Int J Gynecol Cancer 2005, 15, 226232

Dose dense chemotherapy in ovarian cancer

P.A. VASEY*y
*School of Medicine, University of Queensland, Herston, Queensland, Australia; and yRoyal Brisbane and Womens
Hospital, Brisbane, Queensland, Australia

Abstract. Vasey PA. Dose dense chemotherapy in ovarian cancer.

Int J Gynecol Cancer 2005;15(Suppl. 3):226232.
In essence, dose densification is accelerated therapy (a commonly
used phrase in radiotherapeutics) and is a form of dose intensification
because the amount of drug per unit time (dose intensity mg/m2/
week) is increased. There is general consensus that increasing platinum dose intensity in ovarian carcinoma has not been proven despite
a dozen or more randomized trials evaluating up to twofold increases
in dose intensity. Few randomized trials in ovarian carcinoma have
compared weekly dose dense chemotherapy with more conventional
dosing schedules although there are plenty of phase II studies. In
these, dose densification of single agent therapy, for some drugs at
least, appears to be relatively well tolerated, with encouraging levels
of activity in patients purportedly refractory to the same agents when
scheduled in the standard way. However, many studies ostensibly evaluating dose density do not actually evaluate this entity, but actually
split the standard 3-weekly dose into weekly fragments thus maintaining the same dose intensity. Furthermore, as the aim of treatment in
recurrent ovarian cancer is palliation, weekly treatments are less convenient, are probably less cost effective, and have different dose-limiting
toxicities. This article will review the clinical data supporting dose
density as a therapeutic maneuver in ovarian cancer.
KEYWORDS:

chemotherapy, dose density, dose intensity, ovarian

carcinoma.

Advanced (FIGO stage III/IV) ovarian carcinoma is

only occasionally curable at first presentation and is
almost always incurable at relapse. Current standard
first-line therapy involves treatment with a platinum
agent (cisplatin or carboplatin) in combination with
a taxane (paclitaxel or docetaxel) delivered on a 3weekly cycle for six cycles(1). Patients optimally cytoreduced can expect a median progression-free surviAddress correspondence and reprint requests to: Paul A. Vasey
MBChB, MSc, MD, MRCP, FRACP, Royal Brisbane & Womens
Hospital, Post office Herston, Herston Q 4029 Australia. Email:
paul_vasey@health.qld.gov.au

val of 22 months and a median overall survival of

57 months(2), whereas patients with residual tumor
nodules .1 cm in diameter have correspondingly
poorer figures for median progression-free survival
and median overall survival of 18 and 36 months,
respectively(3). No randomized trials of other intravenous cytotoxic regimens or schedules have demonstrated better survival data in the first-line setting,
although emerging data for intraperitoneal cisplatin
paclitaxel may change that paradigm. Ongoing or
planned international randomized trials will integrate
novel biologic agents such as inhibitors of angiogenesis (eg, the monoclonal antibody bevacizimab) or
#

2005 IGCS

Dose dense chemotherapy in ovarian cancer

epidermal growth factor receptor tyrosine kinase

inhibitors (eg, gefitinib, erlotinib) with conventional
cytotoxics. The implication is that we may have
reached a plateau in outcomes from conventional cytotoxic therapy in this disease. First results of Gynecologic Oncology Group Trial 182 (Fig. 1) are expected in
2006 and will either confirm or refute this assumption.
When ovarian cancer recurs, the aim of therapy
changes from potential cure to palliation. Therapy is
guided by the treatment-free interval, and patients
considered platinum-sensitive are likely to be treated with platinum combinations such as carboplatin
paclitaxel or carboplatingemcitabine following recent
trial results(4,5). However, patients with short diseasefree intervals (termed platinum-resistant or platinumrefractory) are a clinical problem and are generally
treated with nonplatinum agents such as liposomal
doxorubicin (Caelyx) administered as monotherapies.
Response rates and durations of responses in this setting are low, and treatment decisions are made with
reference to the convenience of drug administration,
frequency of expected significant toxicities, current
quality of life and expectations for future quality of life,
andif possiblethe cost/benefit ratio. Improving the
efficacy of treatment for recurrent disease without
increasing toxicity is a major therapeutic goal. Of a
number of strategies being tested in the clinic, dose
densification is perhaps the most intriguing. This article
will describe what dose densification is, what data
support its use, and whether it should be viewed as
a standard treatment in recurrent ovarian carcinoma.

