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Systemic Chemotherapy for Management of Recurrent


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SMGr up
Systemic Chemotherapy for Management
of Recurrent Platinum-Sensitive Epithelial
Ovarian Cancer: A Review

Ahmed Abu-Zaid1*, Marah Nayfeh1, Sana Almairi1, Nida Zubairi1, Aseel Eljabali1,
Mohammed Abuzaid2, Osama Alomar3 and Hany Salem1,3
1
College of Medicine, Alfaisal University, Saudi Arabia
2
Department of Obstetrics & Gynecology, King Fahad Medical City, Saudi Arabia
3
Department of Obstetrics & Gynecology, King Faisal Specialist Hospital and Research Centre,
Saudi Arabia
*Corresponding author: Ahmed Abu-Zaid, College of Medicine, Alfaisal University, P.O.
Box 50927, Riyadh 11533, Saudi Arabia, Tel: +966 567 566 622; Fax: +966 11 215 7611;
Email(s): aabuzaid@live.com & aabuzaid@alfaisal.edu

Published Date: September 20, 2017

ABSTRACT
Epithelial ovarian cancer (EOC) is the fifth principal cause of cancer-related mortality in
women. Roughly 75% of women with EOC present with an advanced-stage disease, and the classical
first-line management is optimal cytoreduction (whenever technically feasible) followed by an
adjuvant platinum-based chemotherapy. In spite of the relatively high response rates to first-line
chemotherapy, around 70-85% of patients develop disease recurrence. These patients eventually
require an additional systemic medical treatment, and its selection is based on the platinum-
free interval (PFI) - that is, the time period from completion of platinum-based chemotherapy
to beginning of disease progression. Patients with a PFI greater than a time period of 6 months
are regarded as platinum-sensitive. The aim of study is to review the systemic chemotherapy

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regimens (mono therapy and combination therapy) used for the management of patients with
recurrent platinum-sensitive EOC. The rationale is to review the available literature, compare
different systemic chemotherapeutic agents, and provide updated conclusive recommendations.
The review will not include data pertaining to recurrent platinum-resistant EOC, or the novel
molecularly targeted therapies.

Keywords: Platinum-free interval; Platinum-sensitive; Ovarian; Cancer; Chemotherapy 

INTRODUCTION
Epithelial ovarian cancer (EOC) is the fifth principal cause of cancer-related mortality in
women [1]. It has been estimated that roughly 75% of women with EOC present with advanced-
stage disease (III-IV) which is associated with an unfortunate prognosis [2]. The classical first-line
management for advanced-stage disease is optimal cytoreduction (whenever technically feasible)
followed by an adjuvant platinum-based chemotherapeutic regimen [2,3]. In spite of the relatively
high response rates to first-line chemotherapy, around 70-85% of patients relapse, progress to
locally advanced unresectable or metastatic inoperable disease, or even develop drug-resistant
disease [2,4].

Patients with recurrent EOC will eventually require an additional systemic medical treatment.
The selection of systemic medical treatment is largely based on the response to the first-line
chemotherapy - that is, the platinum-free interval (PFI) [5]. The PFI is defined as the interval from
the completion of first-line platinum-based chemotherapy to the beginning of disease progression
[5]. Patients with a PFI less than or equal to a time period of 6 months are regarded as platinum-
resistant, whereas patients with a PFI greater than a time period of 6 months are regarded as
platinum-sensitive [5]. Recently, BRCA germ-line status, tumor histology, and existence of
hypothetically actionable mutations are additional parameters considered in the selection of
systemic treatment [6,7].

Herein, in this chapter, we review the systemic chemotherapy regimens (mono therapy
and combination therapy) used for the management of patients with recurrent platinum-
sensitive EOC. The rationale is to review the available literature, compare different systemic
chemotherapeutic agents, and provide updated conclusive recommendations. The review will not
include data pertaining to recurrent platinum-resistant EOC. Also, the review will not include the
novel molecularly targeted therapies, such as angiogenesis inhibitors (e.g., bevacizumab), PARP
inhibitors (e.g., rucaparib) and others.

