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\begin{document}

\title{Treatment of high-risk Hodgkin Lymphoma with a modified Stanford V
regimen in the AHOPCA: substituting chemotherapy agents and hampered
outcomes}



\author[1]{Sandra Luna-Fineman}%
\author[2]{Mauricio Castellanos}%
\author[3]{Metzger M}%
\author[4]{Fulgencio Baez}%
\author[5]{Armando Peña Hernandez}%
\author[6]{Miguel Bonilla}%
\author[6]{Soad Fuentes Alabi}%
\author[7]{Rosa Nieves}%
\author[2]{Jessica Blanco}%
\author[8]{Emanuela Rossi}%
\author[9]{Meenakshi Devidas}%
\author[9]{Yichen Chen}%
\author[2]{Magda Arreola}%
\author[10]{Pedro de Alarcon}%
\affil[1]{University of Colorado Anschutz Medical Campus}%
\affil[2]{Unidad Nacional de Oncologia Pediatrica}%
\affil[3]{Medecins Sans Frontieres}%
\affil[4]{Oncología Pediátrica}%
\affil[5]{Hospital Escuela Universitario}%
\affil[6]{Hospital Nacional De Ninos Benjamin Bloom}%
\affil[7]{Hospital Infantil Robert Reid Cabral}%
\affil[8]{Universita degli Studi di Milano-Bicocca Dipartimento di Medicina e Chirurgia}%
\affil[9]{St Jude Children's Research Hospital}%
\affil[10]{University of Illinois Chicago College of Medicine}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\selectlanguage{english}
\begin{abstract}
Background/Objectives: High-risk Hodgkin lymphoma (HRHL) in children is
a curable with combined modality therapy. The AHOPCA is a consortium of
cancer centers from Central America. In 2004, AHOPCA implemented a
guideline with a short course of chemotherapy (mStanfordV), strict
diagnostics and radiation guidelines, aimed at reducing abandonment and
improving outcomes. Methods: Newly diagnosed children less than 18 years
of age with high-risk HL (Ann Arbor stages: IIB, IIIB, IV) from AHOPCA
centers were staged with chest X-ray, and ultrasound or CT. Therapy was
a modified StanfordV (mStanfordV) substituting cyclophosphamide for
mechlorethamine and involved field radiation. Results: Of 219 patients
with HRHL, 181 patients were eligible and evaluable;146 (81\%) were
boys, 22\% being less than 6 years; 43 were stage IIB, 84 IIIB and 54
IV. Thirty-one (17\%) abandoned therapy, 28 (15\%) progressed, 30 (17\%)
relapsed and 8 (4\%) died of toxicity. Radiation guidelines were not
followed. Five-year abandonment-sensitive event-free survival and
overall survival (AS-EFS, AS-OS\selectlanguage{ngerman}±SE) for the cohort were 46±4\% and
56±4\%; 5-year AS-OS for stages IIB, IIIB and IV was 76±7\%, 59±7\%, and
35±7\% (p=0.0006). Conclusion: Despite instituting a short treatment
guideline, it did not improve the abandonment rate (17\%) and did not
achieve the reported outcomes of StanfordV. The cyclophosphamide dose
used to replace merchlorethamine was inadequate. Despite strict
guidelines, the radiation therapy application was inaccuarate. Weekly
chemotherapy may have adversely affected abandonment of therapy by
increasing the burden of travel-time. Based on these results, AHOPCA
established a new abandonment strategy and a new guideline.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{INTRODUCTION}

