Abstract
Purpose:
Pleuropulmonary blastoma (PPB) is the most common lung cancer of infancy and early childhood and is associated with germline DICER1 variants. Type I and Ir PPB are cystic lesions treated surgically, with a subset of children with type I receiving chemotherapy. Type II and III are more aggressive lesions treated surgically and with intensive chemotherapy and potentially radiation. We sought to assess health-related quality of life (HRQoL) in children with PPB and known germline DICER1 variants.
Methods:
Children with a diagnosis of PPB or germline DICER1 pathogenic variant without history of PPB or other DICER1-related neoplasm (DICER1+ only) were enrolled in the International PPB/DICER1 Registry. Parent reports for participants aged 2–17 years for the PedsQL v.4 and PedsQL Multidimensional Fatigue Scale v.3 were collected. Fatigue, physical, and psychosocial function scores were compared.
Results:
Analysis included 84 participants (PPB type Ir=20, type I=15, type II/III=27, DICER1+ only=22). Total fatigue scores of participants with type I and II/III PPB were lower compared to DICER1+ only, with effect size larger in type II/III (−0.82 vs −0.40). Total psychosocial and physical functioning scores were lower in participants with type I and type II/III PPB compared to DICER1+ only with larger effects noted in type II/III. Female sex was suggestive of worse HRQoL for both type I/Ir and type II/III cohorts.
Conclusions:
These data demonstrate the importance of regular HRQoL assessment in patients with a history of PPB as well as the importance and feasibility of studying HRQoL in children with rare tumors.
Keywords: Health-related quality of life, PedsQL, Pleuropulmonary blastoma, DICER1, DICER1 Tumor Predisposition
INTRODUCTION
Pleuropulmonary blastoma (PPB) is the most common lung cancer of infancy and early childhood, seen primarily in children under the age of 7 years; PPB begins as a cystic lesion (type I) with the potential to progress to the overtly malignant type II (mixed cystic and solid) or type III (solid) PPB.1 A fourth type of PPB, type Ir, is a purely cystic lesion, without a subepithelial primitive cellular component, with an attenuated capacity for malignant progression. The distinction between type I and Ir PPB is challenging; in general, type I PPB presents in younger individuals and is larger in size although there is significant overlap between the two and complete pathologic evaluation is required. Surgery is the primary treatment for type I and Ir PPB. Chemotherapy is recommended in a subset of children with type I PPB and is generally not recommended for those with type Ir. Conversely, types II and III PPB are managed with surgery, intensive chemotherapy and potentially radiation therapy. Chemotherapy for types II and III PPB have historically been intensive sarcoma-based regimens and since 2007, IVADo (ifosfamide, vincristine, actinomycin-D and doxorubicin), an anthracycline containing regimen, has been recommended.2 In contrast, a less intensive regimen, VAC (vincristine, actinomycin-D and cyclophosphamide) or more recently VAC/VA, has been recommended for patients with type I PPB when chemotherapy is indicated. In the largest published study, the 5-year overall survival was 91%, 71% and 53% for types I, II and III PPB, respectively.1
The International PPB (now International PPB/DICER1) Registry (NCT03382158) was established in 1987 and now includes more than 700 children and adults with PPB, other DICER1-related conditions and/or a germline DICER1 pathogenic variant.3,4 Approximately 70% of cases of PPB occur in individuals with germline pathogenic variants and virtually all PPBs have biallelic DICER1 pathogenic variants.5 The prevalence of DICER1 loss-of-function variants is estimated to be between 1:3700 and 1:4600.6 The primary features of DICER1 are neoplasms7, thyroid disease8 and macrocephaly9 although the penetrance is incomplete, and many individuals are healthy or only have minor manifestations of DICER1 predisposition. Over the timeline of the Registry, the spectrum of neoplasms related to DICER1 variants has expanded to include tumors of the kidneys, ovaries, brain, and thyroid.10–18 Surveillance and familial testing guidelines are available to facilitate the diagnosis of PPB and other DICER1-associated neoplasms in their earliest and most curable forms.19
Health-related quality of life (HRQoL) is an important consideration when caring for patients with childhood cancer, especially those undergoing intensive chemotherapy including children with type II and III PPB. Fatigue in patients with cancer has been well established.20,21
HRQoL has not yet been systematically evaluated in patients with PPB and other DICER1-associated neoplasms. We hypothesized that chemotherapy and surgery may have an adverse effect on HRQoL in children with PPB and that children with type II/III may have more severe adverse effects on HRQoL due to increased intensity of treatment in comparison to children with type I and Ir PPB. An optional component added to Registry participation in 2016 focused on HRQoL through completion of a PedsQL survey.
