DISCUSSION
This national retrospective demonstrated that stage, the use of
chemotherapy and an elevated serum AFP level at diagnosis were
independently predictive of overall survival. Additionally, female sex
was associated with a significantly lower risk of death (HR 0.284;
p-value 0.037). The MaGIC (Malignant Germ Cell Tumour International
Consortium) Study of 2015 revealed that stage, age and tumour site were
significant predictors of outcome but not sex (24). A recent
epidemiological study of paediatric germ cell tumours conducted in
Danish children revealed a similar female predominance (71%) but did
not show any relationship between sex and risk of death (33). Neither
histology nor nutrition were predictive of outcome in our cohort,
although in the MaGIC study yolk sac tumours were reported to have a
better outcome, although not found to be statistically significant (24).
In our study tumour stage was significantly predictive of outcome
(p<0.001), especially for patients with advanced disease
(Stage III (p=0.0171) and IV (p<0.001)). Our findings
therefore correlated with the MaGIC analysis which demonstrated a
statistically significant relationship between stage IV disease, and
poor outcome, particularly in children over 11 years of age with
advanced stage extragonadal tumours and metastatic ovarian tumours (24).
Earlier studies also documented that advanced disease was predictive of
poorer outcomes (16, 34).
In our cohort a serum AFP level at diagnosis of
>33,000ng/ml was associated with a poorer OS and a level of
> 21,000ng/ml associated with a poorer EFS (p = 0.044).
Previously, serum AFP levels of more than 100,000μg/L have been
associated poorer outcomes in children with hepatoblastoma (35). The
MaGIC analysis found that an elevated serum AFP level
>10,000 was associated with a poorer outcome but it did not
reach the definition for statistical significance (24). Alpha
fetoprotein as a tumour marker has been described as tumour-associated
rather than tumour-specific, given that its production can be elevated
in a variety of both benign and malignant conditions in children and
that the persistence of elevated levels acquired in utero, which
usually normalises by 10 months of age ex utero, can sometimes
persist until 2 years of age. The elevation of serum AFP levels cannot
therefore be considered diagnostic on its own and must be interpreted in
concert with other factors (36).
The MaGIC study was able to demonstrate a threshold of age (11 years)
beyond which outcomes were poorer using a bootstrap technique (24). We
interrogated the same question using age modelled as a penalised spline
because of our smaller sample size, and limiting it to patients with
more advanced disease, but could not demonstrate a threshold of age
beyond which outcomes were either more or less favourable.
In addition to female sex, higher household incomes, in excess of USD
23000 per year, was associated with a significantly lower risk of death
(HR0.071; p=0.039). We also showed a significant relationship between
lower stage disease and higher SES. (p=0.03). However, early
presentation alone could not account for this association. This suggests
that there are SES factors which may impact outcome during treatment.
For example, access to transport may cause delays in chemotherapy or
food insecurity may lead to malnutrition, negatively impacting immunity
and the ability to combat infection or tolerate chemotherapy-related
toxicity. Given our past of enforced racial segregation and the
association between skin colour and poverty, it is critical to isolate
these social determinants of health as skin colour is too easily invoked
as a risk factor, when in reality these relate to privilege and access
to care. In a large (n=3173) population-based study in adult men with
advanced stage prostate cancer in the US, in which ‘race’/ethnicity was
self-declared, socio-economic status together with clinical and
pathological factors accounted for a 15% increased relative risk which
was independently predictive of outcome in men of African-American
decent. The relationship, however, did hold true for Hispanic patients
on multivariate analysis demonstrating the sometimes tenuous
relationships between these factors and the necessity for the
identification of clear risk factors for outcome (31). In children with
acute lymphoblastic leukaemia a single institutional study reported a
higher risk of relapse in children from high poverty areas despite
uniform treatment (32). This is relevant given our intention to embark
on the implementation of a national treatment protocol for MEGCTs and
will be instructive as we interrogate household income and maternal
education as measures of SES. Also proving a significant relationship
between SES and outcome strengthens our collective call for parity not
only in service delivery and access to care but also for adequate social
support for children, which is constitutionally enshrined, but not
necessarily delivered in real time.
Analysis of our treatment interventions demonstrated that the surgical
local control rate in our study was high with a complete resection rate
64.8%. Although the numbers were small it is a notable that patients
who did not undergo re-exploration for negative imaging at first
assessment, and who therefore did not undergo second look surgery when
their imaging revealed no demonstrable disease, died. The critical role
of local control (surgery in the case of MEGCTs) in paediatric solid
tumours is incontrovertible and cannot be under-emphasized (37).
