Comment

Dose-dense chemotherapy in advanced ovarian cancer

In The Lancet today, investigators from the Japanese
Gynecologic Oncology Group (JGOG) report results from
their phase 3 trial,1 showing benet from a dose-dense
(once weekly) schedule of paclitaxel compared with
standard dosing of once every 3 weeks in women with
newly diagnosed epithelial ovarian, fallopian, or primary
peritoneal carcinoma.
During the past 12 years, development of international
phase 3 trials has been facilitated through the Gynecologic Cancer InterGroup (GCIG).2 Collaborative trials
including more than 10 000 women have investigated
the substitution of docetaxel for paclitaxel,3 and the
addition of a third cytotoxic agent (gemcitabine, liposomal doxorubicin, epirubicin, or topotecan) without
improvement in long-term clinical outcomes compared
with standard-regimen carboplatin and paclitaxel.4
In the same period, our knowledge of the optimum
dose and schedule of paclitaxel has evolved. Longer
infusions (24 h) increase toxic eects to the mucosa and
bone marrow, but without improved ecacy.5,6 Shorter
infusions (<3 h) have fewer haematological toxic eects
than do the longer infusions, although high individual
doses can increase the risk of arthralgia or myalgia
and neuropathy. Weekly scheduling allows delivery
of a higher cumulative dose compared with standard
schedules, while keeping haematological toxic eects
and alopecia to a minimum. Importantly, this weekly
scheduling has activity in patients who have recurred
within 6 months of primary therapy with conventional
carboplatin and paclitaxel.7 Results of phase 3 trials
have established the superiority of weekly therapy in
women with breast cancer compared with less frequent
treatment.8,9 Biologically, inhibition of angiogenesis was
initially associated with low-dose weekly paclitaxel, but
this eect is also observed with other schedules.10
The optimum weekly dose to keep toxic eects to a
minimum, be most eective, and inhibit angiogenesis
is unknown. Results of phase 3 trials5,11 do not favour
intensied dosing in recurrent disease. In our clinical
practice, many patients receive 6080 mg/m per week
given consecutively for 3 weeks, with a 28-day cycle
interval. However, we nd that individual patients can
benet from doses as low as 40 mg/m per week.
Combinations of paclitaxel and carboplatin are well
tolerated, perhaps too much so. Patients can receive
www.thelancet.com Vol 374 October 17, 2009

full doses of both drugs, whereas other combinations

need individual dose reductions. This observation has
been attributed to a platelet-sparing eect of paclitaxel
on carboplatin-mediated thrombocytopenia, raising
questions about drug antagonism.12 Weekly therapy
could be preferable because it separates some of the
component dosing.
JGOG selected an experimental group, with dosedense paclitaxel at 80 mg/m per week (continuously),
achieving 240 mg/m per cycle. This schedule is dose
intense and dose dense, exceeding the usual dose
of 175 mg/m per cycle, and was associated with an
increased frequency of dose-limiting haematological
toxic eects, resulting in treatment delays and
modications, and a reduction in the delivered dose
intensity of carboplatin. On the basis of historical
data, dose intensity probably did not, but possibly
could, contribute to improved outcomes. A plausible
explanation is that the observed benet was related to
drug scheduling, and similar results might be achieved

Substitution of docetaxel for

paclitaxel: SCOTROC3

Stage

Number of
patients

IcIV

1077
538

10 (reference)

Docetaxel

539

097 (083113)

IIIIV

See Editorial page 1302

See Articles page 1331
See Seminar page 1371

Progression-free survival
(hazard ratio [95% CI])

Paclitaxel
Incorporation of a third cytotoxic
agent: GOG0182-ICON54

Published Online
September 20, 2009
DOI:10.1016/S01406736(09)61305-2

p=0707

4312

Carboplatin+paclitaxel

864

10

Gemcitabine triplet

864

1028 (09241143)

Gemcitabine doublet

861

1037 (09321153)

p=0503

PEG-liposomal doxorubicin

862

0984 (08841095)

p=0796

861

1066 (09581186)

p=0239

Topotecan doublet
Intraperitoneal chemotherapy:
GOG017213

Optimal III

415

Intravenous

210

10

Intraperitoneal

205

080 (064100)

Dose-dense weekly paclitaxel:

JGOG1

IIIV

p=0610

p=005

631

Carboplatin+paclitaxel

319

10

Dose-dense paclitaxel

312

071 (058088)

p=00015

Incorporation of bevacizumab:
GOG0218

IIIIV

1873
(total*)

Analysis in progress

MRC ICON7

IcIV

1528
(total*)14

Analysis in progress

PEG=polyethylene glycosylated. *Updated accrual numbers.

