Discussion
We report the first longitudinal assessment of HRQoL using PROs in SSA among pediatric cancer patients. We used the Chichewa Pediatric PROMIS-25 to serially measure HRQoL among pediatric lymphoma patients in Malawi. Our experience highlights important disparities in pediatric cancer care experiences and suggests incorporating assessments of HRQoL via PROs in SSA is feasible, generates clinically meaningful data to inform supportive care interventions, and may provide prognostic information.
Our cohort presented with overwhelmingly advanced disease, exemplified by late stage at diagnosis, high LDH, and poor performance status, which is common across SSA.2,36 We have previously demonstrated that HRQoL at diagnosis is poorer among Malawian patients than the PROMIS reference population and similar pediatric oncology populations in the United States, likely reflecting more advanced disease.32 In HICs, children with cancer are frequently diagnosed early in their disease course with no/minimal symptom burden and have preserved HRQoL.17,37 In contrast, our patients reported poor HRQoL and extremely high pain intensity, with 32/75 (43%) of patients reporting a maximum 10/10 pain score at diagnosis. Pain medication is available in Malawi, but the extreme pain burden among our patients suggests their pain may not have been identified or adequately managed prior to referral and/or diagnosis. Efforts to educate providers on appropriate pain management in children and ensure reliable medication access, as well as outreach to facilitate early cancer diagnosis and referral are priorities.1,38–40
Patients reported significantly improved HRQoL during active treatment that far exceeded (>12 points) the MID thresholds of 2-3 points, with the exception of peer relationships which improved by 3.3 points. These improvements likely reflect reduced tumor burden and improved symptom management during active treatment. HRQoL continued to improve after treatment completion and through follow-up. In contrast, children with cancer in HICs have no/ minimal symptom burden at diagnosis, and report decreased HRQoL during cancer treatment due to therapy-related adverse effects, which then improves following treatment completion.17,37
One unique observation was that peer relationships were strong throughout all timepoints. Patients in our cohort often receive treatment in an open pediatric ward and are able to develop strong friendships with other children undergoing similar experiences. Additionally, they remain socially connected in their home villages, where they live in close proximity with their neighbors, family, and friends, and continue to attend school during their treatment course. The preservation of peer relationships throughout cancer treatment in Malawi is likely common in other LMICs but is not observed among pediatric cancer patients in HIC. In HIC, children with cancer are typically treated in private rooms and with infection control restrictions, thus experiencing significant decreases in social HRQoL with poor peer relationship scores during treatment.17,18,20,41,42
We are sad to report that mortality in our cohort was high. Most of our patients died (37/75, 49%) or were LTFU (8/75, 11%), an indication of unverifiable death in our setting.43 One-year overall survival was 47% (95% CI [37-59%]), which is consistent with historical and published survival rates for Burkitt lymphoma across SSA, and is significantly worse than reported survival rates of >90% in HIC.2,22,43–47 Given the high mortality and the challenges associated with cancer treatment in resource-poor health systems, appropriate risk stratification of patients is critical in SSA, where administering aggressive treatment to optimize survival must be weighed against toxicity risks for vulnerable children. Poor LPS has consistently been identified as a risk factor for mortality in research from both LMICs and HICs.2,22,45,46,48 Further, emerging data from HICs suggest PROs offer superior assessment of performance status when compared to traditional physician-reported measures.49We observed significantly increased mortality risk and worse survival in our cohort among patients with physician-reported LPS ≤ 70 and patient-reported Pain Intensity of 10 at diagnosis. Patient-reported poor Mobility domain scores < 40 also increased risk of mortality and worse overall survival, but this trend was not statically significant. Further evaluation of the potential prognostic utility of Pediatric PROMIS-25 in a larger patient cohort with adequate power is necessary to understand how PROs can assist with treatment risk stratification in SSA.
PROs are especially important in SSA, where providers are often over-worked, healthcare infrastructure/access is limited, and shared decision making between patients and providers is not the norm. Assessments of HRQoL via PROMIS can assist providers in quickly identifying and prioritizing patients for referral to ancillary, multidisciplinary providers, such as physiotherapists and palliative/supportive care specialists. Further, PROMIS measures mental wellbeing, which is often overlooked in pediatric oncology despite being a significant problem, and can screen patients for anxiety and depression to facilitate referrals for psychosocial support.50 In addition to generating clinically meaningful data, Pediatric PROMIS-25 surveys were feasible to administer at clinical visits while patients were receiving chemotherapy infusions or waiting to be seen by the provider.
Study strengths include prospective design, longitudinal data collection, and use of the first rigorously validated Bantu-language pediatric PRO instrument to assess HRQoL among pediatric cancer patients in SSA. Our data are limited by high mortality, which is comparable to other pediatric lymphoma studies across SSA, and LTFU, which is low compared to other studies in the region.2,22,44,51,52This may have introduced survivorship bias in observed HRQoL improvements during active treatment and follow-up. However, among the 17 patients who completed surveys at all three timepoints, we observed substantial improvements across all HRQoL domains, except for two patients with relapsed disease. An additional limitation is the use of parent-proxy reporting for some children (35/140, 25%), as parents tend to report worse HRQoL than children self-report.35However, our sensitivity analysis without parent proxy-reported surveys showed that HRQoL mean domain scores did not significantly differ. Finally, raw PROMIS-25 scores were transposed to T-scores based on the Pediatric PROMIS reference population of children in the United States. As PROMIS is increasingly translated and incorporated into care throughout the world, region-specific reference populations will facilitate better interpretation of patient HRQoL scores. In our future work, we are developing voice-enabled tablet-based software to administer PROMIS-25 surveys without an intermediary to allow for a truly patient-reported measure in our low-literacy patient population.