DISCUSSION
We report herein the results of the AHOPCA LH 2004, a prospective
treatment regimen for children presenting with histologically proven
high-risk HL, Ann Arbor stages IIB, IIIB and IV, which accrued patients
from January 2004 through August 2009. The guideline offered a modified,
short and effective therapy (mStanford V) with the aim of limiting late
effects, improve outcomes and decreasing abandonment of therapy through
a faster chemotherapy regimen. However, abandonment of therapy continued
to be high at (17%) without improvement in survival: 5-year AS-EFS and
AS-OS were 46 ± 4% and 56 ± 4%; 5-year AS-EFS EFS by stage were stage
II 65 ± 8%, stage III 52 ± 7%, and stage IV 22 ± 6% (p=0.0001).
The AHOPCA LH 2004 cohort confirmed that HL in low and middle-income
countries (LMIC) presents at an earlier age that HIC. With a median age
at presentation of 9 years and 22% were less than 6 years of age, the
AHOPCA LH 2004 cohort was slightly older than the previous cohort (7.5
years) reported4, but younger than the median age of
15.8 years reported by the Children’s Oncology Group
(COG)16 and median age of 14.8 years from the EuroNet
PHL-C117. Moreover, percentage of very young children
(less than 6 years old: 22%; less than 10 years old 59%); and the high
proportion of males in our cohort (81%), differs from the proportions
reported in HIC (53-56%)16,17. The predominant
histology (44%) was mixed cellularity, which is higher than the 6%
reported by the COG16.
Most patients tolerated the mStanford V regimen well. However, the toxic
death rate (4%) is high, as one (0.0007%) reported bye EuroNet PHL-C1
group17 and none COG study16.
Our aim, to decrease abandonment of therapy using a therapeutic regimen
with a shorter duration and of easy administration, was not successful.
The rate of abandonment (17%) was higher than the 13% from our
previous report4. We hypothesized that a short course
of chemotherapy would be a relief for the families, and decrease
abandonment. However, having to come to clinic once a week, especially
for those that need to travel long, may be a stressor. So, despite the
shorter regimen and decreased toxicity, travel time may impact family
burden and increase abandonment of therapy, as described
previously18.
The 5-year AS-EFS of all patients on the current cohort is 46 ± 4%,
which is lower than the ten-year AS-EFS of 57±7% for the high-risk
group of our previous report 4. However, the current
report has a higher proportion of subjects with stage IV disease (30%)
than the previous report (5%)4. When we compared the
AS-EFS by stage, the AS-EFS in the current cohort is significantly
affected by the 17% abandonment, a prevalent and psychosocial reality
in many LMIC 18,19. However, if those patients who
abandon therapy are censored, the OS appears better than the previous
study: OS for stage II 87 ± 6%, stage III 74 ± 6%, and stage IV 43 ±
8% . Nonetheless, these results are inferior to the results reported
for the original Stanford V regimen in adults5,6 and
most recent report in children7.
Due to the worldwide shortage of mechlorethamine, a drug modification of
Stanford V, using cyclophosphamide at 600mg/m2 was not
equipotent to the doses used in the original regimen. As reported by
Metzger et al7, subjects treated with cyclophosphamide
on the modified Stanford V protocol, had a two-year EFS of 75% vs 88%
for those treated with mechlorethamine, impacting outcomes negatively.
Substituting chemotherapeutic drugs is a frequent practice in LMIC,
where essential medicines for childhood cancer are either not offered by
the country, are frequently in short supply, or are too
expensive20. To the best of our knowledge the
chemotherapy regimen was given in a timely manner, without deviation in
dosing or time in our cohort.
The second modification we introduced was reduction of the total dose of
radiation therapy from the original protocol (3600cGy). Although it is
possible that this substitution may have contributed to the poorer
results, other pediatric treatment regimens21-24 use
15 to 25 Gy in a response adapted fashion. The same treatment regimen
used by the St Jude - Dana-Farber-Stanford- consortium had a better
outcome than ours, utilizing radiation therapy doses of 1500-2500Gy
confirmed an EFS of 75%7. Our cohort suffered
significant deviations in regards to the radiation therapy
adminsitration. Twelve percent did not irradiate all involved sites, and
36% gave the incorrect dose. We did not assess the effect of dose or
field deviations from the guidelines. The variability of dose and the
delay in administration of radiotherapy could have affected EFS for our
cohort. Furthermore, 18% had a delay of greater than 2 months in
administration of radiation after end of chemotherapy; yet, we could not
demonstrate a statistical difference between those patients that
received their radiation therapy on time and those with a delay in
administration.
There are 2 important lessons learnt by this experience: a) the change
of chemotherapeutic agents of well-established and known regimens (due
to local or global shortage or stock-outs of drugs) may lead (as in this
guideline) to increased toxicity, more abandonment, and worse outcomes;
and b) access to radiation therapy for childhood cancer, with timely
planning and adequate dosing and administration are essential to
guarantee good clinical outcomes. These described failures pose a
significant weakness of the guideline study, where the regimen was
changed, not followed as written; and quality assurance not provided in
real-time.
AHOPCA continues to look to improve the survival outcome of their
patients and to decrease abandonment of therapy. To this effect, they
have developed group-wide and comprehensive psychosocial interventions
to decrease and understand abandonment 25,26; and have
implemented a new therapeutic approach to improve EFS and OS in children
with HRHL27.
We hope that the results of this guideline study, aiming to improve
outcomes, serves as an example for LMIC, that changes or adaptations of
regimens (due essential medicines shortage or lack of implementation of
WHO EML list in the country), can be detrimental. An organized and
systematic approach to childhood cancers with continuous evaluation of
outcomes and coordinated implementation science methods and strategies
can improve the lives of these children. This is why, in 2020, World
Health Organization (headquarters and the regional offices) in
conjunction with partners around the world (St Jude Global, St Jude
Children’s Research Hospital, and the International Society of Pediatric
Oncology [SIOP]), members of the multidisciplinary teams (pediatric
oncologists, surgeons, nurses, radiation therapists, psychologists,
etc.), advocacy organizations (SIOP, local non-governmental associations
that help families of children with cancer), and country governments
(through ministries of health and cancer control programs), have
instituted the Global Initiative for Childhood Cancer, using the
CureALL framework, to make comprehensive diagnosis, appropiate
treatment and continous outcomes measures, not only accessible, but
financially feasible for all children around the world, to be treated,
cared and supported, through their diagnosis of childhood cancer and
into survivorship28(https://apps.who.int/iris/handle/10665/347370).
Conflict of interest: the authors of this manuscript do not have any
conflict of interest.
Acknowledgements: We thank all the study coordinators, and all the data
managers of the participating institutions.
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