Additionally, there was a 5% surgical refusal rate which is a cause for
concern considering that half of those patients died of disease as a
result. In a systematic review of factors influencing refusal of therapy
in adult cancer patients, discomfort of treatment, fear of side effects
and transportation difficulties were cited as the most important
contributing to refusal of surgery (38). In a recent study from Vietnam
adherence to cancer treatment in children was found to be determined by
prognosis whilst being associated with local perceptions of cancer and
the economic power of affected families (39). It is possible that a more
rigorous informed consent and assent process such as that proposed for a
national treatment protocol may help to allay the fears associated with
paediatric cancer treatment specifically with respect to the surgery
which remains a cornerstone of care.
By comparison, the use of chemotherapy was strongly predictive of
outcome with no single regimen performing better than any other
(carboplatin vs. cisplatin-based) and all regimens producing superior
results compared to no chemotherapy at all (p<0.001). This is
corroborated by a recent MaGIC report demonstrating equipoise in
contemporaneous trials using cisplatin compared to carboplatin-based
regimens in paediatric germ cell tumours (19).
Radioisotope GFR measurement is recommended as part of the standard of
care guidelines for renal function assessment in paediatric oncology
practice as it impacts the dosing of platinum alkylators. As such
standardising methodologies is critical (40). Rates of formal GFR
assessment (even in the absence of radio-isotope instruments) and also
audiology assessment were infrequent, which is related to the lack of
availability of or access to these services at all POUs across the
country, as well as the large burden of patients presenting with
advanced disease, whose poor performance status (renal or pulmonary) may
preclude radioisotope testing at the time diagnosis. Similarly, the use
of calculated GFRs was low in the absence of formal radio-isotope
testing. In a more recent study calculated GFRs were found to either
over or underestimate the GFR. The recommendation was that radioisotope
GFR determination should remain standard of care for platin dosing to
ensure accuracy (41). Unfortunately, this may not always be possible in
our setting and a calculated GFRs may be the best method to determine
glomerular function when no radio-isotope determination is available.
The value of calculated versus radioisotope GFR measurement can be
prospectively tested in the context of a national protocol and
calculated GFRs as a surrogate for more accurate renal function
evaluation could become standardised practice.
In addition, to renal function assessment, significant numbers of
hearing-impaired children may have evaded detection because of low rates
of routine audiology testing which has the potential to impact school
performance and subsequently employability. This is notable because the
unemployment rate for the hearing impaired in South Africa ranges from
21.2% - 35.3% with low average annual household incomes of
approximately 2000 USD for the moderately hearing impaired and 1500 USD
for those with severe deficits (42), placing them close to the upper
limit poverty line of 800USD per household per year (43).
Treatment-related mortality was low. Three patients died from
infections, two from chemotherapy toxicity and one from surgical
complications. Although a small number of complications is likely to be
inevitable, it would be instructive to determine whether the rate of
complications can be reduced with the implementation of a standardised
chemotherapy and surgical guidelines. Despite this, the 5-year OS for
the entire cohort was very encouraging (80.4%) and patients who
relapsed were salvaged (5-year EFS 75.3%).
We recognise that the sample size and hence the number of events were
small and that this could have limited the statistical power to detect
significant effects. Different treating centres made use of
institutionally specific treatment protocols, often determined by
resource constraints. Where space and bed capacity were at a premium,
outpatient approaches, like JEb was favoured over inpatient regimens
like BEP or PEb. Access to formal radio-isotope testing and audiology
testing was fragmented across POUs, limiting the accurate assessment of
renal function for platin dosing and hearing assessments.
This retrospective analysis was undertaken to assist with the
development of a national protocol for children with MEGCTs in South
Africa to standardise management and toxicity assessments. In the new
national protocol the choice of platinum will be influenced by several
factors: firstly, previous local reports of the cost effectiveness of
JEb as an outpatient strategy (22) and the significant relationship
between SES and outcome reported here; secondly, the rates of
platin-related ototoxicity reported here and that under-testing has
potentially resulted in a failure to detect significant numbers of
hearing impaired children, and; lastly, the availability of audiology
services and nuclear medicine facilities which are not ubiquitously
available and tend to be clustered near larger POUs in wealthier urban
areas.
In addition, the finding of significant relationships between serum AFP
levels and SES opens opportunities for the interrogation of these
factors in a prospective way in the context of the new protocol as we
seek to provide guidance for best practice and as we advocate for social
justice in medicine. Creating the discipline of standardised practice by
teams with disease-specific expertise able to collaborate across
institutional divides will improve paediatric oncology care in South
Africa. Thereafter, we can advocate for the establishment of bilateral
funding agreements, to open doors to children and families from across
the sub-continent to receive expert, coordinated care at our national
centres of excellence.