In this study, we compare HRQoL, including fatigue, physical and psychosocial function, in patients with type Ir, I and II/III PPB to individuals with a germline DICER1 pathogenic variant without any DICER1-related neoplasms.
METHODS
Procedure
Individuals with PPB, a known germline DICER1 pathogenic variant and/or a suspected DICER1-related condition, provided consent (and assent as applicable) for participation in the International PPB/DICER1 Registry (Registry). All study procedures were approved by the Children’s Minnesota institutional review board (#1611–130) and relevant human subjects’ committees. Beginning in 2016, consent for the Registry included an optional HRQoL component. Participants who opted into this HRQoL component were sent two surveys, the PedsQL v.4 and PedsQL Multidimensional Fatigue Scale v.3 (PedsQL-MFS), by mail six months after enrollment and then every two years thereafter. If a survey was not returned, an additional attempt was sent approximately 1 year after the first attempt. If the second attempt went unreturned, this was considered passive refusal and no further attempts were made. Exclusion criteria included patients who did not consent for the HRQoL component of the Registry, children under the age of 2 years, individuals with missing personal mailing addresses and individuals whose primary language was not English or Spanish.
The PedsQL v.4 and PedsQL-MFS have been validated for use in childhood cancer patients.22 PedsQL v.4 Generic Core Total Score (child- and parent-report alphas 0.88 and 0.93, respectively) and PedsQL-MFS (child- and parent-report alphas 0.89 and 0.92, respectively) have acceptable internal consistency reliability and have been shown to distinguish healthy children from children with cancer as a group.22 Survey forms were sent based on the age of the patient (ages: 2–4, 5–7, 8–12, 13–18 and adult) and were essentially identical in content and differed only in developmentally-appropriate language and the use of first or third person tense. Spanish language versions were available for families reporting Spanish as their preferred language. Questionnaires were completed by a parent or primary caregiver, or individual receiving the survey for ages 18+, and returned to the Registry via mail. Patients were considered respondents if at least one survey was completed and returned to the Registry; otherwise individuals with unreturned surveys were considered non-respondents. Three subcategories of HRQoL were assessed: fatigue, physical and psychosocial.
Respondents
Parent reports for participants aged 2–17 years and individual reports for participants aged 18+ were collected and analyzed. Surveys completed from 2017 to February 2022 were utilized for this study. Individuals participating in this study self- or parent-reported race and ethnicity, which was categorized as White/Caucasian, Black or African American, Hispanic or Latino, Asian, American Indian or Alaska Native and/or other. Survey distribution and responses were tracked in a SQL Database.
Analysis Cohorts
Among the respondents, participants aged 2–17 years at the time of the survey with a history of type Ir, I, II or III PPB confirmed by central pathology review who had completed treatment were selected for this analysis. For the purposes of this analysis, patients with type II and III PPB were combined and termed type II/III PPB. Additionally, a cohort including respondents aged 2–17 years with a germline DICER1 variant without tumor diagnoses or other DICER1-associated conditions (DICER1+ only) was also analyzed. When surveys at multiple time points were received for an individual patient, the first survey returned after the completion of treatment was used for this analysis.
Fatigue
Fatigue was assessed using PedsQL-MFS. The 18-item questionnaire has three subcategories: general fatigue (6 items), sleep/rest fatigue (6 items), and cognitive fatigue (6 items). The survey is a 5-point Likert scale in which the parent indicates to what extent the child has had difficulties with the stated problem in the past month: never (0), almost never (1), sometimes (2), often (3) and almost always (4). Survey responses were scored through standardized procedures.22 Each item was reverse scored and linearly transformed to a 0 to 100 scale (0=100, 1=75, 2=50, 3=25, and 4=0). At least 50% of each survey had to be completed to be considered for analysis. Higher scores indicate higher levels of functioning (i.e., fewer symptoms of fatigue). Total fatigue is derived by averaging general fatigue, sleep/rest fatigue and cognitive fatigue.