Background and definitions

227

clinical setting leads to the theory that the rate of

tumor volume regression from chemotherapy is proportional to the rate of growth, and furthermore, that
a fixed amount of tumor cell death results from exposure to a fixed dose of a cytotoxic agent to which the
tumor is homogeneously sensitive (Fig. 2). Unfortunately, this model was soon to be found wanting.
While exponential cell survival curves would be
expected if cell lethality was due to simple molecular
interactions between drug and DNA (for example)
few tumors are so homogeneous with respect to proliferative rate and factors such as intrinsic drug sensitivity, damage repair, and cellular uptake. Few
advanced cancers were cured despite therapy utilizing
these principles, and in the 1970s Norton and Simon.
refined this model, taking into account an alternative
description of tumor growth first outlined in the 19th
century by Benjamin Gompertz(7). Here, cells growing
with Gompertzian kinetics attained a plateau phase of
slow growth as the tumor bulk increases. Small tumors therefore grow faster than large ones, as a consequence of having a higher proliferation rate (Fig. 3).
The basis of the NortonSimon hypothesis was that
the efficacy of cytotoxic antiproliferative chemotherapy was greater in tumors with higher growth rates
(and therefore by definition, early tumors which have
smaller volumes) and conversely tumor regrowth is
more rapid when cell numbers decrease. Using the
NortonSimon hypothesis, it could be assumed that
more frequent drug administration would be a more
effective way of minimizing residual tumor burden or
could abrogate the regrowth of cell populations,
which are resistant to the agents used. Norton then
proposed models showing the effect of varying the

The work by Skipper in the 1960s outlined novel principles of neoplasia in which an exponential pattern of
tumor growth occurs(6). Extrapolating this into the
1.0

Survival (log)

RANDOMIZE

GOG182 / ICON5: Stage III-IV

I

Carboplatin AUC 6 (d1)

Paclitaxel 175 mg/m2 (d1)

x8

II

Carboplatin AUC 5 (d1)

Paclitaxel 175 mg/m2 (d1)
Gemcitabine 800 mg/m2 (d1,8)

x8

III

Carboplatin AUC 5 (d1)

Paclitaxel 175 mg/m2 (d1)
Doxil 30 mg/m2 (d1, every other cycle)

x8

Carboplatin AUC 5 (d3)

IV
2

Topotecan 1.25 mg/m (d1(d1-3)

Carboplatin AUC 6 (d8)

Gemcitabine 1 g/m2 (d1,8)

Slowly proliferating
Cell population
10-1

Rapidly proliferating
Cell population

x4
Carboplatin AUC 6 (d1)
x4
Paclitaxel 175 mg/m2 (d1)

10-2
Drug concentration

x4

Figure 2. Model cell survival curves after drug exposure based on

Skipper(6).

Figure 1. Schema for Gynecologic Oncology Group 182.

#

2005 IGCS, International Journal of Gynecological Cancer 15 (Suppl. 3), 226232

228 P.A. Vasey

Proliferation
rate

Plateau of growth phase

Exponentially increasing
Growth phase

Hypoxic
centre

Tumour size
Figure 3. Gomperzian kinetic model.

dose and intensity of cytotoxic agents which essentially demonstrated that poorer outcomes emerge
when dose reductions and delays, resulting in
decreased dose intensity, occur(8,9).
Furthermore, dose intensity was defined by
Hryniuk and Bush in 1984 as the amount of drug
administered in a unit of time (mg/m2/week)(10).
Using a conventional 3-weekly schedule as a baseline,
there are a number of ways to increase dose intensity
(Fig. 4). This includes giving increased doses 3-weekly,
increased doses weekly, or by decreasing the time
between cycles and either keeping the dose same or
increasing the dose (dose densification). If dose desensification is to be termed dose intense, the weekly
dose must be greater than a third of the 3-weekly
dose; otherwise, the correct term should be dose splitting or simply dose fractionation. Dose densification is
analogous to accelerated therapy, a commonly used
phrase in radiotherapeutics. As Hryniuk et al. himself
wrote in 2004, The implication that it [Dose Density]
is somehow different does not recognize the identical
concept espoused by earlier investigators. the entity
mg/m2/wk, regardless of schedule(11).
Strategy

Cumulative Dose

Increasing number of cycles

Increasing dose per cycle

Decreasing cycle interval
(Dose densification)
Decreasing interval,
and increasing dose
Figure 4. Dose intensity strategies.
#