Hodgkin Lymphoma (HL) is one of the most prevalent tumors (9\%) treated
at the Association of Pediatric Hematology-Oncology of Central America
(AHOPCA), a childhood cancer network of pediatric cancer centers from
Central America, Dominican Republic, and Haiti\textsuperscript{1}. This
network designs uniform treatment guidelines, for children with cancer
diagnosed at the individual centers. Over time, AHOPCA has studied
baseline treatment outcomes for different pathologies in the region, and
has addressed unique psychosocial needs in low- and middle income
countries (LMIC)\textsuperscript{1,2}. Because radiation therapy is not
easily accessible in every country in Central America, the AHOPCA Center
in Nicaragua designed a chemotherapy only regimen consisting of four
cycles of cyclophosphamide, vincristine, prednisone and procarbazine
(COPP) for patients with early stage HL and two to four additional
courses of chemotherapy consisting of doxorubicin, bleomycin and
vinblastine (COPP/ABV) for advanced stage HL\textsuperscript{3}. Based
on encouraging results for this regimen, AHOPCA implemented a
chemotherapy-only treatment guideline\textsuperscript{4}: AHOPCA LH-1999
using the same risk assessment and treatment schema for all subjects
presenting to an AHOPCA Center. Castellanos et al reported an event-free
survival (EFS) of 60\% regardless of risk assignment\textsuperscript{4}.
However, the EFS for patients with Ann Arbor stage IV HL was only 20\%.
This report identified two critical factors that influenced the poor
outcomes: abandonment of therapy (13\%), accuracy of diagnosis and
appropriate staging\textsuperscript{4}.

To improve survival, improve diagnostic accuracy and reduce abandonment,
AHOPCA introduced in 2004 three risk groups, low, intermediate, and high
with strict staging and risk assignment criteria, response assessment
and clear radiation therapy guidelines. AHOPCA hypothesized that a
regimen that could be administered over a short period of time (to
prevent abandonment), that had an established low toxicity profile with
lower anthracycline dose (150mg/m\textsuperscript{2}), and low
infertility\textsuperscript{5}, would be effective in a resource-limited
setting. Based on the excellent results reported with the Stanford V
regimen\textsuperscript{5} \textsuperscript{6}, a short 12-week course
of chemotherapy with doxorubicin, vinblastine, vincristine, bleomycin,
etoposide, prednisone and mechlorethamine and 36 Gy radiotherapy to
bulky sites of disease (\textgreater{} 5cm) at diagnosis. AHOPCA adopted
this regimen as a treatment guideline for children presenting with
pre-defined high-risk HL (HRHL). In 2004 there was a world-wide shortage
of merchlorethamine\textsuperscript{7}, leading AHOPCA to modify the
treatment regimen substituting merchlorethamine with cyclophosphamide at
a dose that was expected to be an equipotent substitution. Furthermore,
radiation therapy was modified to (20-25 Gy) involved field in order to
limit radiation-related long-term effects\textsuperscript{8-10}. We
report here the experience of AHOPCA with this regimen, AHOPCA HRHL 2004
(mStanford V), as applied between August 2004 and August 2009.

\textbf{METHODS}

The treatment guidelines were implemented as standard of care and not
research, as the adaptation was felt to be necessary to fit the
resources of the region. The guidelines were approved according to
institutional requirements, and general treatment consent was obtained
from the legal guardians.

\emph{Subjects}

AHOPCA HRHL 2004 enrolled subjects between January 2004 and August 2009.
Consecutive patients, less than 18 years of age, with histologically
confirmed previously untreated high-risk (Table 1s); defined as modified
Ann Arbor stages IIB, IIIB and IV, irrespective of bulky disease
{[}mediastinum \textgreater{} 1/3 diameter, or peripheral lymph nodes
greater then 6cm{]}) HRHL (classical and nodular lymphocyte predominant)
presenting to one of the AHOPCA centers (El Salvador, Guatemala,
Honduras, Nicaragua and Dominican Republic), were treated according to
the guidelines and are the subject of this report. Patients previously
treated for HL or seropositive for the human immunodeficiency virus were
excluded. As a treatment guideline to improve quality of diagnosis and
treatment, all countries consented for therapy according to the local
policies.

Prior to starting therapy, all patients underwent a complete medical
history, physical examination and evaluation by imaging and laboratory
studies consisting of complete blood cell count, erythrocyte
sedimentation rate (ESR), blood chemistries including renal and liver
function studies, and albumin. All underwent an excisional biopsy from
an easily accessible lymph node or a ``trucut'' biopsy of the
mediastinum or abdominal mass. Pathology was reported for El Salvador,
Guatemala and Dominican Republic with immunohistochemistry's (CD30,
CD15, CD20) to confirm diagnosis of HL (classical histology or nodular
lymphocyte predominant). Honduras and Nicaragua reported diagnosis using
morphology only. Patients with B symptoms or advanced disease had a
bilateral bone marrow biopsy performed.

