardized translations, users are not permitted to translate PRO-CTCAE without a prior written agreement with the National Cancer Institute.
If you have interest in developing and linguistically validating the item library in another language, please be in touch with us by e-mail to discuss this interest and your planned approach.
Can adolescents 16 years of age or older complete the PRO-CTCAE adult version?
Yes. While the PRO-CTCAE adult version was validated for use in individuals 18 years or older, recent evidence indicates that it can be used in adolescents as young as 16 years (see Reeve et al. 2017). A pediatric version and parent-proxy version of PRO-CTCAE for children and adolescents with cancer (ages 7-17) are currently being tested.
Is there a version of PRO-CTCAE for children and adolescents?
A version of PRO-CTCAE for use in children and adolescents is currently in development. PRO-CTCAE adult version is validated for use in individuals 18 years or older, but can be used in adolescents as young as 16 years (see Reeve et al. 2017). A pediatric version and parent-proxy version of PRO-CTCAE for children and adolescents with cancer (ages 7-17) are undergoing testing. There is currently no proxy measure available for PRO-CTCAE (e.g. for people with cognitive or communication deficits).