Table: Selected strategies to improve clinical outcomes in advanced-stage ovarian cancer

1303

Comment

with a dose of 60 mg/m per week, with improved

tolerability.
The biology of ovarian cancer in Japan is characterised
by a higher proportion with clear-cell histology than
is reported in western Europe or North America. An
analysis of hazard ratios conrmed the benet of dosedense therapy in Japanese women with serous tumours,
with uncertain eects in clear-cell tumours, and these
ndings should be generalisable to other countries. The
proportion of patients with clear-cell tumours in todays
study was lower than in other Japanese trials, in part
attributable to enrolment of patients with clear-cell
histology in other trials.
Overall, the JGOG study reported a lower rate of
optimum cytoreductive surgery than in US trials, and
women with stage II disease were included. However,
median progression-free survival was similar to that
in other studies. Although the groups were balanced
according to routine clinical prognostic factors,
reporting of the proportion of patients with no visible
(microscopic) residual disease after cytoreductive
surgery would have been useful, because these data are
a more robust predictor of clinical outcomes than are
macroscopic residual disease.
In todays study, physicians had much exibility about
timing of surgery, whether second-look surgery was
done, and duration of chemotherapy. These clinical
factors were not entirely balanced between groups, but
a sensitivity analysis showed no eect on progressionfree survival. Exclusion of potential bias is dicult, and
hence registration of physicians intent before patients
were randomly assigned would have been preferable.
Indeed, more eligible patients in the control group
received six or more cycles of chemotherapy (73%) than
did those in the dose-dense group (62%), even though
measurable response rates were similar, suggesting
that experimental treatment duration was limited by
haematological toxic eects.
The US Gynecologic Oncology Group has done
a phase 3 trial of intraperitoneal therapy that incorporated a second weekly dose of paclitaxel.13 The
net contribution of weekly paclitaxel to the overall
survival advantage associated with intraperitoneal
therapy will hopefully be addressed in future studies.
Possibly the antiangiogenic activity of weekly paclitaxel
will recapitulate some of the benet anticipated from
ongoing phase 3 trials with bevacizumab.
1304

Todays study is an important phase 3 trial and a

substantial achievement for JGOG, which will aect
future trial design and evolving standards of care. The
mature data for progression-free survival are highly
signicant (table), and are generally predictive of
overall survival in ovarian cancer. Conrmatory trials
are planned within member groups of GCIG to assess
once-per-week intravenous dosing, with and without
bevacizumab. The use of such dose-dense therapy
should be decided on an individual basis together with
other options for women with advanced-stage ovarian
cancer, including intraperitoneal therapy, neoadjuvant
treatment, or substitution of docetaxel.
Michael A Bookman
Arizona Cancer Center, Tucson, AZ 85724, USA
[email protected]
I thank Mark Brady, statistician, from the Gynecologic Oncology Group, for
updating the accrual numbers for the GOG0218 trial and for his thoughtful
review of this Comment. I have served on ad-hoc advisory boards for
Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, sano-aventis, Novartis,
Pzer, Abbott Pharmaceuticals, and Boehringer Ingelheim.
1

8
9

10

Katsumata N, Yasuda M, Takahashi F, et al, for the Japanese Gynecologic

Oncology Group. Dose-dense paclitaxel once a week in combination with
carboplatin every 3 weeks for advanced ovarian cancer: a phase 3,
open-label, randomised controlled trial. Lancet 2009; published online
Sept 20. DOI:10.1016/S0140-6736(09)61157-0.
du Bois A, Quinn M, Thigpen T, et al. 2004 consensus statements on the
management of ovarian cancer: nal document of the 3rd International
Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference
(GCIG OCCC 2004). Ann Oncol 2005; 16 (suppl 8): viii712.
Vasey PA, Jayson GC, Gordon A, et al, on behalf of the Scottish
Gynaecological Cancer Trials Group. Phase III randomized trial of
docetaxel-carboplatin versus paclitaxel-carboplatin as rst-line
chemotherapy for ovarian carcinoma. J Natl Cancer Inst 2004;
96: 168291.
Bookman MA, Brady MF, McGuire WP, et al. Evaluation of new
platinum-based treatment regimens in advanced-stage ovarian cancer:
a phase III trial of the Gynecologic Cancer Intergroup. J Clin Oncol 2009;
27: 141925.
Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, et al.
European-Canadian randomized trial of paclitaxel in relapsed ovarian
cancer: high-dose versus low-dose and long versus short infusion.
J Clin Oncol 1994; 12: 265466.
Spriggs DR, Brady MF, Vaccarello L, et al. Phase III randomized trial of
intravenous cisplatin plus a 24- or 96-hour infusion of paclitaxel in
epithelial ovarian cancer: a Gynecologic Oncology Group
Study. J Clin Oncol 2007; 25: 446671.
Markman M, Blessing J, Rubin SC, et al. Phase II trial of weekly paclitaxel
(80 mg/m) in platinum and paclitaxel-resistant ovarian and primary
peritoneal cancers: a Gynecologic Oncology Group study.
Gynecol Oncol 2006; 101: 43640.
Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant
treatment of breast cancer. N Engl J Med 2008; 358: 166371.
Seidman AD, Berry D, Cirrincione C, et al. Randomized phase III trial of
weekly compared with every-3-weeks paclitaxel for metastatic breast
cancer, with trastuzumab for all HER-2 overexpressors and random
assignment to trastuzumab or not in HER-2 nonoverexpressors: nal
results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 2008;
26: 164249.
Lau D, Guo L, Gandara D, Young LJ, Xue L. Is inhibition of cancer
angiogenesis and growth by paclitaxel schedule dependent?
Anticancer Drugs 2004; 15: 87175.