Physical and Psychosocial
Physical and psychosocial functioning was assessed with the PedsQL v.4 survey. The questionnaire includes 4 subcategories, physical functioning (8 items), emotional functioning (5 items), social functioning (5 items) and school functioning (5 items). For patients aged 2–4 years, the school functioning component contains 3 items. The PedsQL v.4 survey utilized the same 5-point Likert scale as above and was rescaled in the same method, with higher scores indicating better HRQoL. A composite psychosocial functioning score was derived from an average of emotional, social and school functioning.
Statistical Analysis
General information for potential participants included age at survey distribution, sex, race and ethnicity, survey language, country of origin, DICER1 germline status, primary diagnosis and disease status (if any). Characteristics of the survey respondents and non-respondents were compared with standard summary statistics as well as chi-square and Mann-Whitney U-test for categorical and numeric data, respectively. Additional information available for respondents with PPB included age at diagnosis, time since completion of treatment, chemotherapy and other DICER1-related conditions.
Mean and standard deviation for fatigue and physical and psychosocial function scores were calculated and compared. If only one survey (PedsQL v.4 or PedsQL-MFS) was complete for a given patient, it was included in the respective analysis. Comparisons of HRQoL between the DICER1+ only cohort and each of the type Ir, type I and type II/III PPB cohorts were made using t-test and Cohen’s d, a standardized measure of effect size relative to the standard deviation. Effect sizes between 0.2 and 0.5 were considered small, between 0.5 and 0.8 were considered moderate, and ≥ 0.8 was considered large.23 Among type I and Ir patients, linear regression was used to assess associations with HRQoL measures and patients characteristics like sex, use of chemotherapy, surgical approach (thoracotomy versus thorascopic), PPB type (I versus Ir), age at diagnosis, and time since end of therapy. A similar linear regression analysis was performed among type II/III patients with patient characteristics of sex, surgical approach (pneumonectomy versus tumorectomy, wedge, or lobectomy), age at diagnosis, and time since end of therapy. Regression results are reported as coefficients with 95% confidence intervals calculated using empirical (i.e., robust) standard errors.
RESULTS
Since 2016 the Registry has enrolled 487 participants, and of these, 348 individuals were sent at least one HRQoL survey (Figure 1). In total, the Registry has collected at least one survey from 184 unique respondents (53% response rate). Supplemental Table 1 compares respondents to non-respondents; age and sex were similar across the two groups. A larger proportion of non-respondents were germline DICER1 negative, had non-PPB or DICER1+ only diagnoses or lived outside the United States. A larger portion of respondents reported race as White/Caucasian compared to non-respondents whereas more non-respondents reported race as Black or African American.
Figure 1:
Flow diagram of survey response and inclusion and exclusion of respondents in study analysis.
Of the respondents, 84 patients qualified for this analysis (type Ir=20, type I=15, type II/III=27 and DICER1+ only=22). The 100 patients that did not qualify included 22 participants with PPB or DICER1+ only that were 18 years of age or older when the survey was completed, 4 participants with type II/III PPB that were undergoing treatment and 74 patients with a primary diagnosis that was not PPB or DICER1+ only.
Characteristics
Characteristics for the type Ir, type I, type II/III, and DICER1+ only cohorts are displayed in Table 1. The median age of participants in the type Ir, type I and type II/III cohorts was 3.7 years (range 2.0–12.3 years), 3.3 years (range 2.0–17.1 years) and 4.9 years (range 2.0–16.9 years), respectively compared with a median age of 6.9 years (range 2.2–16.5 years) for the DICER1+ only participants. The median time from end of treatment to time of survey was 1.5 years (range 0.0–8.9 years) for type Ir, 1.5 years (range 0.0–15.3 years) for type I and 1.0 years (range 0.0–11.1 years) for type II/III. Children with type I PPB received chemotherapy in 47% of cases; 100% of children with types II/III PPB received chemotherapy and only 2 (10%) with type Ir PPB received chemotherapy. Additional chemotherapy, surgical and radiation information are provided in Table 1. Three patients (15%) with type Ir PPB had an additional DICER1-assocated neoplasm compared to 5 (33%) patients with type I PPB and 1 (4%) patient with type II/III PPB. Respondents from 47 institutions were included in this analysis, with 73 (87%) respondents from the US and the remainder from Canada, Finland, Israel, Norway, Serbia and Spain.