\emph{Imaging and Laboratory Evaluation}

Imaging studies included two-view chest x-ray, contrast enhanced neck,
chest, abdominal and pelvic computed tomography (CT). Patients who could
not have a CT scan (they were too ill, or CT was not available) had an
evaluation with an ultrasound of the neck, axilla, abdomen, pelvis and
inguinal regions. There was a response assessment at the end of 12-week
chemotherapy and after completion of radiation therapy.

\emph{Treatment Regimen}

The mStanford V regimen (Table 2s) consisted of chemotherapy for 12
consecutive weeks followed by involved-field radiation therapy (IFRT).
The chemotherapy was: prednisone 40mg/m2 orally divided bid every other
day for 10 weeks followed by a 2 week taper, doxorubicin 25
mg/m\textsuperscript{2} and vinblastine 6 mg/m\textsuperscript{2} on
weeks 1, 3, 5, 7, 9 and 11; cyclophosphamide 600
mg/m\textsuperscript{2}on weeks 1, 5 and 9; vincristine 1.4
mg/m\textsuperscript{2} (maximum of 2mg) and bleomycin 5
UI/m\textsuperscript{2} on weeks 2, 4, 6, 8, 10 and 12 and etoposide 60
mg/m\textsuperscript{2} on days 1 and 2 of weeks 3, 7 and 11. The
modification from the original StanfordV regimen\textsuperscript{7},
consisted of the substitution of cyclophosphamide 600
mg/m\textsuperscript{2}/dose, instead of mechlorethamine
6mg/m\textsuperscript{2}/dose. Radiation therapy (cobalt unit or linear
accelerator) was administered to all originally involved sites of
disease according to their response to chemotherapy at either 2000cGy to
the sites that achieved an anatomic complete remission (\textgreater{}
80\% reduction of the sum of the perpendicular diameters or return to
normal size lymph nodes) or 2500cGy to the sites that did not achieved a
complete remission. Chemotherapy was held for 1 week if ANC was less
than 1000 and/or platelets less than 100,000 on the weeks that included
doxorubicin. All patients received pneumocystis jovenci prophylaxis with
trimethoprim/sulfamethoxazole. Some units were able to give filgrastim
to patients with prolonged neutropenia and infection at the discretion
of the local teating physician and availability of the drug. All members
met weekly by video conference through www.cure4Kids.org to discuss
problem cases.

\emph{Response Criteria}

Two weeks after completion of chemotherapy, all subjects had imaging
studies to evaluate response. We defined the level of response as: a
complete remission (CR) if there was complete disappearance of all sites
of disease (as evaluated by physical examination and imaging studies)
and B symptoms. Partial remission (PR), defined as disappearance of all
constitutional symptoms and decrease of [?] 50\% of the sum of the product
of two perpendicular diameters of all lesions present at diagnosis and
no appearance of new lesions. No response (NR) defined as no change or
\textless{}50\% decrease in the product of two perpendicular diameters
of any lesion present at diagnosis without new lesions. Progressive
disease (PD), defined as increase of [?] 50\% of the product of two
perpendicular diameters of any lesion or the appearance of new lesions
during therapy or within 3 months of end of radiation therapy. Relapse
(R), defined as appearance of new lesions after 3 months from end of
radiation therapy confirmed by biopsy in most cases.

\emph{Data Management and Statistical Analysis}

Data were collected prospectively and entered by the local center's data
manager into the database POND (Pediatric Oncology Network
Database)\textsuperscript{11} (this database was retired in 2019). Data
frozen as of December 31\textsuperscript{st} 2017 are included in this
report. The data were reviewed and confirmed by the primary country team
and the PI, with constant quality reviews. Abandonment of therapy was
defined as failure to return to continue treatment for 4 weeks or
more\textsuperscript{12}. Lost to follow-up was defined as 2 years from
the end of therapy. Upfront refusals were excluded from the analysis.

Primary outcomes were abandonment-sensitive event-free survival (AS-EFS)
and abandonment-sensitive overall survival (AS-OS)\textsuperscript{13}.
AS-EFS was defined as the time from date of diagnosis to date of first
event (progressive disease, relapse, abandonment, or toxic death) or
date of last contact for those who were event-free. AS-OS was calculated
as time from diagnosis to abandonment or death, or last contact for
those still alive. In addition, EFS and OS rates censoring abandonment,
were also calculated. Survival rates were estimated using the
Kaplan-Meier method with standard errors of Peto et
al\textsuperscript{14,15} The two-sided log-rank test was used for
comparison of survival curves. P-values \textless{}0.05 were considered
statistically significant for all comparisons. All analyses were
performed using SAS\selectlanguage{ngerman}® version 9.4. Graphics were generated using R
(http://www.R-project.org, version 4.1.1).

