Management of Platinum-Sensitive Recurrent Ovarian Cancer Jacobus Pfisterer and Jonathan A. Ledermann

Management of Platinum-Sensitive Recurrent Ovarian Cancer Jacobus Pfisterer and Jonathan A. Ledermann

Management of Platinum-Sensitive
Recurrent Ovarian Cancer
Jacobus Pfisterera and Jonathan A. Ledermannb
The majority of patients with ovarian cancer will relapse despite state-of-the-art first-line
surgery and chemotherapy. There are two subgroups of patients with recurrent ovarian
cancer: those with platinum-resistant disease and those with platinum-sensitive disease.
Re-treatment with single-agent platinum has long been considered standard therapy for
patients with platinum-sensitive disease, and, based on its favorable therapeutic profile,
carboplatin has become the treatment agent of choice. High response rates are seen with
platinum agents used in combination with paclitaxel or gemcitabine. The International Collaborative Group for Ovarian Neoplasia (ICON) and the Arbeitsgemeinschaft für Gynaekologische
Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) recently conducted a trial (ICON4/
AGO-OVAR-2.2) comparing platinum monotherapy with platinum plus paclitaxel combined.
Results showed that overall survival and progression-free survival are improved by combination therapy. Similarly, a significant benefit in progression-free survival for carboplatin
plus gemcitabine versus carboplatin monotherapy was seen in the Gynecologic Cancer
InterGroup trial. The toxicity profiles and schedules of carboplatin plus paclitaxel and
carboplatin plus gemcitabine are different, with the taxane combination having greater
neurotoxicity and alopecia, less hematologic toxicity, and requiring longer drug infusions
(although fewer days of treatment per cycle) than the gemcitabine combination. Based on
the results of these two trials, combination chemotherapy should be considered the
standard treatment of recurrent platinum-sensitive ovarian cancer. The choice of treatment
needs to take into account the increase in side effects when using combination chemotherapy compared with carboplatin monotherapy, and the different toxicities of the two
combination regimens.
Semin Oncol 33(suppl 6):S12-S16 © 2006 Elsevier Inc. All rights reserved.
D
espite progress in the first-line treatment of ovarian cancer, the majority of patients relapse and die within 5
years because relapsed disease is incurable.1,2 The goal of
treatment is to eliminate or reduce symptoms, prolong symptom-free survival, and maintain or improve quality of life
(QOL), with the aim of prolonging progression-free survival
and overall survival. The management of relapsed ovarian
cancer is complex. Once diagnosed, much of the care for
patients is in the context of relapsed disease. Given the choice
of drugs that are active in ovarian cancer, careful consideration is needed when selecting the most appropriate drug(s)
based on the extent and severity of the disease, the potential
side effects, and patient preference. Retrospective studies of
platinum-based second-line therapies have identified two
subgroups of patients with recurrent ovarian cancer: those
with platinum-resistant disease and those with platinumsensitive disease3,4; the latter is defined by a relapse-free period of ⱖ6 months following a response to the final dose of
platinum treatment.
aKlinik
für Gynäkologie und Geburtshilfe Campus Kiel, Universitätsklinikum Schleswig-Holstein, Germany.
bCancer Research UK and The University College of London Cancer Trials
Centre, Department of Oncology, University College London, London,
United Kingdom.
Prof Pfisterer has received speaker’s honoraria from Eli Lilly & Co. Dr Ledermann has served as a medical consultant and invited speaker for Eli
Lilly & Co.