Table 1:
Characteristics of patients with type Ir, type I, type II/III PPB and DICER1+ only.
| Type Ir PPB (n = 20) |
Type I PPB (n = 15) |
Type II/III PPB (n = 27) |
DICER1+ Only (n = 22) |
|
|---|---|---|---|---|
| Age at diagnosis (y), median (range) | 1.5 (0.3 – 12.3) |
1.3 (0.3 – 7.9) |
3.1 (0.3 – 7.7) |
n/a |
| Age at time of survey (y), median (range) | 3.7 (2.0 – 12.3) |
3.3 (2.0 – 17.1) |
4.9 (2.0 – 16.9) |
6.9 (2.2 – 16.5) |
| Time since end of treatment (y), median (range) | 1.5 (0.0 – 8.9) |
1.5 (0.0 – 15.3) |
1.0 (0.0 – 11.1) |
n/a |
| Male, n (%) | 12 (60) | 9 (60) | 12 (44) | 12 (55) |
| Chemotherapy received, n (%) | 2 (10) | 7 (47) | 27 (100) | n/a |
| Other, n/N (%) | 0/2 (0) | 0/7 (0 | 3/27 (11) | |
| No Information, n (%) | 1 (5) | 2 (13) | 0 (0) | |
| No Information, n (%) | 0 (0) | 0 (0) | 1 (4) | |
| Radiation received, n (%) | 0 (0) | 0 (0) | 5 (19) | n/a |
| DICER1 germline +, n/N (%) | 14/17 (82) | 12/14 (86) | 13/20 (65) | 22/22 (100) |
| Additional DICER1-related condition, n (%) | 3 (15)& | 5 (33)# | 1 (4)$ | n/a |
IVADo = ifosfamide, vincristine, actinomycin-D and doxorubicin, n = number, N = number assessed, PPB = pleuropulmonary blastoma, VAC = vincristine, actinomycin-D and cyclophosphamide, VAC/VA = vincristine, actinomycin-D and cyclophosphamide/vincristine and actinomycin-D, y = year
cystic nephroma (3)
ciliary body medulloepithelioma, cystic nephroma, Sertoli-Leydig cell tumor and PPB Ir (2)
cystic nephroma
Fatigue Score (FS)
PedsQL-MFS scores for cognitive, general, sleep/rest and total fatigue are displayed in Table 2 for type Ir, type I, type II/III and DICER1+ only cohorts. Total FSs were lower in participants with type Ir (86.6), type I (83.8) and type II/III PPB (78.9), reflecting more fatigue symptoms compared to patients with DICER1+ only (91.6). Effect sizes among the fatigue domains in the type Ir cohort compared to the DICER1+ only cohort were small (−0.23 to −0.46). In the type I cohort, effect sizes were minimal to moderate (−0.14 to −0.54) among the fatigue domains compared to the DICER1+ only cohort. In contrast, effect sizes were moderate to large (−0.50 to −0.86) in the type II/III cohort compared to the DICER1+ only cohort, and the difference in total FS was statistically significant (p=.003).
Table 2:
PedsQL Multidimensional Fatigue Scale scores for type Ir, type I and type II/III PPB and comparison with DICER1+ only cohort using t-test and Cohen effect sizes.
