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Reply to F.M. Muggia
- Corresponding author: Michael A. Bookman, MD, Arizona Oncology, 603 N Wilmot Rd, Suite 151, Tucson, AZ 85711
+ Author Affiliations
Muggia1 offers some interesting comments on our own editorial,2
and we appreciate the opportunity to briefly respond. Of note, we
believe that new approaches might actually take us further
than anticipated because of individualized therapeutic
decisions, early incorporation of synthetic lethality and immune
checkpoint
inhibition, exploitation of the peritoneal-tumor
microenvironment, and development of new molecular targets associated
with
drug resistance. However, these topics were clearly
beyond the scope of a short editorial regarding intraperitoneal (IP)
chemotherapy.
We also need to learn from the limitations,
as well as from the strengths, of prior clinical research. Whether IP
cytotoxic
chemotherapy should be a standard component of future
research should not simply be accepted, but should be based on ongoing
scientific and clinical validation as well as
prioritization of limited resources. In this regard, we should aspire to
move
beyond citing pharmacologic advantage, which is
conveniently measured within the peritoneal infusate, but is of
uncertain
relevance to the tumor or host. We need to broadly
consider the complex biologic and clinical implications of drug exposure
within the tumor microenvironment, a unique feature of
this disease.
It is worth remembering that none of the
reasonable modifications to the IP regimen of the GOG-0172 trial have
been validated
in a prospective randomized trial, and there are no
data to support that IP administration of cisplatin 75 mg/m2,
or that substituting IP carboplatin (area under the curve = 6) or
changing the paclitaxel dose and schedule, will be superior
to treatment with a standard intravenous
platinum-taxane therapy. This could be especially relevant if the
pharmacologic advantage
is a truly critical determinant of long-term outcomes.
In addition, primary intravenous therapy has evolved from the GOG-0172
trial to include the substitution of carboplatin and
the potential incorporation of dose-dense, weekly paclitaxel or
bevacizumab.
It is clear that we need to make appropriate
adjustments in IP treatment delivery, but this would be much easier to
accomplish
if we understood the targets and mechanisms of IP
chemotherapy that are associated with clinical benefit.
The retrospective analysis of outcomes in
relationship to BRCA1 protein expression suggests prognostic value, and
these exploratory
data are of interest from the perspective of
hypothesis generation3;
however, these outcomes do not further validate the role of IP
chemotherapy, nor do they establish BRCA1 expression as a
predictive marker for IP chemotherapy. In addition,
low BRCA1 protein expression or alterations in BRCA2 or other genes
involved
in homologous recombination DNA repair, could be
prognostic factors for improved clinical outcomes in a number of
settings,
including nonplatinum chemotherapy and immunologic
interventions related to increased neoantigen expression in the setting
of high-level genomic diversity. Further details
should emerge from the GOG-0252 trial (NCT00951496), which incorporates genomic analysis for enrolled patients.
We still have much to learn from the past 20
years of debate regarding IP therapy, and look forward to clinical and
translational
data from the GOG-0252 and Intraperitoneal Therapy for
Ovarian Cancer With Carboplatin (NCT01506856) trials to sustain our interest over the next 10 years. Without doubt, Muggia1 will continue to remind us to address some of the most important clinical questions.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Reply to F.M. Muggia
The following represents disclosure
information provided by authors of this manuscript. All relationships
are considered compensated.
Relationships are self-held unless noted. I =
Immediate Family Member, Inst = My Institution. Relationships may not
relate
to the subject matter of this manuscript. For
more information about ASCO's conflict of interest policy, please refer
to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Michael A. Bookman
Employment: McKesson US Oncology Research
Honoraria: Genentech
Consulting or Advisory Role: Boehringer Ingelheim, Genentech, AstraZeneca, AbbVie, Sanofi, Novartis, Immunogen, Endocyte, Gradalis
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