Dose Intensity

In the clinical setting, there are many instances

where dose intensification, or at least maintaining adequate dose intensity, can be shown to be important. In
breast cancer, INT 9741 randomized four arms of
doxorubicin, cyclophosphamide and paclitaxel combinations in a 2 3 2 factorial design testing dose densification(12). Here, the superiority of dose dense therapy
compared with conventionally scheduled therapy was
confirmed, with no significant increase in important
toxicities such as cardiotoxicity or secondary malignancies. However, this study lacked any quality of life
evaluation or an assessment of the cost effectiveness
of accelerating therapy. In addition, while increased
dose densification of paclitaxel can be shown to significantly increase response rates compared with
3-weekly dosing(13), this effect may in fact be particular to paclitaxel and/or tumor type specific and
indeed extrapolating results of trials such as INT 9741
to other situations is potentially risky. In a recent trial
by Jackisch et al., a neoadjuvant dose dense doxorubicin
docetaxel combination was demonstrated to be inferior to a more conventional sequential adriamycin and
cyclophosphamide (AC) / docetaxel combination[14]
with regard to important endpoints such as breast
conservation and complete pathologic responses.
Clinical trials of platinum dose intensity in
ovarian cancer
In ovarian cancer, many randomized prospective trials
of first-line platinum dose intensification not requiring
colony-stimulating factor support have been performed. Results from these trials suggest that increasing the dose intensity of platinum by twofolda level
achievable without resorting to myelogenous growth
factor support or incurring unacceptable toxicitiesis
only of limited long-term benefit in the chemotherapy
of advanced ovarian cancer. Indeed, within this range
of dose intensification, the total dose of platinum may
be at least as important a factor in determining outcome. In the ten studies described here, eight had
a planned increase in dose intensity of cisplatin or carboplatin of twofold, but only three demonstrated
a beneficial outcome for this therapeutic maneuver
(Table 1; references in Vasey and Kaye(15)). Interestingly, two out of these three studies(16,17) had actually
also administered a significantly increased total cumulative dose of platinum to the patients randomized
to the high-dose arm, suggesting that the relative
dose intensity of platinum in itself may not be the
major determinant of treatment response, but that
the total dose actually received could be at least as
important. Indeed, a review of the data indicates that

2005 IGCS, International Journal of Gynecological Cancer 15 (Suppl. 3), 226232

Dose dense chemotherapy in ovarian cancer

229

Table 1. Randomized trials in ovarian cancer platinum dose intensity

Reference

DI factor

No. of patients

Outcome

Ngan et al. 1989

McGuire et al. 1995
Kaye et al. 1996
Colombo 1993
Jakobsen 1995
Gore 1996
Ehrlich 1983
Bella 1994
Conte 1993
Lambert 1997

2
2
2
2
2
2
1.5
2
2
1

65
485
165
306
222
241
56
101
133
233

Double 3YS but DI toxicity 111

No difference
Improvement in survival; toxicity of DI cisplatin 111
No difference
No difference
No difference, DI toxicity 111
No difference
Improved survival
No difference
No difference

DI, dose intensity; YS, year survival.

the platinum doseresponse curve flattens off after

25 mg/m2/week(15).
Recurrent disease and weekly regimens
From randomized trials in platinum-resistant ovarian
cancer who have also received paclitaxel the standard
of care is probably liposomal doxorubicin/Doxil. In
a pivotal phase III study of recurrent and refractory
patients, Doxil was compared with topotecan hydrochloride and not only demonstrated a better toxicity
profile but long-term follow-up indicated significantly
prolonged survival(18). The survival benefit was more
pronounced in patients with platinum-sensitive disease, and although the difference in survival was not
significant in the platinum-resistant patients, the ease
of administration schedule (1 h every 4 weeks) and the
side effects made Doxil the treatment of choice. In
the UK, the National Institute for Clinical Excellence
have recently issued guidelines stating that Doxil is
the only single agent recommended for patients in
the newly recognized category of partially platinumsensitive ovarian cancer patientsthose whose tumors
relapse between 6 and 12 months after completion of
initial platinum-based therapy(19). This announcement
from National Institute for Clinical Excellence also
acknowledged that Doxil was both clinically and cost
effective. The study of Gordon et al.(18) and other data
for Doxil from nonrandomized studies are informative and relevant when evaluating new therapies in
recurrent ovarian cancer because factors such as antitumor activity, survival, toxicity, convenience, and cost
benefit are important considerations.
Preclinical data with paclitaxel suggests that
increased cytotoxicity should be evident with lower
doses given as continuous (not intermittent) infusions(20). This assumption is supported by nonrandomized studies in which further responses were
observed in patients whose tumors had progressed
#