| PedsQL - MFS | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cognitive Fatigue | General Fatigue | Sleep/Rest Fatigue | Total Fatigue | |||||||||
| Mean (SD) | p-value | d | Mean (SD) | p-value | d | Mean (SD) | p-value | d | Mean (SD) | p-value | d | |
|
DICER1+ Only (n = 22) |
86.7 (19.1) |
- | - | 93.8 (11.6) |
- | 94.3 (8.8) |
- | - | 91.6 (12.3) |
- | - | |
| Type Ir PPB (n = 20) |
80.3 (21.9) |
.310 | −0.30 | 90.4 (14.3) |
.408 | −0.23 | 89.2 (11.2) |
.103 | −0.46 | 86.6 (13.9) |
.224 | −0.36 |
| Type I PPB (n = 15) |
83.3 (25.2) |
.642 | −0.14 | 82.5 (20.7) |
.041 | −0.54 | 85.6 (19.7) |
.074 | −0.44 | 83.8 (19.7) |
.146 | −0.40 |
| Type II/III PPB (n = 27) |
74.7 (24.3) |
.064 | −0.50 | 81.1 (14.7) |
.002 | −0.86 | 81.0 (17.5) |
.002 | −0.76 | 78.9 (15.5) |
.003 | −0.82 |
d = Cohen effect size, MFS = multidimensional fatigue scale, n = number, PPB = pleuropulmonary blastoma, SD = standard deviation
Physical Functioning (PF) Score
PedsQL v.4 scores for PF are displayed in Table 3. PF was similar in participants with type Ir PPB (94.8) compared to the DICER1+ only cohort with no notable effect (0.05). PF scores were lower in participants with type I PPB (87.2) and type II/III PPB (75.2) reflecting poorer PF, compared to participants with DICER1+ only (94.5). Compared to the DICER1+ only cohort, the effect size of the PF domain was moderate (−0.52) among the type I and large (−1.04) among the type II/III cohort, with both comparisons being statistically significant (p=.048 and p<.001, respectively).
Table 3:
PedsQL v.4 scores for type Ir, type I and type II/III PPB and comparison with DICER1+ only cohort using t-test and Cohen effect sizes.
| PedsQL v.4 | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Physical | Psychosocial | ||||||||||||||
| Physical Functioning | Emotional Functioning | School Functioning | Social Functioning | Total Psychosocial | |||||||||||
| Mean (SD) | p-value | d | Mean (SD) | p-value | d | Mean (SD) | p-value | d | Mean (SD) | p-value | d | Mean (SD) | p-value | d | |
| DICER1+ Only (n = 22) |
94.5 (7.6) |
- | - | 88.2 (12.4) |
- | - | 90.0 (13.5) |
- | - | 95.0 (8.3) |
- | - | 91.1 (9.2) |
- | - |
| Type Ir PPB (n = 20) |
94.8 (8.4) |
.877 | 0.05 | 83.0 (14.6) |
.222 | −0.35 | 87.4 (16.8) |
.589 | −0.16 | 91.8 (11.8) |
.306 | −0.27 | 87.7 (11.7) |
.320 | −0.29 |
| Type I PPB (n = 15) |
87.2 (13.9) |
.048 | −0.52 | 70.8 (22.2) |
.004 | −0.78 | 78.1 (23.1) |
.062 | −0.52 | 88.0 (16.1) |
.092 | −0.43 | 78.6 (18.1) |
.011 | −0.69 |
| Type II/III PPB (n = 25) |
75.2 (18.5) |
<.001 | −1.04 | 69.4 (21.2) |
.001 | −0.88 | 70.2 (26.2) |
.004 | −0.76 | 81.8 (18.8) |
.004 | −0.70 | 74.3 (17.1) |
<.001 | −0.98 |
d = Cohen effect size, n = number, PPB = pleuropulmonary blastoma, SD = standard deviation
Psychosocial Functioning (PSF) Score
PedsQL v.4 scores for emotional, school, social and total PSF scores are displayed in Table 3. Total PSF scores were lower in participants with type I PPB (78.6) and type II/III PPB (74.3) compared to participants with DICER1+ only (91.1). Participants with type Ir PPB (87.7) demonstrated little difference in total PSF scores with no effect to small effect sizes among the domains (−0.16 to −0.35) compared to the DICER1+ only cohort. In the type I cohort, effect sizes were small to moderate (−0.43 to −0.78) among the psychosocial domains compared to the DICER1+ only cohort. Effect sizes were moderate to large (−0.70 to −0.98) in the type II/III cohort compared to the DICER1+ only cohort. Differences for total PSF were statistically significant in the type I and type II/III cohorts (p=.011 and p<.001, respectively).
