2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

than other tumors in which consensus conference or metaanalysis
have already been conducted. 12-14 In the cervical
cancer, neoadjuvant chemotherapy followed by radical hysterectomy
improved survival compared with radiation alone.
But neoadjuvant chemotherapy followed by radiation therapy
negatively affected survival compared with radiation
alone, and the benefit of neoadjuvant chemotherapy followed
by radical hysterectomy has not been concluded in comparison
with radical hysterectomy. It has not been compared
with current standard, chemoradiotherapy. In prostate cancer,
neoadjuvant hormone therapy was proven to be effective
only when radiation therapy was applied afterward, but not
beneficial if surgery was conducted after antiandrogenic
therapy. 13 In breast cancer, neoadjuvant therapy was first
used, in the 1980s, typically for patients with inoperable
locally advanced or inflammatory breast cancer, and the
breast-conserving surgery rate dramatically increased. The
next step for the neoadjuvant therapy was to use it as an in
vivo test for chemosensitivity by assessing pathologic complete
response. Currently, by using pathologic response and
other biomarkers as intermediate end points, results from
trials of new regimens and therapies that use neoadjuvant
therapy are aimed to proceed and anticipate the results from
larger adjuvant trials. 12
In ovarian cancer, primary debulking surgery followed
by adjuvant chemotherapy is a gold standard procedure.
Although some investigators reported their favorable experience
of neoadjuvant chemotherapy followed by interval
debulking surgery, meta-analysis suggested that neoadjuvant
chemotherapy was associated with poorer outcome.
12,15,16 However, there had been no randomized trial
that prospectively demonstrated that primary debulking
surgery is better than neoadjuvant chemotherapy followed
by less-invasive interval debulking surgery. EORTC55971 is
the first prospective randomized study of advanced (stage
IIIC or IV) ovarian carcinoma, fallopian tube carcinoma, or
primary peritoneal carcinoma to compare overall survival
between patients who received standard primary debulking
surgery followed by chemotherapy and those who received
352
FUJIWARA, KATSUMATA, AND ONDA
Fig. 3. Study design of ICON8-
ENGOT OV-13 trial.
Abbreviations: AUC, area under the
curve; DPS, delayed primary surgery;
EOC, epithelial ovarian cancer; FTC,
fallopian tube cancer; IPS, immediate
primary surgery; PFS, progression-free
survival; PPC, primary peritoneal cancer.
neoadjuvant chemotherapy plus interval debulking surgery.
5 The majority of patients who entered this trial (n �
670) had extensive stage IIIC or IV disease at the treatment.
The largest residual tumor 1 cm or less in diameter was
achieved in 41.6% of patients after primary debulking and in
80.6% of patients after interval debulking. The HR for death
in the neoadjuvant chemotherapy group compared with the
primary debulking surgery group was 0.98 (90% CI, 0.84 to
1.13; p � 0.01 for noninferiority), and the HR for progressive
disease was 1.01 (90% CI, 0.89 to 1.15). Complete resection
of all macroscopic disease (at primary or interval surgery)
was the strongest independent variable in predicting overall
survival. Postoperative rates of adverse events and mortality
were higher after primary debulking than after interval
debulking.
This study raised considerable controversies 13,17-19 ; thus,
additional phase III trial(s) are necessary to clarify the
benefit of the neoadjuvant strategy. Fortunately, two prospective
randomized trials have already completed accrual,
one from the United Kingdom and another from Japan.
The United Kingdom trial CHORUS (Chemotherapy or
Upfront Surgery) is a randomized trial to determine the
impact of timing of surgery and chemotherapy in patients
with newly diagnosed stage III/IV ovarian, primary peritoneal,
or fallopian tube carcinoma. Study design is similar to
that of EORTC55971. The patients were randomly assigned
to receive either immediate primary debulking surgery followed
by six cycles of chemotherapy, or neoadjuvant chemotherapy
for three cycles followed by interval debulking
surgery, and then an additional three cycles of chemotherapy.
For patients assigned to receive neoadjuvant chemotherapy,
however, histologic or cytologic confirmation of
target diseases was necessary before starting treatment.
The target accrual was 550 and accrual has already been
accomplished. The data will be combined with EORTC55971
to reliably exclude a 5% to 6% difference in 3-year overall
survival. This trial accomplished enrollment and is waiting
for analysis.
JCOG conducted a randomized trial (JCOG0602) 20 in