during shorter infusions of the drug(21,22). In 2004,

Spriggs et al. reported on a phase III study involving 293 chemonaive and suboptimally cytoreduced
patients who were randomly assigned to receive six,
3-weekly cycles of cisplatin 75 mg/m2 in combination
with paclitaxel either as a 3-h infusion of 175 mg/m2
or as a 96-h infusion of 120 mg/m2 (23). The primary
endpoint was overall survival. The trial was stopped
early after an interim futility analysis showed no differences emerging in progression-free survival (12.4 vs
12.6 months) or overall survival (29.9 vs 30.5 months).
However, this patient population may not be the ideal
test-bed to evaluate this hypothesis because the vast
majority of data in the chemo-nave scenario indicates
that platinum sensitivity is the most important predictive factor and is likely to overwhelm other factors
such as the schedule of paclitaxel.
Preclinical data for other agents (eg, S-phase
specific agents such as topotecan hydrochloride(24)) also
suggest that shorter cycle lengths may be more advantageous. In addition, phase II data for weekly paclitaxel
and weekly cisplatin report activity in patients previously treated with these agents at conventional
schedules and with acceptable toxicity profiles(2527).
For paclitaxel, doses used in these studies average 80
mg/m2/week, which represents a 37% increase in
dose intensity compared to 3-weekly paclitaxel, and
produce response rates consistently over 40%. Weekly,
short intravenous infusions of paclitaxel mimic (to
a degree) prolonged drug exposures and may be more
clinically useful because infusions longer than 96 h
require central-line access and are impractical in what
is a palliative setting. The only published study of
weekly chemotherapy vs conventional scheduling in
this setting is a trial of weekly paclitaxel vs 3-weekly
paclitaxel in platinum-pretreated patients(28). Here,
208 patients with recurrent ovarian cancer who had
failed platinum-based therapy were randomly assigned to receive paclitaxel 200 mg/m2 3-weekly or

2005 IGCS, International Journal of Gynecological Cancer 15 (Suppl. 3), 226232

230 P.A. Vasey

dose fractionation at 67 mg/m2/week, ie, no increase

in planned dose intensity. The results showed a marginally but statistically significant increase in delivered dose intensity for the fractionated arm (77.6 vs
72.7 mg/m2/week), but this did not translate into
increased survival (13.6 vs 14.7 months). Nevertheless,
the weekly schedule was as expected less toxic and
better tolerated. Unfortunately, nonrandomized studies with the more potent taxane, docetaxel, given in
a weekly schedule at doses of 3040 mg/m2/week
actually demonstrate reduced tolerability with a different, unwanted toxicity profile which includes clinically important asthenia and cutaneous/nail toxicities.
In one study of weekly docetaxel in a heavily pretreated group of patientsmedian number of prior
regimens/therapies was 3% and 66% were paclitaxelresistantthere was less myelosuppression observed,
but the simultaneous occurrence of multiple grade 12
nonhematologic toxicities was problematic and the
response rate was only 7%(29).
Weekly topotecan hydrochloride fares little better
despite being S-phase specific, a characteristic associated with firm preclinical data supporting the use of
regular and oft-repeated exposures. In vitro data demonstrate that the cytotoxic effect of topotecan reaches
a plateau with prolonged exposure, correlating with
a downregulation of the topoisomerase I enzyme, the
drugs primary target(30). Furthermore, these data suggest that giving topotecan weekly would have similar
effectiveness to prolonged exposure. In the clinical
setting, many studies using 4 mg/m2 starting doses
and a 30-min weekly infusion report low toxicity, with
antitumor activity similar to 3-weekly regimens.
However, one randomized phase II study (no phase III
studies are published) utilizing a weekly 24-h infusion of 1.75 mg/m2 vs the conventional 3-weekly 1.5
mg/m2, days 15 given every 3 weeks reported no
difference in median survival and, in fact, a lower
response rate for the weekly arm(31).
Combinations in dose dense schedules?
Prolonged schedules of oral etoposide have demonstrated consistent response rates of around 25% in
platinum-resistant patients with a favorable toxicity
profile(32). Etoposide and cisplatin are synergistic
when administered concurrently(33), and therefore
a schedule of weekly cisplatin plus oral etoposide
(Fig. 5) was piloted by Van der Berg et al.(34). Here, 98
evaluable patients with platinum-pretreated ovarian
cancer received six to nine cycles of a regimen consisting of cisplatin 5070 mg/m2 on days 1, 8, 15, 29, 36,
and 43 plus continuous oral etoposide 50 mg/m2
#

Figure 5. Schema for dose dense cisplatin/etoposide.