Regression Analysis
Type I and type Ir PPB were combined to assess HRQoL measures amongst patient characteristics with a linear regression analysis (Table 4). Age at diagnosis did not appear to impact any HRQoL domains. Interestingly, increased time since end of treatment was suggestive of worsening HRQoL scores (i.e total FSs, p=.045). Female sex was suggestive of worse HRQoL, specifically with total FSs (−8.4, 95% CI: −20.0, 3.2). Having received chemotherapy was not suggestive of worsening HRQoL in any domain among the type I and Ir cohort. Further, an analysis of type I patients who received chemotherapy versus those who did not showed no noticeable difference in any HRQoL domain (Supplemental Table 2).
Table 4:
Linear regression analysis amongst type I/Ir PPB and type II/III PPB cohorts, respectively.
| Characteristic | Total Fatigue | Physical Functioning | Total Psychosocial | |||
|---|---|---|---|---|---|---|
| Regression Coefficient (95% CI) |
p-value | Regression Coefficient (95% CI) |
p-value | Regression Coefficient (95% CI) |
p-value | |
| Type I/Ir PPB | ||||||
| Type I PPB | −2.3 (−12.6, 7.9) |
.654 | −3.2 (−10.4, 4.0) |
.379 | −2.2 (−13.5, 9.1) |
.701 |
| Age at Diagnosis | −0.4 (−2.1, 1.4) |
.686 | −0.1 (−1.0, 0.9) |
.890 | 0.4 (−0.8, 1.6) |
.544 |
| Time Since EOT | −1.9 (−3.8, −0.04) |
.045 | −0.8 (−2.1, 0.4) |
.198 | −1.5 (−3.1, 0.2) |
.087 |
| Female Sex | −8.4 (−20.0, 3.2) |
.157 | −3.1 (−10.8, 4.6) |
.425 | −3.8 (−13.3, 5.7) |
.438 |
| Chemotherapy | 5.5 (−8.9, 19.9) |
.458 | −2.5 (−13.5, 8.5) |
.656 | −2.5 (−16.8, 11.9) |
.737 |
| Thoracotomy | −0.1 (−10.9, 10.8) |
.991 | −1.5 (−8.4, 5.4) |
.663 | 6.6 (−2.1, 15.2) |
.137 |
| Additional DICER1-related conditions | 4.3 (−4.3, 13.0) |
.324 | 1.4 (−5.6, 8.5) |
.692 | 3.8 (−6.2, 13.8) |
.456 |
| Type II/III PPB | ||||||
| Age at Diagnosis | −0.2 (−2.8, 2.3) |
.864 | −0.2 (−3.7, 3.3) |
.893 | −0.1 (−2.8, 2.6) |
.937 |
| Time Since EOT | −0.9 (−2.1, 0.3) |
.140 | −2.7 (−4.8, −0.6) |
.013 | −1.3 (−3.3, 0.8) |
.227 |
| Female Sex | −12.6 (−22.8, −2.4) |
.015 | −9.5 (−23.2, 4.2) |
.175 | −7.4 (−19.5, 4.8) |
.234 |
| Pneumonectomy | −5.4 (−19.0, 8.2) |
.436 | −2.1 (−19.1, 14.9) |
.812 | −13.8 (−28.7, 1.1) |
.069 |
| Radiation | 0.1 (−15.4, 15.6) |
.992 | −5.5 (−19.3, 8.2) |
.431 | 1.9 (−13.3, 17.1) |
.803 |
CI = confidence interval, EOT = end of treatment, PPB = pleuropulmonary blastoma
Patients’ characteristics in the type II/III PPB cohort were also assessed with a linear regression analysis (Table 4). Similar to type I/Ir, increased time since end of treatment was suggestive of worsening HRQoL scores (i.e total PF score, p=.013). As with type I and Ir, female sex was suggestive of worse HRQoL with most noticeable effect in total FS (−12.6, 95% CI: −22.8, −2.4). Pneumonectomy was suggestive of worse PSF compared to tumorectomy, wedge or lobectomy (−13.8, 95% CI: −28.7, 1.1).
