DISCUSSION
Ever since Einhorn4 in
his seminal paper elucidated the role of multi-agent chemotherapy in
germ cell tumors in adults, it has formed the basis of treatment across
all age groups. The above regimen has been employed to paediatric GCTs
albeit with
modifications13, owing
to concerns about cumulative toxicities if given at the same schedule as
in adults. Precise comparison of outcomes in paediatric GCTs treated on
multimodality regimens across various trials has been fraught with
challenges because of its inherent heterogeneity, relative rarity and
lack of uniform risk stratification across major study
groups10. In
resource-limited countries, these tribulations are further compounded by
factors like flawed surgical approach in inexperienced centres leading
to imprecise staging, late presentation, significant attrition rate, and
higher incidence of sepsis-related deaths.
This retrospective study is an attempt to highlight the highly
favourable outcome of germ cell tumors especially in low and
intermediate risk groups treated at our centre. Our series showed an
overall bimodal distribution of tumors with a female preponderance which
is consistent with previous
experiences1,2.
This trend is secondary to higher incidence of ovarian tumors as
compared to testicular tumors in the adolescent age group. Extragonadal
tumors, especially those arising from mediastinum, however showed a male
predominance similar to that in earlier
studies3. In
literature1,13,14,
extragonadal tumors have been shown to be of slightly higher prevalence
as compared to gonadal counterparts because of inclusion of intracranial
GCTs as an extragonadal site. The occurrence of
extracranial-extragonadal GCTs was otherwise similar to that in our
cohort.
Notwithstanding the necessarily adaptive nature of our risk
stratification (Figure2), the outcomes of our cohort parallels the
results of similar
studies11,13,15,16.
Gonadal tumors had a better outcome as compared to extragonadal tumors.
Amongst ovarian GCTs, inability to ensure strict compliance to the
surgery guidelines can result in incomplete staging in up to 57%
patients17. Nearly 75%
patients in patients who were operated prior to presentation were
upstaged to stage III as a suitable compromise because of incomplete
surgical details.
Testicular tumors had an excellent outcome irrespective of the stage.
The adherence to high inguinal orchiectomy and diligent monitoring of
tumor marker trend post-operatively cannot be overemphasized in this
group as stage I tumors require only surgery. Several limitations exist
in extrapolating this approach to LMICs like lack of accurate tumor
marker measurement at presentation, inappropriate primary surgery often
at a non-oncological centre and non-compliant follow-up during
observation period. Nearly 3/4th of orchiectomies in our cohort were
performed prior to presentation of which only half were HIO. While there
was no statistically significant survival difference of because of this
flawed surgical approach, an Indian study in adult GCTs has reported
scrotal orchiectomy to be an adverse prognostic factor in testicular
GCT18. Several
investigators in the United States, Germany, France and United Kingdom
report a similar outcome in testicular GCTs irrespective of the
stage13,19-21.
Extragonadal tumors across all sites were found to be associated with
relatively dismal EFS, which was statistically significant on univariate
analysis (p<0.001) and a trend towards statistical
significance was noted on multivariate analysis (p–0.07). Baranzelli et
al in a study classifying all extragonadal tumors as high risk
demonstrated a 43% 3-year failure-free survival and 77% overall
survival rate, treated on a protocol comprising of alternating cycles of
Cyclophosphamide-Dactinomycin and
Vinblastine-Bleomycin-Etoposide22.
Recently, the outcomes of 165 extragonadal tumors treated on a more
contemporary protocol showed a 5-year EFS and OS as 79.0% and
83.4%,respectively with age ≥ 12 years and mediastinal site tumors
being poor prognostic
variables16. The
superior EFS of extragonadal tumors in the said cohort can be imputed to
the usage of high dose PEB in nearly half of the patients. Outcome of
sacrococcygeal tumors treated on a German Trial MAKEI
83/8623with total
cumulative doses of cisplatin and etoposide comparable to the former
study15, cite a 5-year
EFS of 76% with a better outcome in tumors with delayed but complete
tumor resection. Considering that the above chemotherapy
regimens15,23come with their share of significant toxicities, extending these
regimens to developing countries to achieve similar outcomes would be a
challenge. A high background prevalence of malnutrition and higher
incidence of both rectal carriage and bloodstream infection with
multi-drug resistant organisms are hurdles specific to LMIC countries,
that prevent this
extrapolation24,25.
Furthermore, dose intensification of chemotherapeutic agents that has
been described in phase I/II studies to improve outcomes in high risk
GCTs may not have the same applicability in LMIC
populations26.
Prognostic variables used for adult GCTs do not hold the same pertinence
in children on account of differences in histology, primary site and age
distribution27,28.
With an attempt to risk stratify malignant extracranial paediatric GCTs,
the Malignant Germ Cell Tumor International Collaborative (MaGIC) did a
recent meta-analysis on seven GCT trials, which identified age ≥ 12
years, ovarian stage IV disease and extragonadal stage III to IV disease
as conferring a significantly worse
prognosis29. Elevated
levels of pre-treatment AFP level, initially reckoned to be a poor
prognostic indicator was not linked to inferior outcome in this
meta-analysis22,30.
On implementing the MaGIC risk stratification to our cohort of malignant
GCTs (n=192)29, we
found that the SR-1 (Standard Risk – 1) subset had an unexpectedly
inferior survival compared to SR-2 (Standard Risk – 2). While all the
31 patients in SR-2 had ovarian GCT and none had extragonadal GCT,
78/136 (57.4%) SR-1 patients had tumors in extragonadal sites. Though
this association was not statistically significant, we presume that a
higher frequency of unfavourable site tumors adversely influenced the
survival in SR-1. The lack of association of age in our cohort could
also be due to fewer numbers of patients aged over 11 years in our
study.
Both PEb and JEb regimens in our cohort was reasonably tolerated with a
toxicity profile akin to published
studies15,21,23.
There was no survival difference between the two regimens in our cohort
as is reported in
literature31. A few
patients, in whom hybrid regimen (PEb and JEb) was employed, had worse
outcomes. This could be attributed to the use of this hybrid regimen in
a relatively morbid cohort (extragonadal GCTs or large ovarian GCTs with
obstructive uropathy at presentation). Nonetheless, as outcomes were
similar on both JEb and PEb, we believe switching between either regimen
midway during treatment may not be a worthwhile strategy. While the
incidence of anaemia was higher in PEb regimen, the incidence of
neutropenia and thrombocytopenia was expectedly higher in JEb. The
incidence of myelosuppression and septic episodes noted in an Indian
study was substantially less, probably because of a longer cycle
interval (28 days) and a higher neutrophil count cut-off to administer
chemotherapy32.
Protocols employing carboplatin in lieu of cisplatin had a higher
incidence of non-fatal haematological toxicity but ototoxicity,
pulmonary toxicity and nephrotoxicity were
rare21. One child had
fatal bleomycin toxicity suggesting that although rare, even 1 day of
bleomycin in the regimen can be detrimental. Overt oto-toxicity or
nephrotoxicity was not found in any child, which could partly be
attributable to inconsistent gathering of data on audiograms of all
children and lack of a methodical long-term follow-up. Despite the
overall promising outcomes of GCTs in a resource-limited centre like
ours, we do understand the limitations that come with a retrospective
study and relatively less number of adolescent patients. A systematic
study encompassing long-term effects would be more capable of unmasking
the ostensibly absent nephrotoxicity, pulmonary toxicity and the
frequency of second malignant neoplasms.