\textbf{RESULTS}

\emph{Demographics}

A total of 219 patients with HRHL were referred to the participating
AHOPCA centers. Seven patients were not eligible because of prior
therapy (n=6) or being HIV positive (n=1). Thirty-one were not
evaluable: 20 treated with a different regimen, 6 refused therapy, 4 had
a wrong stage, and 1 died before starting therapy. One hundred
eighty-one patients were evaluable for this report (Figure 1).

Table 1 summarizes demographic data for all subjects. The median age at
presentation was 9 years (range 3-18 years). Twenty-two percent (n=39)
of subjects were younger than 6 years of age at diagnosis, 37\% were
ages 6 to 10 (n=67) and 41\% (n=75) were 10 or older. There were 146
(81\%) males. The predominant histologic subtype was mixed cellularity
in 80 (44\%), followed by nodular sclerosis 77 (43\%), lymphocyte
predominant in 11 (6\%), lymphocyte depleted in 6 (3\%) and in seven
(4\%), the histologic subtype was not specified. The distribution of
stage at diagnosis was stage IIB 43 (24\%), IIIB 84 (46\%), IVA 4 (2\%)
and IVB 50 (28\%).

\emph{Chemotherapy and response}

Of the 181 patients, thirty patients did not complete chemotherapy: 21
abandoned therapy, 7 died during therapy (6 infection and 1 PD), and 2
PD (taken off protocol). 151 patients proceeded to response evaluation;
of them 66 (44\%) had CR, 71 (47\%) had PR, 4 (3\%) had PD (taken off
therapy), and 10 (7\%) did not report the response evaluation (Table 2).

\emph{Radiation therapy}

Of the 151 patients who continued on therapy, the 4 had PD, 1 progressed
while waiting for radiation, 1 relapse (refused radiation and relapsed
11 months after the end of chemotherapy), and 8 abandon therapy after
response evaluation were taken off protocol therapy (Figure 1). Of the
137/151 (91\%) who proceeded to receive radiation therapy after
chemotherapy, 110 (80\%) received radiation therapy on time, 25 (18\%)
started radiation more than 2 months after completion of chemotherapy, 2
(2\%) abandoned therapy during radiation. Of the 135 who completed
radiation, 16 (12\%) did not get radiation to all involved sites.
Forty-eight (36\%) were given the incorrect dose: 39 (29\%) was too high
(2700-5040cGy), and 9 (7\%) too low (1500-1800CGy). Of the 87 who
received radiation within the correct dose range: 11 received the
incorrect dose assigned according to CR (n=8) or PR (n=3).

\emph{Abandonment of therapy}

A total of 31/181 (17\%) patients abandoned therapy: 21 during
chemotherapy, 8 before radiation therapy, and 2 during radiation
therapy. Of the 31, 19 (61\%) patients never returned. Of the twelve
that returned: 8 returned in relapse or progressive disease. Among these
12, five restarted mStanfordV therapy (chemotherapy and radiation) and
one received only radiation. Last status of these 12 returned patients
are: 6 expired (4 months to 7 years from diagnosis), 2 abandoned therapy
second time (17 and 33 months from diagnosis to last contact), 1 lost to
follow-up in CR (5 years from diagnosis to last contact), and 3 alive (8
to 11 years from diagnosis to last contact).

\emph{Toxic deaths}

Of the 181 patients that started therapy, 8 (4\%) had a toxic death
event. Of these, 7 were during chemotherapy, and one expired after
radiation therapy. There were delays in chemotherapy, but none more than
2 weeks; except 1 patient who changed to a different protocol (at the
investigator's choice) as the family could not attend weekly.