Address reprint requests to Prof Dr Jacobus Pfisterer, Klinik für Gynäkologie
und Geburtshilfe Campus Kiel, Universitätsklinikum Schleswig-Holstein 24105 Kiel, Germany. E-mail: jpfisterer@email.uni-kiel.de
S12
0093-7754/06/$-see front matter © 2006 Elsevier Inc. All rights reserved.
doi:10.1053/j.seminoncol.2006.03.012
Considerations
for the Management
of Platinum-Sensitive
Recurrent Ovarian Cancer
Treatment decisions over the last 15 years have been based
on empirical observations of platinum sensitivity. These have
Platinum-sensitive recurrent ovarian cancer
not been tested prospectively and it should be noted that
platinum sensitivity in relation to the platinum-free interval
is a discontinuous variable. Until recently, there were few
practical alternatives to re-treatment with platinum, and platinum-based compounds remain the most active single agents
for relapsed ovarian cancer. The decision to re-treat women
with relapsed disease is based on the presence of symptoms
and the volume of disease, rather than purely on the basis of
a rising CA-125 level. The rationale for considering combination therapy at relapse is to overcome the relative resistance to platinum-based therapy. Higher response rates
could control symptoms more quickly and might increase
the time without chemotherapy and extend survival time.
However, any benefit needs to be considered carefully against
the risk of increased toxicity with combination chemotherapy. Any true benefit can be assessed only by including patients in prospective randomized studies and having a full
discussion of the benefits and side effects with individual
patients.
Treatment of
Platinum-Sensitive
Recurrent Ovarian Cancer
For platinum-sensitive patients, re-treatment with singleagent platinum is considered to be standard therapy. The
expected tumor response rate (depending on the platinumfree interval)3,4 is between 22% and 59%, which is somewhat
higher than that seen with non-platinum drugs such as topotecan, paclitaxel, or pegylated liposomal doxorubicin.5,6
Based on its favorable therapeutic profile, carboplatin (rather
than cisplatin) has become the agent of choice.7
High response rates have been reported by combining active drugs with platinum in the treatment of platinum-sensitive relapsed ovarian cancer. In a phase II trial, Dizon et al8
reported a 62% response rate for carboplatin plus paclitaxel
in platinum-sensitive relapse. A similar response was seen
when gemcitabine was combined with carboplatin.9
However, the interpretation of results of non-randomized
trials is difficult, because patients with relapsed ovarian cancer are usually heterogeneous, and those treated with longer
platinum-free intervals respond better to chemotherapy. Bolis et al10 performed a randomized phase II study in 190
patients with carboplatin plus epidoxorubicin. The response
rate to combination chemotherapy was 61.7% versus 56.2%
with carboplatin monotherapy. However, there was no significant difference in response rate or time to progression in
either group. The benefit of combination chemotherapy over
monotherapy has been established in two randomized controlled trials that evaluated combination chemotherapy (platinum plus paclitaxel and carboplatin plus gemcitabine) versus single-agent platinum therapy in relapsed ovarian cancer.
Platinum Plus Paclitaxel
Combination Chemotherapy
The International Collaborative Group for Ovarian Neoplasia
(ICON) initiated a randomized trial in 1996 to assess the
S13
combination of platinum plus paclitaxel for treating patients with platinum-sensitive relapsed ovarian cancer.
The ICON4 trial was coordinated by the Medical Research
Council (MRC) in the UK and the Mario Negri Institute
(IRFMN) in Italy. The German group Arbeitsgemeinschaft
für Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) performed a similar but smaller trial
(AGO-OVAR-2.2). A prospective combined analysis was
planned for these two parallel studies and the results were
published in 2003.11 Patients enrolled in the ICON4/AGOOVAR-2.2 trial who required platinum chemotherapy were
randomized either to standard platinum or to platinum plus
paclitaxel. There were differences in the entry criteria: a platinum-free interval of 12 months was required by the IRFMN
while the MRC/AGO-OVAR required 6 months; a prior paclitaxel dosage of 175 mg/m2 was specified by the MRC/
IRFMN while the AGO-OVAR stated 185 mg/m2; and six
prior cycles of treatment were needed for the MRC/IRFMN
studies while it was six to eight cycles for the AGO-OVAR
study. Entry of patients in second relapse was permitted in
the MRC protocol. The choice of platinum (cisplatin or carboplatin) was made by the physician at the time of randomization, and the minimum dose of carboplatin given was area
under the curve (AUC) 5. The minimum dose of cisplatin
alone was 75 mg/m2, while cisplatin given in conjunction
with doxorubicin and cyclophosphamide was given at a dose
of 50 mg/m2. All cycles were planned at 3-week intervals.