SYSTEMIC CHEMOTHERAPY
Several non-randomized and randomized controlled phase II/III clinical trials have
been conducted to explore the efficacy and safety of mono therapy or combination systemic
chemotherapy for management of patients with recurrent platinum-sensitive EOC.

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Mono therapy (Single-Agent) Systemic Chemotherapy
Several single-agent systemic chemotherapies have been evaluated in patients with recurrent
platinum-sensitive EOC. Such agents included: pegylated liposomal doxorubicin (PLD), etoposide,
gemcitabine (GEM), nanoparticle albumin-bound paclitaxel (nab-paclitaxel), trabectidine and
topotecan. Whenever available, clinical parameters that will be examined include: disease-free
survival (DFS), progression-free survival (PFS), time to progression (TTP), overall survival
(OS), duration of response (DOR), overall response rate (ORR), complete response (CR), partial
response (PR), disease stabilization (DS), and disease progression (DP).

Table 1: A summary of major phases II/III studies on single-agent systemic chemotherapy in


patients with recurrent platinum-sensitive EOC.
ORR DS TTP PFS OS
Ref Authors Phase Year Single-Agent Chemotherapy n
(%) (%) (mon) (mon) (mon)
PLD 109 28.4 37.6 NR 7.2 27
[8] Gordon et al. III 2001
Topotecan 111 28.8 37.8 NR 5.8 17.8

PLD 109 NR NR NR NR 27
[9] Gordon et al. III 2004
Topotecan 110 NR NR NR NR 17.5

[10] PLD 76 16 43 4 NR 14
Ferrandina et al. III 2008
GEM 77 29 43 5 NR 12.8

[11] Katsumata et al. II 2008 PLD 11 27.3 27.3 5.7 NR NR

[12] Rose et al. II 1998 Etoposide 41 34.1 NR NR 6.3 16.5

Paclitaxel 50 45 21 NR 9 25.8
[13] Cantù et al. I/II 2002
CAP 47 55 30 NR 15.7 34.7

[14] Teneriello et al. II 2009 nab-paclitaxel 47 64 31.8 NR 8.5 NR

[15] Sessa et al. II 2005 Trabectidine 29 43 39 7.9 NR NR

[16] Krasner et al. II 2007 Trabectidine 62 29 35 5.2 5.1 NR

Trabectidine
54 38.9 38.9 6.2 NR NR
(1.5 mg/m2 over 24 hrs) q3w
[17] Del Campo et al. II 2009
Trabectidine
53 35.8 47.2 6.8 NR NR
(1.3 mg/m2 over 3 hrs) q3w

[19] Morris et al. II 2008 Topotecan 41 22 42 3.6 NR 21.2

CAP: cyclophosphamide doxorubicin and cisplatin; DS: disease stabilization; GEM: gemcitabine;
HRS: hours; MON: months; N: sample size; NAB-PACLITAXEL: nanoparticle albumin-bound
paclitaxel; NR: not reported; ORR: overall response rate; OS: overall survival; PFS: progression-
free survival; PLD: pegylated liposomal doxorubicin; Q3w: three times per week; Ref: reference;
TTP: time to progression

Pegylated liposomal doxorubicin (PLD)


In 2001, Gordon et al. [8] (phase III trial) randomized 474 patients with platinum-sensitive
and platinum-resistant EOC to receive either PLD (50 mg/m2, one-hour infusion every 28 days)

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[n=239] or topotecan (1.5 mg/m2/d for 5 successive days every 21 days) [n=235]. For all patients,
the PLD group achieved higher (statistically insignificant) ORR (19.7 vs. 17.0%) and median OS
(60 vs. 56.7 weeks) than the topotecan group. Sub-analysis of platinum-sensitive patients only
[n=220], the PLD group [n=109] achieved statistically significant benefits in terms of OS (108 vs.
71.1 weeks, p=0.008) and PFS (28.9 vs. 23.3 weeks, p=0.037) than the topotecan group [n=111].
The topotecan group demonstrated higher occurrence of hematologic adverse events, and they
were influenced by administration of blood/growth factor products or dosage alteration. The
study concluded that PLD is favorable over topotecan based on the suitable dosing, equivalent
efficacy and acceptable safety profile.

