2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Table 1. Pharmacologic Advantage for Intraperitoneal
Chemotherapy
Drug Molecular Weight
IP cisplatin. In the 546 eligible patients, the estimated
median survival was substantially longer in the IP group (49
months) compared with the IV group (41 months). The HR
for the risk of death was 0.76 (p � 0.02) in favor of IP
therapy. Although moderate to severe abdominal pain was
more frequent in the IP group, likely related to the catheter
and volume of infusate, grade 3/4 granulocytopenia and
tinnitus, clinical hearing loss, and grade 2 to 4 neuromuscular
toxic effects were markedly more frequent in the IV
group. This is the “purest” of the IP trials to date as it used
the same drugs and same doses in both arms with only the
route of administration being different. Despite the benefits
observed in this trial, IP therapy was not widely embraced
by the gynecologic oncology community at the time of this
publication. This may be because of the publication in the
same year of the benefits of paclitaxel in patients with
suboptimally debulked disease. 9
A second IP trial was also conducted by GOG (GOG #114)
and Southwest Oncology Group (SWOG #9227). In this trial
426 patients were randomly assigned to receive either IV
paclitaxel 135 mg/m 2 over 24 hours followed by IV cisplatin
75 mg/m 2 every 3 weeks for six cycles or IV carboplatin
(AUC 9) every 28 days for two cycles followed by a regimen
of IV paclitaxel 135 mg/m 2 over 24 hours followed by IP
cisplatin at 100 mg/m 2 every 3 weeks for six cycles (eight
total cycles of chemotherapy). 10 This study demonstrated an
improved progression-free survival (median, 28 vs. 22
months; HR � 0.78; p � 0.01) and overall survival (median,
63 vs. 52 months; HR � 0.81; p � 0.05) in favor of the IP
KEY POINTS
Ratio of Drug AUC,
Peritoneal Cavity/Plasma
Cisplatin 300 12
Carboplatin 371 10–18
Topotecan 458 54
Docetaxel 862 181
Gemcitabine 300 759
Paclitaxel 854 1,000
Abbreviation: AUC, area under the curve.
Adapted and modified from Markman 3 and Fujiwara et al. 4
● Current recommendations for intraperitoneal (IP)
therapy are for patients with disease optimally debulked
after initial surgery.
● Three North American randomized phase III trials
comparing IP with intravenous therapy have demonstrated
substantial improvement in progression-free
and overall survival.
● Cisplatin is the mainstay of IP platinum treatment
but a recently completed trial (GOG 252) is the first to
use IP carboplatin in an arm of a randomized phase
III trial.
● IP therapy after neoadjuvant therapy and interval
debulking is currently being tested.
● IP therapy has not been rigorously tested for patients
with recurrent disease.
346
ARMSTRONG, FUJIWARA, AND JELOVAC
group. Toxicities grade 3 or worse, including neutropenia,
thrombocytopenia, and GI and metabolic toxicities, were
markedly more frequent in the IP group. As a result, 18% of
the patients on the IP arm received fewer than two courses
of IP therapy. Despite the substantial survival improvement
in this study, the gynecologic oncology community again did
not accept IP chemotherapy as standard treatment for ovarian
cancer. Many attributed the benefits seen in the experimental
arm to patients receiving eight cycles of therapy or to the
intensive carboplatin rather than the IP therapy.
The third trial was conducted by GOG (GOG #172). In this
study 417 eligible patients with optimally debulked stage III
ovarian cancer were randomly assigned to receive IV paclitaxel
(135 mg/m 2 /24 hours) followed by IV cisplatin (75
mg/m 2 ) or IV paclitaxel (135 mg/m 2 /24 hours) followed by IP
cisplatin (100 mg/m 2 ), plus IP paclitaxel (60 mg/m 2 ) on day
8. 11 Treatments were repeated every 21 days for six cycles.
The median progression-free survival was 18.3 months in
the IV group and 23.8 months in the IP group (HR � 0.77,
p � 0.05). The median overall survival was 49.7 in the IV
group and 65.6 months IP group (HR � 0.73, p � 0.03). The
magnitude of improvement in median overall survival associated
with IP/IV administration of chemotherapy is similar
to that observed with the introduction of either cisplatin or
paclitaxel. The 66-month median survival for the IP arm of
GOG 172 is the longest survival reported to date from a
randomized trial of advanced ovarian cancer.
Once again, the data in support of IP therapy have not
resulted in widespread acceptance of the IP approach. Many
argued that it was the additional drug delivered in the IP
arm of GOG 172 that resulted in the improved outcome. This
is somewhat circuitous logic in that those doses of drug
cannot be delivered intravenously. The IP arm was designed
to be intentionally intense, exploiting the ability to administer
more drug per unit of time IP than can be delivered
with IV therapy.
There were substantially more patients with grade 3 and
4 leukopenia, thrombocytopenia, and GI toxicity, renal toxicity,
neurologic toxicity, fatigue, infection, metabolic toxicity,
and pain toxicity in the IP arm compared with the IV
arm. Because of these toxicities and/or catheter problems,
48% of patients in the IP arm received three or fewer IP
treatments, and only 42% patients received the planned six
cycles of IP therapy. Given that the study results are based
on an intent-to-treat analysis, modifications of the regimen
to improve tolerability could allow for improved completion
rates and possibly even better outcomes.
In a separate quality-of-life (QOL) analysis, patients who
received IP therapy had a worse QOL during therapy, but
there was no difference 1 year after completion of treatment.
12 We and others have shown that the GOG 172 IP
regimen can be administered successfully with a reasonable
toxicity profile when patients are appropriately selected and
the therapy is performed at an experienced center with the
assistance of a skilled and dedicated support staff. 13
Some have suggested that GOG 172 may overestimate the
benefit of IP therapy. Ozols and colleagues have reported on
a preliminary cross-trial analysis comparing the results of
IP therapy in GOG 172 with IV carboplatin/paclitaxel in
392 similarly staged patients in GOG #158, 14 calculating
that instead of the 15.9-month improvement in median
overall survival, the difference may be substantially less (8.2
months) if carboplatin/paclitaxel had been the comparative