A total of 802 patients were recruited from five countries
for the trial, which closed in 2002; 92% of patients were
randomized after first relapse and 75% were randomized
more than 12 months after completion of platinum-based
chemotherapy. Overall, 43% of patients had previously received a taxane. Carboplatin was used as a single agent in
71% of the control group, and in combination with paclitaxel
in 85% of the experimental group. At the median follow-up
of 42 months, 530 deaths had occurred. There was a significant survival advantage in favor of platinum plus paclitaxel
(hazard ratio [HR], 0.82; 95% confidence interval [CI],
0.69 – 0.97; P ⫽ .023) (Fig 1A). At 2 years after randomization, the HR indicated an absolute improvement in survival
rate in the combination arm of 7%, from 50% to 57% (95%
CI for difference, 1%–12%). The difference in median survival time was 5 months, from 24 to 29 months (95% CI for
difference, 1–11 months). A significant benefit was also seen
in progression-free survival, which increased by 3 months,
from 10 to 13 months (95% CI for difference, 1–5 months)
(Fig 1B). The addition of paclitaxel to platinum did not cause
a significant increase in toxicity, nor did it adversely affect the
QOL of the patient. In particular, neurotoxicity was no more
prevalent or severe in patients who had previously received a
taxane as part of first-line therapy.
These results showed, for the first time, that platinum plus
paclitaxel improved the progression-free and overall survival
of patients with relapsed ovarian cancer, but the reason for
this benefit remains unclear. One possibility is that the
ICON4/AGO-OVAR-2.2 trial tested the sequential use of
paclitaxel. More than half of the patients in the study had not
received paclitaxel as part of their first-line therapy, and an
S14
J. Pfisterer and J.A. Ledermann
of non-platinum drugs. The population of cells with mutant
p53 is greater in relapsed ovarian cancer, and this could also
alter the pattern of drug sensitivity.12
Despite the benefits of the ICON4/AGO-OVAR-2.2 study,
many patients previously treated with paclitaxel were probably excluded from entering the trial because of persistent
neurotoxicity. This is a common side effect of platinum plus
paclitaxel combination therapy, where grade 1– 4 neurotoxicity is seen in 75% of patients treated with carboplatin plus
paclitaxel and in 83% of those receiving cisplatin plus paclitaxel as first-line therapy.1 Neurotoxicity decreased slowly
after cessation of therapy but often persisted for 2 years or
more. Therefore, even though treatment with platinum plus
paclitaxel at relapse improves survival, concerns about neurotoxicity remain, which emphasizes the need to explore
other platinum combinations.
Carboplatin Plus
Gemcitabine Combination Chemotherapy
Figure 1 (A) Overall survival and (B) progression-free survival (PFS)
of patients treated with platinum plus paclitaxel (plat–tax) or platinum monotherapy (plat– chemo) in the International Collaborative
Ovarian Neoplasm (ICON)4/Arbeitsgemeinshaft für Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR)2.2 trial. (Reprinted with permission.11)
exploratory subgroup analysis observed no clear evidence
that paclitaxel plus platinum was more (or less) effective in
this taxane-naive subgroup. Further subgroup analyses
showed no difference in outcome based on several factors:
length of time since completion of last chemotherapy, number of lines of previous chemotherapy, intended platinum
agent, age of patient, performance status, and randomizing
group. Another possibility is that greater benefit was derived
from adding a second agent to the treatment regimen for
patients with disease partially resistant to platinum therapy.