(with a 2-week break between days 15 and 29 each

cycle). This regimen demonstrated high activity in
patients considered to be platinum-sensitiveintermediate sensitive group (platinum-free interval [PFI]
412 months), response rate 91%; sensitive group
(PFI .12 months), response rate 92%. More interesting
was the refractory group (PFI ,4 months), which
had a response rate of 46%. However, very few (8) of
these patients had received paclitaxel as part of frontline therapy. In addition, overall tolerance was considered acceptable by the investigators despite the fact
that hematologic toxicity resulted in several treatment
delays and dose reductions.
Meyer et al. performed a similar study using cisplatin 60 mg/m2 and similar etoposide scheduling
in 42 patients of whom 35 (83%) had received less
than two prior regimens(35). Here, the overall response
rate was lower (44%) with no difference observed between patients in the platinum-sensitive (PFI .6 months)
and platinum-resistant (PFI ,6 months) groups; 43%
vs 46%.
These nonrandomized studies hint at a high level of
efficacy for this combination, with manageable side
effects experienced by these selected patient groups.
However, the contribution of the dose dense weekly
scheduling of cisplatin in these combinations has not
been fully disentangled or evaluated, and it may simply be synergy with oral etoposide that is responsible
for the high response rates. Biochemical synergy,
attacking multiple sites in biosynthetic pathways and/
or several processes involved in essential macromolecular function, is of course understood to be the underlying rationale for successful cytotoxic combinations.
Furthermore, a recent trial of nondose dense gemcitabine in combination with oral etoposide in 20

2005 IGCS, International Journal of Gynecological Cancer 15 (Suppl. 3), 226232

Dose dense chemotherapy in ovarian cancer

evaluable platinum-resistant patients also produced

a high response rate of 65%, giving credence to the
possibility that it may be schedule and agent synergy
which is primarily responsible(36).
Many nonrandomized studies of weekly schedules
of carboplatin in combination with paclitaxel have
been presented and/or published and have shown
promising results in recurrent ovarian carcinoma. In
one phase II study, 29 patients with recurrent (one to
four prior regimens) ovarian carcinoma were treated
with carboplatin area under the curve 2 plus paclitaxel 80 mg/m2 on days 1, 8, and 15 every 28 days(37).
This produced an overall 83% response rate (24/29
patients), which included a 37.5% response rate in 8
platinum-refractory patients and a 100% response rate
for patients with platinum-sensitive disease. Another
similar schedule using higher doses of carboplatin
area under the curve 4 plus paclitaxel 90 mg/m2 given
weekly for six cycles (with a 2-week break between
cycles 3 and 4) produced a 53% response rate in 18 of
50 enrolled platinum-resistant patients who had a PFI
of ,6 months(38). However, this regimen was used as
a form of induction therapy as responding patients
were then treated by six conventional 3-weekly cycles
of carboplatinpaclitaxel.

Summary
Randomized trials of increased dose intensity have
been performed in many tumor types and the results
are variable. There is evidence pointing to results
being drug and/or disease specific. It is also important
to note that few studies testing dose density regimens
actually plan increased dose intensity and merely utilize dose-fractionation principles. Furthermore, disentangling dose dense/intense effects means excluding
other deviations such as inadequate number of cycles
being delivered resulting in a decreased cumulative
dose of the drug in question.
At the end of the day, weekly visits are less convenient for the patient and, in the case of the taxanes can
expose the patient to chronic doses of corticosteroids.
While the weekly schedules of carboplatin plus paclitaxel appear to be well tolerated, it is important to
note that these are nonrandomized phase II data
which are of course potentially biased by the small
and selective number of patients involved. It is well
known that phase II data do not stand up well in comparison with randomized phase III data, and to date,
no randomized trials have been reported comparing
dose dense therapies as single agents or in novel combinations with conventionally scheduled agents in
truly resistant patients.
#

231

The overriding principal aim of treatment in recurrent ovarian cancer is palliation, and therefore, experience suggests that until more convincing data are
available, the use of potentially toxic dose dense
combination therapy in patients with resistant disease is best reserved for motivated, younger, fitter
women within a clinical trial setting. Dose densification of single agent therapy, for some drugs at least,
appears to be relatively well tolerated and may
engage further clinical responses. However, little data
exists for increased dose intensity being relevant, and
most reported regimens are using dose fractionation
and not dose intensification. Finally, weekly treatments are less convenient schedules for patients
and are certainly less cost effective if treatment time,
medical/nursing time, and outpatient staffing time
are factored in.

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Accepted for publication July 17, 2005

2005 IGCS, International Journal of Gynecological Cancer 15 (Suppl. 3), 226232