\emph{Outcomes}

Of The 181 patients who started therapy, 135 completed chemotherapy and
radiation therapy. Of the 181 patients, 97 (54\%) experienced an AS-EFS
event: 31 (32\%) abandoned therapy, 28 (29\%) progressed, 30 (31\%)
relapsed and 8 (8\%) died of toxicity. The median follow-up for the
patients who are alive and have not abandoned therapy, is 8 years (range
0-12 years).

The 5-year AS-EFS and AS-OS for the 181 eligible and evaluable patients
were, 46 ± 4\% and 56 ± 4\%, respectively (Figure 2A). The 5-year EFS
and OS for the cohort, were 54 ± 5\% and 69 ± 4\% , respectively (Figure
2B). The 5-year AS-EFS rates by stage were: stage II 65 ± 8\%, stage III
52 ± 7\%, and stage IV 22 ± 6\% (p=0.0001) (Figure 3A). The 5-year AS-OS
rates by stage were: stage II 76 ± 7\%, stage III 59 ± 7\%, and stage IV
35 ± 7\% (p=0.0006) (Figure 3B). When abandonment is censored, 5-year
EFS rates by stage were: stage II 73 ± 8\%, stage III 62 ± 7\% and stage
IV 25 ± 7\% (p\textless{}0.0001) (Figure 4A); 5-year OS rates by stage
were: stage II 87 ± 6\%, stage III 74 ± 6\%, and stage IV 43 ± 8\%
(p\textless{}0.0001) (Figure 4B).

\textbf{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) reported\textsuperscript{4}, but younger than the median age of
15.8 years reported by the Children's Oncology Group
(COG)\textsuperscript{16} and median age of 14.8 years from the EuroNet
PHL-C1\textsuperscript{17}. 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\%)\textsuperscript{16,17}. The predominant
histology (44\%) was mixed cellularity, which is higher than the 6\%
reported by the COG\textsuperscript{16}.

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
group\textsuperscript{17} and none COG study\textsuperscript{16}.

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 report\textsuperscript{4}. 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
previously\textsuperscript{18}.

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 \textsuperscript{4}. However, the current
report has a higher proportion of subjects with stage IV disease (30\%)
than the previous report (5\%)\textsuperscript{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 \textsuperscript{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 adults\textsuperscript{5,6} and
most recent report in children\textsuperscript{7}.

Due to the worldwide shortage of mechlorethamine, a drug modification of
Stanford V, using cyclophosphamide at 600mg/m\textsuperscript{2} was not
equipotent to the doses used in the original regimen. As reported by
Metzger et al\textsuperscript{7}, 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
expensive\textsuperscript{20}. 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 regimens\textsuperscript{21-24} 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\%\textsuperscript{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 \textsuperscript{25,26}; and have
implemented a new therapeutic approach to improve EFS and OS in children
with HRHL\textsuperscript{27}.

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
Cure\emph{ALL} 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
survivorship\textsuperscript{28}(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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\textbf{Figure Legends}

\textbf{Figure 1} . AHOPCA LH 2004 High-Risk Consort Diagram

\textbf{Figure 2.} Survival curves for entire cohort. \textbf{Panel
A:}5-year AS-EFS and AS-OS curves. \textbf{Panel B:} 5-year EFS and OS
curves.

\textbf{Figure 3.} AS-EFS and AS-OS curves by stage II, III and
IV.\textbf{Panel A:} 5-year AS-EFS by stage II, III and IV.
\textbf{Panel B:} 5-year AS-OS by stage II, III and IV.

\textbf{Figure 4.} EFS and OS curves by stage II, III and
IV.\textbf{Panel A:} 5-year EFS by stage II, III and IV. \textbf{Panel
B:}5-year OS by stage II, III and IV.

\textbf{Hosted file}

\verb`AHOPCA LH 2004 Figures PBC 6-26-23.docx`  available at \url{https://authorea.com/users/457823/articles/651932-treatment-of-high-risk-hodgkin-lymphoma-with-a-modified-stanford-v-regimen-in-the-ahopca-substituting-chemotherapy-agents-and-hampered-outcomes}

\textbf{Hosted file}

\verb`AHOPCA LH 2004 Tables PBC 6-26-23.docx`  available at \url{https://authorea.com/users/457823/articles/651932-treatment-of-high-risk-hodgkin-lymphoma-with-a-modified-stanford-v-regimen-in-the-ahopca-substituting-chemotherapy-agents-and-hampered-outcomes}

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