In 2004, Gordon and colleagues [9] provided a long-term survival data for the earlier above-
mentioned phase III clinical trial [8]. Survival data were mature (87% of patients died, n=413).
For all patients, patients treated with PLD achieved an 18% decrease in the hazard of mortality
(median survival: 62.7 vs. 59.7 weeks, p=0.050) than patients treated with topotecan. For
patients with recurrent platinum-sensitive EOC (n= 219), patients treated with PLD [n=109] had
a statistically significant 30% decrease in the risk of mortality (median survival: 108 vs. 70 weeks,
p=0.017) than patients treated with topotecan [n=110]. There was no survival difference among
patients with recurrent platinum-resistant EOC. The study concluded that PLD yields longer
survival benefits than topotecan in patients with recurrent platinum-sensitive EOC.

In 2008, Ferrandina et al. [10] (phase III clinical trial) randomized 153 patients with recurrent
EOC who experienced relapse within 12 months following completion of an initial platinum-based
chemotherapy. Patients were randomized to receive either GEM (1 g/m2 on days 1, 8, and 15
every 28-day cycle) [n=77] or PLD (40 mg/m2 every 28 days) [n=76]. PLD group achieved a higher
median OS (14 vs. 12.8, p=0.048) than the GEM group. Similarly, PLD group achieved a higher
ORR (29 vs. 16%, p=0.056) than the GEM group. There was no statistically significant difference
in TTP (p=0.411) among both groups. With respect to drug-related side effects, GEM group had
statistically significant rates of grade III/IV neutropenia (p=0.007). On the other hand, PLD group
had higher, although not statistically significant, rates of palmar-plantar erythrodysesthesia (6
vs. 0%, p=0.061) than the GEM group. The study concluded that GEM is not favorable over PLD
in the context of TTP. That being said, GEM may be considered as a potential rescue treatment in
management of patients with recurrent EOC.

In 2008, Katsumata and colleagues [11] (phase II clinical trial by the Japanese Gynecologic
Oncology Group) explored the efficacy of PLD (50 mg/m2) every 28 days in 73 patients with
recurrent EOC. Only 11 patients were platinum-sensitive (16%). Among the platinum-sensitive
patients, only 10 patients were evaluable. The CR, PR, DS and DP occurred in 0, 3, 3 and 4 patients,
respectively. The study concluded that PLD is somehow effective in the platinum-sensitive patient
population. However, additional studies are needed.

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Etoposide
In 1998, Rose et al. (phase II clinical trial by a Gynecologic Oncology Study Group) [12] examined
the role of prolonged oral etoposide (30-60 mg/m2/d for 3 weeks, every 4 weeks) in 99 patients
with platinum-sensitive and platinum-resistant EOC. There were 41 patients with platinum-
sensitive EOC. The ORR was 34.1%, as follows: 19.5% PR and 14.6% CR rates. The median DOR,
progression-free interval (PFI) and OS were 7.5, 6.3+, and 16.5+ months, respectively. A total
of 97 patients were evaluable for toxicity. Grade III/ IV drug-related hematologic side effects
predominated. The most repeatedly encountered of them (in a descending order) were grade IV
neutropenia (25%), grade III neutropenia (20%), anemia (13.4%), grade III thrombocytopenia
(5%) and grade IV thrombocytopenia. Only one patient experienced leukemia. Three drug-related
mortalities were recorded, as follows: neutropenic sepsis (n=2) and thrombocytopenic bleeding
due to an overdose (n=1). The study concluded that etoposide is therapeutic in both types of
recurrent EOC.