www.thelancet.com Vol 374 October 17, 2009

Comment

11

12

Omura GA, Brady MF, Look KY, et al. Phase III trial of paclitaxel at two dose
levels, the higher dose accompanied by lgrastim at two dose levels in
platinum-pretreated epithelial ovarian cancer: an Intergroup study.
J Clin Oncol 2003; 21: 284348.
Guminski AD, Harnett PR, deFazio A. Carboplatin and paclitaxel interact
antagonistically in a megakaryoblast cell linea potential mechanism for
paclitaxel-mediated sparing of carboplatin-induced thrombocytopenia.
Cancer Chemother Pharmacol 2001; 48: 22934.

13

14

Armstrong DK, Bundy B, Wenzel L, et al, for the Gynecologic Oncology

Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer.
N Engl J Med 2006; 354: 3443.
ICON7. Overview. Feb 16, 2009. http://www.ctu.mrc.ac.uk/icon7/overview.
asp (accessed July 27, 2009).

The yin and yang of paracetamol and paediatric immunisations

www.thelancet.com Vol 374 October 17, 2009

that the most attractive mechanism is interference with

the early interactions of dendritic cells, T cells, and B cells
of the primary immune response through a reduction
of inammatory signals at the injection site, which
would also explain the decreased eect of paracetamol
on immunogenicity of the booster dose. However,
despite being an inhibitor of cyclo-oxygenase 2 (COX-2),
paracetamols anti-inammatory activity is contested,
perhaps related to inhibition of activity in highperoxide environments that are common at sites of
inammation.10 Paracetamols COX-2 inhibiting activity
might be restricted to the CNS, where oxidative stresses
are more tightly controlled. An anti-inammatory
mechanism would be of particular concern with
ibuprofen for the prevention and treatment of adverse
events after immunisation. Ibuprofen is a more potent
COX-2 inhibitor with greater anti-inammatory activity
than paracetamol, particularly at peripheral sites of tissue
inammation. The eect of ibuprofen on the antibody
response postimmunisation (and postinfection) is not
known.

See Articles page 1339

Science Photo Library

Although highly eective, whole-cell pertussis vaccines

are associated with high rates of injection-site reactions,
fever, and less commonly febrile seizures. Two trials
in the 1980s showed that rates of postimmunisation
fever could be reduced through the prophylactic
administration of paracetamol (acetaminophen),1,2
which led the US Advisory Committee on Immunization
Practice to recommend it is reasonable to consider
administering antipyretics (such as acetaminophen) at
age-appropriate doses at the time of vaccination and
every 46 h for 4872 h to children at higher risk for
seizures than the general population.3 In practice, the
administration of paracetamol to all children receiving
whole-cell pertussis vaccine became widespread.
In Canada, the National Advisory Committee on
Immunization advised because of the lower incidence
of fever associated with [acellular pertussis] vaccines,
there may be less justication for routine use of
prophylactic acetaminophen, as had been recommended
with the whole-cell pertussis vaccines.4 Lewis and
colleagues2 had cautioned about the possible eects
of anti-inammatory agents on a diminished immune
response. But, because no eect on immunogenicity
was noted with paracetamol and whole-cell pertussis
vaccine,5,6 the extensive prelicensure trials with
acellular pertussis studied the eect of paracetamol on
reactogenicity, not immunogenicity.7,8
In The Lancet today, Roman Prymula and colleagues
are the rst to examine this issue carefully with a current
paediatric vaccine regimen.9 Unexpectedly, they found
reduced immunogenicity of common paediatric vaccines
with use of paracetamol in open-label randomised trials
for both primary and booster doses. The investigators
discuss several potential mechanisms for the observed
eect on the antibody response. Prevention of
inammation and fever is unlikely because the immune
responses (and the eect of paracetamol) in children
with and without fever were similar. The authors propose

1305