DISCUSSION
This study is the first to evaluate the impact of PPB on HRQoL and, to the best of our knowledge, the first of its kind in a rare malignancy defined by tumor predisposition. Importantly, this study demonstrates the feasibility of collecting HRQoL data for children with rare tumors from a variety of treating institutions.
The control cohort is composed of patients with a known germline DICER1 pathogenic or likely pathogenic variant with no known manifestations of DICER1. Learning disabilities, developmental delays, cardiac disease and/or other significant fatigue-inducing issues have not been described as primarily associated with DICER1, thus the control cohort was expected to be generally healthy. In comparison to a sample of healthy pediatric patients reported by Varni et al22 we found similar-to-improved average proxy-reported PF (89.32, SD 16.35), PSF (86.58, SD: 12.79) and total FSs (89.63, SD: 11.38). Given the recommended surveillance guidelines19 for individuals with known DICER1 germline variants, it is encouraging to observe similar-to-improved HRQoL scores compared to a published cohort of healthy children, which suggests that surveillance is well tolerated.
Fatigue is commonly experienced by children with cancer. In our cohort, we observed increased fatigue in association with type Ir, type I and type II/III PPB, but the effects were most pronounced in those with type II/III PPB; this is likely in part due to the more intensive treatment in those with type II/III PPB as only about half of patients with type I PPB in this cohort and 2 patients with type Ir PPB received chemotherapy. When comparing participants with type I who received chemotherapy versus those who did not, total fatigue scores were not notably different, consistent with the less intensive chemotherapy in type I compared to type II/III PPB. This result is limited in part by small sample size and warrants further investigation. For patients with type II/III PPB, this analysis only considered those who had completed treatment at the time of the survey; all fatigue domains were impacted, supporting the impression that fatigue remains an important concern for patients with type II/III PPB even beyond the completion of treatment.
An analysis of long-term reported fatigue by Mulrooney, et al found that sleep disturbances and daytime sleepiness are increased among adult survivors of childhood cancer.24 An additional study demonstrated that cancer-related fatigue in children improves over time and increased physical activity is accompanied by less cancer-related fatigue.25 Intervention with fatigue-related education has been shown to reduce fatigue in children with cancer and increase quality of life.26 The increased fatigue in patients with PPB warrants further evaluation and possible targeted interventions to reduce fatigue, however, we acknowledge that longitudinal data would be particularly helpful in determining the indications for intervention and further longitudinal data collection is underway.
Pulmonary surgery is a substantial component of therapy for nearly all children with PPB with some patients undergoing multiple operative procedures. All patients with PPB in this analysis underwent at least one thoracic surgery. Operative risks and potential long-term effects on lung function are important considerations. In general, type Ir represents a smaller lesion than type I PPB and as PPB advances to type II/III the extent of disease increases, necessitating more aggressive surgical intervention. The cohort of participants with type I PPB included a subset of those who only underwent surgery with no notable difference in HRQoL scores from the subset of participants receiving surgery and chemotherapy. All domains of HRQoL assessed in the type I cohort demonstrated a small to moderate effect compared to DICER1+ only suggesting surgical intervention plays a role in HRQoL. Similarly, nearly all of the type Ir participants underwent surgery alone and demonstrated a small effect in total fatigue scores and PSF. The role of surgical intervention on HRQoL warrants further investigation.
Anthracyclines are a common component in the management of type II/III PPB with nearly all patients in our cohort receiving an anthracycline-containing regimen. Anthracyclines are associated with increased risk for cardiotoxicity.27 A previous study investigated the role of anthracycline exposure in pediatric cancer and the potential effect on HRQoL in the domains of physical and PSF (fatigue functioning was not assessed).28 The authors noted increasing anthracycline doses decreased PedsQL scores in all domains.28 In comparison to the prior published cohort of patients that received anthracyclines, we found notably lower physical (75.2, SD: 18.5 vs 88.3, SD: 13.5) and PSF (74.3, SD: 17.1 vs 82.6, SD: 13.9) scores in patients with type II/III PPB.28 Of note, our study had a shorter time from diagnosis to survey on average and utilized parent report compared to patient report in the prior study.