Gemcitabine (GEM)
One study was conducted in 2008 by Ferrandina et al. [10]. This study is reported earlier.

Paclitaxel
In 2002, Cantù and partners [13] (phase I/II trial) randomized a total of 97 patients with
recurrent platinum-sensitive EOC to receive either monotherapy paclitaxel (175 mg/m2 IV over 3
hours) or cyclophosphamide, doxorubicin and cisplatin (CAP; 500 mg/m2, 50 mg/m2 and 50 mg/
m2 (CAP) IV, respectively). The paclitaxel group had 50 patients whereas the CAP group had 47
patients; median number of cycles was 6 for both groups. At a median follow up of 49 months,
the CAP group achieved a higher statistically significant median PFI (15.7 vs. 9 months, p=0.038)
and OS (34.7 vs. 25.8 months, p=0.043) than the paclitaxel group. Regarding ORR, the PR and CR
rates in the CAP group were 25 and 30%, respectively. Conversely, the PR and CR rates in the
paclitaxel group were 28 and 17%, respectively (p=0.062). Drug-related adverse events of grade
III/IV leukopenia (34 vs. 4%), grade II/IV neutropenia (36 vs. 13%) and grade II/III nausea/
vomiting (51 vs. 17%) were higher in the CAP group more than the paclitaxel group. On the other
hand, toxicities of allergic reactions (15 vs. 2%) and grade I/II myalgia (19 vs. 4%) were higher in
the paclitaxel group more than the CAP group. The study concluded that mono therapy paclitaxel
is not superior to a platinum-based regimen in patients with recurrent platinum-sensitive EOC.
Large-sized multicenter studies are warranted.

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel)


In 2009, Teneriello et al. [14] (phase II clinical trial) studied the role of nab-paclitaxel (260
mg/m2 IV for 30 min on day 1 of each 21-day cycle, for either a total of 6 cycles or occurrence
of disease progression) in 47 patients with recurrent platinum-sensitive EOC. There were only
44 evaluable patients, and the ORR was 64%, as follows: PR (n=13, 30%) and CR (n=15, 34%).

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Among patients who were evaluated according to Response Evaluation Criteria In Solid Tumor
(RECIST) only [n=11], ORR was 45.5%, as follows: PR (n=4, 36.4%) and CR (n=1, 9.1%). Among
non-measurable disease patients [n=11] with elevated CA-125 (>70 U/mL), the ORR was 82%, as
follows: PR (n=2, 18.2%) and CR (n=7, 63.6%). Among patients evaluated with both RECIST and
CA-125 parameters, the ORR was 64%, as follows: PR (n=7) and CR (n=7). The median DOR and
PFS were 1.3 and 8.5 months, respectively. The most commonly encountered grade III/IV drug-
related side effects were neuropathy (9%) and neutropenia (24%). The study concluded that
nab-paclitaxel yields beneficial therapeutic outcomes with a tolerable toxicity profile. However,
additional research studies of nab-paclitaxel in combination with platinum-based therapy are
necessary.
Trabectidine
In 2005, Sessa et al. [15] (European multi-center phase II clinical trial) evaluated the efficacy
and safety of trabectidine (1,300 mcg/m2 for 3-hour infusion every 3weeks) in 59 patients with
recurrent platinum-sensitive (n=29) and platinum-resistant (n=30) EOC. In platinum-sensitive
patients, the ORR and median TTP were 43% and 7.9 months, respectively. There were only 2
responses (7%) documented in the platinum-resistant patients. Overall, the most frequently
reported side effects were asthenia, neutropenia and self-limited elevations in aminotransferases,
not necessitating alteration or ceasing of treatment. The study concluded that trabectidine is
potentially safe and active in patients with recurrent platinum-sensitive EOC. Further research
studies are needed either as single-agent or in combination with other therapeutic agents.
In 2007, Krasner and colleagues [16] (multicenter phase II trial) evaluated the efficacy and
safety of trabectidine (0.58 mg/m2 for an 3-hour infusion weekly for 3 weeks of a 4-week cycle) in
147 patients with recurrent platinum-sensitive (n=62, evaluable patients) and platinum-resistant
(n=79, evaluable patients) EOC. In platinum-sensitive patients, the ORR and median PFS were
29% and 5.1 months, respectively. In platinum-resistant patients, the ORR and median PFS were
6.3% and 2 months, respectively. The most common chemotherapy-related adverse effects (in
an ascending order) were: nausea (5%), vomiting (5%), fatigue (5%), neutropenia (8%), and
reversible hepatic alanine transferase (10%). The study concluded that trabectedin has favorable
therapeutic and tolerable safety profiles in patients with recurrent platinum-sensitive EOC.
In 2009, Del Campo and partners[17] (randomized, open-label, phase II clinical trial)
administered trabectidine to 107 patients with recurrent platinum-sensitive EOC. One group
(group A, n=54) of patients received trabectidine at 1.5 mg/m2 over 24 hours, whereas the other
group (group B, n=53) received trabectidine at 1.3 mg/m2 over 3 hours. Both groups received the
dose every 3 weeks. Group A had higher ORR (38.9 vs. 35.8%), nausea/vomiting (24 vs. 15%),
fatigue (15 vs. 10%), and transient non-cumulative neutropenia (55 vs. 37%) than Group B.
Conversely, Group B had higher median TTP (6.8 vs. 6.2 months) and elevated transient non-
cumulative alanine aminotransferase (59 vs. 55%) than Group A. The study concluded that both
regimens were fairly active and rationally well-endured in patients with recurrent platinum-
sensitive EOC. The encouraging results warrant additional confirmatory research.