There is clinical evidence for this, as response rates are lower
in monotherapy studies. Furthermore, the presence of a tumor with a different biological constitution may favor the use
The activity of the nucleoside analog gemcitabine in ovarian
cancer and its promising phase II results in combination therapy with carboplatin9,13-15 led to the randomized controlled
trial of carboplatin plus gemcitabine versus carboplatin
monotherapy. The randomized Gynecologic Cancer InterGroup study was conducted by the AGO-OVAR, the National
Cancer Institute of Canada Clinical Trials Group, and the
European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group.16,17 The primary objective
of the trial was to compare progression-free survival between
treatment arms in patients with platinum-sensitive recurrent
ovarian cancer. Secondary objectives included comparisons
of response rate, duration of response, overall survival, QOL,
and toxicity.
Three hundred sixty-five patients with platinum-sensitive
recurrent ovarian cancer were randomized to either carboplatin monotherapy or carboplatin plus gemcitabine. Patients in the experimental arm received gemcitabine 1,000
mg/m2 on days 1 and 8, and carboplatin AUC 4 on day 1;
patients in the control arm received carboplatin AUC 5 on
day 1 (based on the Calvert formula).18 The AUC calculation
was based on the glomerular filtration rate calculation according to the formula by Jelliffe.19 Cycles were repeated
every 21 days for six to 10 cycles unless progressive disease
was documented, and the arms were well balanced for baseline characteristics. Patients in the carboplatin plus gemcitabine arm received 75.6% of the planned mean dose of gemcitabine (92.8% on day 1, 63.4% on day 8) and 96.2% of the
planned dose of carboplatin. Patients in the carboplatin
monotherapy arm received 98.2% of the planned dose.
Grade 3/4 hematologic toxicities were significantly more frequent in the gemcitabine plus carboplatin arm than the carboplatin monotherapy arm. Neutropenia was the predominant toxicity but had minimal clinical relevance. No
significant difference between treatment arms was seen in the
frequency of febrile neutropenia and use of intravenous antibiotics. The overall incidence of grade 3/4 non-hematologic
toxicities was modest, with less than 5% of patients in either
Platinum-sensitive recurrent ovarian cancer
S15
arm experiencing nausea, vomiting, motor/sensory neuropathy, or renal toxicity. Of note, grade 2 alopecia was reported
in 14.3% of carboplatin plus gemcitabine patients and 2.3%
of carboplatin monotherapy patients.
With a median follow-up of 17 months, the HR for progression-free survival was 0.72 (95% CI, 0.58 – 0.90; logrank, P ⫽ .0031), indicating a statistically significant improvement of 39% in the carboplatin plus gemcitabine arm.
Median progression-free survival was 8.6 months (95% CI,
7.9 –9.7 months) for the carboplatin plus gemcitabine arm
and 5.8 months (95% CI, 5.2–7.1 months) for the carboplatin monotherapy arm, which was a significant improvement
for the combination (Fig 2A). Overall survival was assessed
when 71% of the study population had died. The study was
not designed or powered to detect overall survival differences
between treatment arms. The HR for overall survival was
0.96 (95% CI, 0.75–1.23; log-rank, P ⫽ .7349). Median
overall survival was 18.0 months (95% CI, 16.2–20.2
months) for the carboplatin plus gemcitabine arm and 17.3
months (95% CI, 15.2–19.3 months) for the carboplatin
monotherapy arm, which did not constitute a significant difference (Fig 2B). The response rate was significantly higher in
the carboplatin plus gemcitabine arm than in the carboplatin
monotherapy arm (47.2% v 30.9%; P ⫽ .0016). Median duration of response was 8.4 months (95% CI, 7.6 –9.6
months) in the carboplatin plus gemcitabine arm and 7.3
months (95% CI, 5.9 – 8.2 months) in the carboplatin monotherapy arm (log-rank, P ⫽ .2511).
An exploratory subgroup analysis showed that improved
progression-free survival was maintained in patients who received platinum plus taxane therapy in the first-line setting
and in patients whose platinum-free interval was less than 12
months. The QOL scores showed no statistically significant
treatment differences for baseline scores between treatment
arms, or for score changes from baseline to treatment discontinuation between arms.