When assessing individual characteristics amongst type I/Ir and II/III PPB cohorts, female sex was suggestive of worse HRQoL outcome. Interestingly, time since end of treatment did not result in improvements in HRQoL, although we expect that ongoing longitudinal data will provide valuable knowledge and hypothesize that individual improvements overtime will be observed. Given the small sample size it is challenging to elucidate patterns in characteristics and resulting effects on HRQoL. Continued expansion of data collection will provide additional insight into characteristics associated with HRQoL outcomes in patients with PPB.
As more than 70% of children with PPB have a germline pathogenic variant in DICER1 and surveillance recommendations for children with germline predisposition and/or chemotherapy exposure include ongoing evaluation in long-term follow-up and cancer predisposition clinics, health care providers have a unique opportunity to evaluate HRQoL in individual children and families over time. This study highlights the importance of regular assessment of HRQoL in patients treated for PPB with targeted interventions to mitigate concerning symptoms when detected.
Strengths of this analysis include cohorts of patients with uniform diagnoses with the control cohort having a known DICER1 germline variant without any DICER1-associated neoplasms or conditions. This highlights the role of a PPB-related diagnosis on HRQoL beyond the clinical evaluations and surveillance imaging recommended for individuals with a DICER1 germline variant. Additionally, we were able to compile multi-institutional and international data.
Limitations to this study are largely due to the small sample size inherent in rare tumor research. HRQoL surveys were mailed to patients creating challenges with international addresses and a higher-than-expected proportion of participants based in the United States. Additionally, our study primarily included English-speaking patients, as we utilized surveys only in English and Spanish with nearly all participants and non-participants receiving an English language survey.
Future directions include transition to an electronic survey delivery format and inclusion of additional language translations of the PedsQL instrument to increase participant representation and survey completion rate. We noted differences in respondents versus non-respondents by self- or parent reported race and ethnicity. Importantly, minority status has been associated with worse PSF in childhood cancer survivors.29,30 Increasing sample size and inclusion in questionnaire distribution will also allow assessment of additional contributing factors to decreased or increased HRQoL. Additionally, longitudinal data collection, underway in this cohort, may also elucidate patterns in HRQoL over time.
In conclusion, we highlight more symptoms of fatigue and lower physical and PSF scores in patients with both type I and type II/III PPB compared to those with DICER1+ only, with a larger effect noted in patients with type II/III PPB. Parents of children with type Ir PPB report better child functioning than both the type I and II/III cohort with a small effect on fatigue and PSF and no effect on physical functioning. These data demonstrate the importance of regular evaluation of HRQoL in patients treated for PPB and prompt interventions including psychosocial support and targeted interventions to address fatigue when concerns are noted. Additional analyses are ongoing to understand factors contributing to HRQoL in children with PPB and other DICER1-related conditions. Importantly, this study also demonstrates the feasibility of studying HRQoL in pediatric rare tumors within a multi-institutional and international cohort.
Supplementary Material
Acknowledgments:
The authors wish to thank the many treating physicians, genetic counselors, patients and families who collaboratively support the International PPB/DICER1 Registry as well as the Pine Tree Apple Classic Fund whose volunteers, tennis players and donors have provided more than 35 years of continuous support for PPB Research. The authors gratefully acknowledge the contributions of Jason Albrecht to ongoing PPB research initiatives. The International PPB/DICER1 Registry is also supported by the Children’s Minnesota Foundation, Mendon F. Schutt Foundation and Rein in Sarcoma.
This analysis was supported by a grant from the Children’s Minnesota Internal Research Grant Program and supported by funding from National Institute of Health National Cancer Institute grants 1R37CA244940-01, 2R01CA143167-06A1 and the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, Rockville, MD.
Glossary
- PPB
Pleuropulmonary blastoma
- IVADo
ifosfamide, vincristine, actinomycin-D and doxorubicin
- VAC
vincristine, actinomycin-D and cyclophosphamide
- HRQoL
Health-related quality of life
- Registry
International PPB/DICER1 Registry
- PedsQL-MFS
PedsQL Multidimensional Fatigue Scale v.3
- FS
Fatigue score
- PF
Physical functioning
- PSF
Psychosocial functioning
Footnotes
Conflicts of interest: The authors have no conflicts to disclose.
Data Availability Statement:
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.