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In 2013, Del Campo and colleagues [18] conducted a retrospective pooled analysis of three
phase II trials of single-agent trabectidine [15-17] in management of patients with relapsed
EOC (n=295). They compared the above-mentioned 3 different dosing regimens, namely,
3-hour infusion weekly every 3 weeks of a 4-week cycle, 3-hour infusion once every 3 weeks
(q3w), and 24-infusion q3w. The weekly regimen was associated with lower ORR (16 vs. 36%;
p=0.0001), disease stabilization (46 vs. 66%; p=0.0007) and shorter median PFS (2.8 vs. 5.6
months, p<0.0001) than both q3w regimens. There were similar clinical outcomes documented
for the 3-hour and 24-hour infusions q3w regimens. Slightly worse drug-related side effects,
with respect to vomiting, fatigue and neutropenia, were observed for the 24-hour infusion q3w
regimen as opposed to the 3-hour infusion q3w regimen. The review concluded that mono-therapy
trabectidine (administered as a 3-hour infusion q3w) is the recommended dosing, and its potency
and drug-related adverse events satisfactorily parallel other active salvage chemotherapies.

Topotecan
One study was conducted in 2001 by Gordon et al [8]. A follow-up long-term survival data was
conducted in 2004 by Gordon and partners [9]. Both studies are reported earlier.

In 2008, Morris et al [19] (phase II clinical trial) explored the efficacy and safety of topotecan
(4 mg/m2 weekly as tolerated until disease progression) in 41 patients with recurrent platinum-
sensitive EOC. A median of 9 topotecan cycles were administrated and ranged from as low as 1
to as high as 45 cycles. Overall, the drug schedule was well-endured; there were no incidences
of grade IV anemia or thrombocytopenia. However, around 9 (22%) and 7 (17%) patients
developed grade III/IV fatigue and neutropenia, respectively. There was a total of 38 patients
who were assessable for drug-related response. A sum of 1, 8, 13, and 16 patients developed CR
(3%), PR (21%), DP (34%), and DS (42%), respectively. The study concluded that weekly dosing
of topotecan was efficacious, well-endured, and yield analogous outcomes to that of the classical
5-day regimen.

