2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

the opportunity for regrowth of tumor cells between cycles of
chemotherapy.
Clinically, the benefit of dose-dense chemotherapy was
first proven in breast cancer. Two randomized phase III
trials on breast cancer showed improved survival benefit by
administering paclitaxel with weekly compared with every-
3-weeks administration. 7,8
In ovarian cancer, the Japanese Gynecologic Oncology
Group (JGOG) first demonstrated the survival advantage
of dose-dense weekly administration of paclitaxel. 9 In
JGOG3016, 637 patients were randomly assigned to receive
six cycles of either paclitaxel (180 mg/m 2 ; 3-hour intravenous
[IV] infusion) plus carboplatin (area under the curve
[AUC] 6 mg/mL/min), administered on day 1 of a 21-day
cycle (conventional regimen; n � 320), or dose-dense paclitaxel
(80 mg/m 2 ; 1-hour IV infusion) administered on days 1,
8, and 15 plus carboplatin administered on day 1 of a 21-day
cycle (dose-dense regimen; n � 317). The primary end point
was progression-free survival, and secondary end points
were overall survival and toxicity. A total of 631 patients
were eligible (dose-dense regimen, n � 312; conventional
regimen, n � 319). Median progression-free survival was
significantly longer in the dose-dense treatment group (28.0
months; 95% CI, 22.3 to 35.4 months) than in the conventional
treatment group (17.2 months; 95% CI, 15.7 to 21.1
months; hazard ratio [HR] � 0.71; 95% CI, 0.58 to 0.88; p �
0.0015). Overall survival at 3 years was higher in the
dose-dense regimen group (72.1%) than in the conventional
treatment group (65.1%; HR � 0.75: 95% CI, 0.57 to 0.98;
p � 0.03). Early discontinuation of the treatment was more
frequent in dose-dense group (n � 165) than in the conventional
group (n � 117) primarily because of the toxicities
(n � 113 vs. n � 69). The most common adverse event was
neutropenia (dose-dense regimen, 286 [92%] of 312 patients;
conventional regimen, 276 [88%] of 314 patients), but not
statistically different. The frequency of grade 3 and 4 anemia
was significantly higher in the dose-dense group (n �
214 [69%]) than in the conventional treatment group (n �
137 [44%]; p � 0.0001). The frequencies of other toxicities
including peripheral neuropathy were similar between
groups. On the basis of these results, it was concluded that
dose-dense weekly paclitaxel plus carboplatin improved sur-
KEY POINTS
● One trial of dose-dense chemotherapy (Japanese Gynecologic
Oncology Group [JGOG]-3016) has shown
significant improvement in progression-free survival
and overall survival in patients with advanced ovarian
cancer. Three confirmatory studies are ongoing
worldwide.
● One trial of neoadjuvant chemotherapy (European
Organisation for Research and Treatment of Cancer
[EORTC]) has shown that there was no substantial
difference in OS in patients with stage III/IV ovarian
cancer. Two confirmatory studies are ongoing worldwide.
● The role of dose-dense chemotherapy and neoadjuvant
chemotherapy will be clarified with solid highlevel
evidence in the near future.
350
FUJIWARA, KATSUMATA, AND ONDA
vival compared with the conventional triweekly administration
of paclitaxel with the cost of modest increase in
toxicities.
The result of this trial has markedly influenced the
designs of clinical trials, which were planned at the time the
JGOG3016 result was presented. The GOG252 trial was
scheduled to compare IV administration of paclitaxel (day 1)
plus intravenous carboplatin (day 1; arm 1) versus IV
paclitaxel (day 1) plus IP carboplatin (day 1; arm 2) versus
modified GOG172 trial winner regimen, which was IV paclitaxel
(day 1) plus IP cisplatin (day 2) plus IP paclitaxel
(day 8; arm 3) (see http://clinicaltrials.gov/ct2/show/
NCT01167712?term�GOG0262&rank�1 for trial information).
All three arms incorporated concurrent and
maintenance bevacizumab. Only arm 3 had administration
of paclitaxel on day 8. This was greatly criticized because
there might be a possibility that day-8 administration of
paclitaxel contributed to the improvement of overall survival,
not to the result of IP chemotherapy. Therefore, as
Bookman described in the Commentary, 10 “it should be
proven that the net contribution of weekly paclitaxel to the
overall survival advantage associated with intraperitoneal
therapy will hopefully be addressed in future studies.” In
fact, the GOG decided to incorporate weekly dose-dense
administration of paclitaxel into the two carboplatin arms.
Another scheduled IP trial was OV-20, a National Cancer
Institute of Canada/Gynecologic Cancer Intergroup (GCIG)
trial. The trial design of OV-20 was similar to that of
GOG252 trial, except that one of two IP arms would be
chosen by randomized phase II fashion, and they did not
combine bevacizumab. This trial design was amended to
incorporate day-8 administration of paclitaxel (not dosedense
weekly) for IV and IP carboplatin arms (arm 1 and
arm 2).
Another great movement among gynecologic oncology clinical
trials was to conduct confirmatory trials of dose-dense
chemotherapy. In addition to the confirmation of the same
dose-dense weekly regimen of paclitaxel, these trials try to
answer the following questions. The first is whether weekly
administration of carboplatin also contributes to improve
survival. The second question is whether simple division of
total dose of paclitaxel will demonstrate similar efficacy with
less toxicity.
At this time, three randomized trials are ongoing. The
GOG262 trial applied exactly the same trial arms—conventional
triweekly regimen of paclitaxel plus carboplatin—
although it only included stage III/IV patients. Use of
bevacizumab is patient choice (Fig. 1). This trial was closed
in early 2012. The second trial is MITO-7 study, led by the
Multicenter Italian Trials in Ovarian Cancer Group (Fig. 2).
This study compares the efficacy and toxicity of weekly
administration of carboplatin in addition to weekly administration
of paclitaxel. The dose of paclitaxel in the experimental
arm is 60 mg/m 2 instead of 80 mg/m 2 in the
JGOG3016 study. The dose of carboplatin in the experimental
arm is AUC 2 administered every week. This trial was
opened in 2008, and accrual of 800 patients was completed
recently. The third trial is an ambitious study conducted by
Integrated Community Oncology Network (ICON) and European
Network of Gynaecological Oncological Trial Groups
(ENGOT; Fig. 3). ICON8-ENGOT OV-13 is a three-arm trial
with conventional triweekly administration of paclitaxel
plus carboplatin as a comparator (arm 1), and two experi-