Future Studies
These results have led to the Gynecologic Cancer InterGroup
conducting the CALYPSO study, comparing standard carboplatin AUC 5 and paclitaxel 175 mg/m2 administered every
3 weeks versus carboplatin AUC 5 and pegylated liposomal
doxorubicin 30 mg/m2 every 4 weeks. The trial is designed as
a non-inferiority study, and its primary endpoint is progression-free survival. Overall survival, toxicity, and QOL will
also be compared.
Figure 2 (A) Kaplan–Meier estimates of progression-free survival
(PFS) for carboplatin monotherapy (C) versus carboplatin plus
gemcitabine (GC). The HR for recurrence in the GC arm, as compared with the C arm, was 0.72 (95% CI, 0.58 – 0.90; log-rank, P ⫽
.0031).16 (B) Kaplan–Meier estimates of overall survival for C versus
GC. The HR for survival in the GC arm, as compared with the C arm,
was 0.96 (95% CI, 0.75–1.23; P ⫽ .7349). The study was not
powered to detect significant differences in overall survival.16
Conclusion
cently, single-agent platinum was the primary treatment used
until tumor resistance intervened, while combination chemotherapy was used less often and was mainly confined to
phase II studies.
Improvement in overall survival is the “gold-standard” for
treatment, and this was the primary endpoint of the very
large ICON4/OVAR-2.2 trial. The use of multiple therapies
after the completion of a randomized study in relapsed ovarian cancer might obscure the benefit of combination therapy.
On this basis the carboplatin plus gemcitabine study was
Median survival time of patients with advanced ovarian cancer is approximately 44 months.1 Almost half the patients
will have relapsed by 18 months and three quarters by 30
months.1 Thus, the management of relapsed disease remains
a major issue in the care of patients with ovarian cancer.
Many of these patients have a good performance status and
respond well to chemotherapy, and so should be treated with
new agents in combination with chemotherapy. Until re-
J. Pfisterer and J.A. Ledermann
S16
Table 1 Efficacy and Toxicity Between Two Randomized Trials of Platinum-Based Combinations in the Treatment of Relapsed
Ovarian Cancer
References
Efficacy
Dosing schedule
Toxicity
Alopecia rate
Quality of life
Carboplatin Plus Paclitaxel
Versus Carboplatin
Carboplatin Plus Gemcitabine
Versus Carboplatin
11
Effective (PFS, OS)
Day 1 every 3 weeks
Neurotoxicity
86%
No worsening
16
Effective (PFS)
Days 1 and 8 every 3 weeks
Hematologic toxicity
15%
No worsening
Abbreviations: OS, overall survival; PFS, progression-free survival.
designed to show a significant benefit in progression-free
survival. Extension in progression-free survival increases
the time without chemotherapy and can be valuable in a
situation where patients have several courses of treatment
to extend their survival. The results of two recent randomized trials have shown that platinum-based combination
chemotherapy has a significant effect on the outcome of platinum-sensitive relapsed ovarian cancer. For platinum plus
paclitaxel, there was an increase in survival but this was
associated with additional symptomatic toxicity. Alopecia
and neurotoxicity were not significant side effects seen with
carboplatin plus gemcitabine. However, this combination
showed only an increase in progression-free survival, and
was associated with greater hematologic toxicities, although
they were not usually symptomatic. Although the schedule of
attendance for treatment with carboplatin plus gemcitabine
on days 1 and 8 was greater, the infusion of platinum plus
paclitaxel was longer. When selecting a particular treatment
option, careful consideration should be given to the results of
these trials, and mainly to the levels of toxicity of both combinations versus carboplatin monotherapy (Table 1). The
benefits of such drugs may be useful at this stage of the
disease, and the findings may assist future first-line studies,
where progress is much needed.
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