Iproplatin
In 1991, Weiss and colleagues [20] explored the role of iproplatin (initial dose: 270 mg/m2,
range: 135-340 mg/m2 as per toxicity) as a second-line salvage therapy in 105 patients with
recurrent platinum-sensitive and platinum-resistant EOC. There were 101 patients who had
measurable disease. The DOR ranged from 2 to 20 months.In patients who were resistant to
carboplatin, the ORR was 12% (total=2/18, PR=2, CR=0) whereas in patients who were resistant
to cisplatin, the ORR was 12% (total=7/60, PR=4, CR= 3). Most importantly, in platinum-sensitive
patients treated with cisplatin, the ORR was 26% (total=5/19, PR=2, CR= 3). The most frequently
reported side effects (in an ascending order) were diarrhea (40%), anemia (68%), leukopenia
(76%) and thrombocytopenia (93%). The study concluded that iproplatin is not advised as
therapeutic second-line chemotherapy in patients with platinum-sensitive as well as platinum-
resistant EOC (due to cross-reactivity with platinum-based agents, namely carboplatin and
cisplatin).

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COMBINATION SYSTEMIC CHEMOTHERAPY REGIMENS
Numerous combinations of systemic chemotherapies have been investigated in patients
with recurrent platinum-sensitive EOC. Such combinations included: platinum-based and non-
platinum-based regimens.

Table 2: A summary of major phases II/III studies on combination chemotherapy in patients


with recurrent platinum-sensitive EOC.
ORR DS TTP PFS OS
Ref Authors Phase Year Single-Agent Chemotherapy n
(%) (%) (mon) (mon) (mon)
PLD 76 16 NR 16 NR 14
[21] Parmar et al. Paclitaxel plus a platinum-based
I/II 2003 392 66 NR NR 13 29
chemotherapy
[23] Rose et al. II 2005 Carboplatin plus paclitaxel 28 77 17.9 NR 14 NR

[25] Carboplatin plus paclitaxel 96 58 NR 10.8 NR 29.4


Bafaloukos et al. II 2010
Carboplatin plus PLD 93 51 NR 11.8 NR 24.7

Pujade-lauraine Carboplatin plus paclitaxel 509 NR NR NR 9.4 18


[26] III 2010
et al. Carboplatin plus PLD 467 NR NR NR 11.3 26

[28] PLD plus carboplatin 467 NR NR NR NR 30.7


Wanger et al. III 2012
Paclitaxel plus carboplatin 509 NR NR NR NR 33

[29] Ferrero et al. II 2007 Carboplatin plus PLD 104 63 19.2 NR 9.4 32
II
[30] Weber et al. 2009 Carboplatin plus PLD 81 65.4 22.2 NR 13.6 38.9

Carboplatin 178 30.9 38.8 NR 5.8 17.3


[31] Pfisterer et al. III 2006
Carboplatin plus gemcitabine 178 47.2 38.2 NR 8.6 18

Carboplatin 95 56.2 20.9 16 12 NR


[32] Bolis et al. III 2001
Carboplatin plus epidoxorubicin 95 61.7 28 18 25 NR

[33] van der Burg et al. II 1991 Cyclophosphamide plus carboplatin 30 32 53 NR 8 12

[34] Zanaboni et al. II/III 1991 Cisplatin plus epirubicin or etoposide 40 60 NR NR NR 13.5

Trabectidine plus PLD 218 35.3 NR NR 9.2 27


[35] Monk et al. III 2010
PLD 213 22.6 NR NR 7.5 24.1

Trabectidine plus PLD 123 NR NR NR 7.4 23


[36] Poveda et al. III 2011
PLD 91 NR NR NR 5.5 17.1

[38] Joly et al. II 2009 Gemcitabine plus topotecan 42 20 48.5 NR NR 15.6

DS: disease stabilization; MON: months; N: sample size; NR: not reported; ORR: overall
response rate; OS: overall survival; PFS: progression-free survival; PLD: pegylated liposomal
doxorubicin; REF: reference; TTP: time to progression.

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Platinum-Based Combination Systemic Chemotherapy Regimens
Cisplatin and carboplatin were the two most commonly platinum-based drugs employed in
the combination systemic chemotherapy regimens.

Paclitaxel plus a platinum-based chemotherapy


In 2003, Parmar and colleagues [21] (international, randomized, multicenter, phase I/II, the
ICON4/AGO-OVAR-2.2 clinical trial) randomized 802 patients with recurrent platinum-sensitive
EOC to receive either paclitaxel plus a platinum-based chemotherapy (n=392) or a conventional
platinum-based chemotherapy (n=410). A total of 530 patients died after a median follow up of
42 months. A total of 717 patients developed progressive disease or died. The paclitaxel plus
platinum-based chemotherapy group achieved a higher statistically significant 2-year survival
rate (57 vs. 50%, p=0.02), median OS (29 vs. 24 months), 1-year PFS rate (50 vs. 40%, p=0.0004),
and median PFS (13 vs. 10 months) than the conventional platinum-based chemotherapy group.
The study concluded that a regimen of paclitaxel plus platinum-based chemotherapy is superior
to a conventional platinum-based chemotherapy regimen, in terms of OS and PFS, in patients with
recurrent platinum-sensitive EOC.

Carboplatin plus paclitaxel


In 1998, Rose and partners [22] (phase II clinical trial) evaluated the role of re-treatment
with paclitaxel (135 mg/m2 as a 24-hour infusion) plus carboplatin (area under curve [AUC] of
5-6) every 21 days in 25 patients with recurrent platinum-sensitive EOC. Only 20 patients had
measurable and assessable disease, of which 4 (20%) and 14 (70%) patients experienced PR
and CR, respectively. The ORRs were 91% and 89% for measurable and assessable diseases,
respectively. The median PFI for measurable/assessable and non-assessable disease was 9 and 7
months, respectively. At a ranging interval between 2 and 15 months (median 9.0 months) after
secondary remedy, 15 patients (60%) were reported to have relapse. Moreover, at a ranging
interval between 2 and 21 months (median 10 months), 2 patients (8%) were reported to be
dead. The study concluded that carboplatin plus paclitaxel combination is associated with higher
ORR and long PFI in patients with recurrent platinum-sensitive EOC.

In 2005, Rose et al. [23] (phase II clinical trial) examined the role of paclitaxel (80 mg/m2
over 1 hour infusion on days 1, 8 and 15) plus carboplatin (AUC of 5 on day 1 only) in 28 patients
with recurrent platinum-sensitive EOC. A median of 6 courses was administered and ranged
from as low as 1 to as high as 13 cycles. Paclitaxel dose decreased to 60 mg/m2 were deemed
necessary in around 85% of patients. Grade III thrombocytopenia, grade III neutropenia, grade IV
thrombocytopenia, grade IV neutropenia and neutropenic fever were observed in 5, 14, 0, 1 and 1
patients, respectively. Around 77% of the evaluable patients (n=20/26) demonstrated response
to treatment, of which 15 and 5 patients exhibited CR and PR, respectively. The study concluded
that a regimen of weekly paclitaxel (60mg/m2) plus carboplatin (AUC of 5) is largely endured and
therapeutic in patients with recurrent platinum-sensitive EOC.
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In 2009, Hoekstra and associates [24] performed a retrospective chart review exploring the
role of weekly paclitaxel (80 mg/m2 on days 1, 8, 15) and monthly carboplatin (AUC 5 on day
1) of a 28-day cycle in 20 patients with recurrent EOC. A total of 15 patients were regarded as
platinum-sensitive whereas 5 patients were regarded as platinum-resistant. For all patients, the
ORR was 85% (n=17/20), as follows: PR (12%, n=2/17) and CR (78%, n=15/17). Specifically,
in platinum-sensitive patients, the ORR was 94% (n=14/15). Even after a median follow up of
2 years and 4 months, median survival could not be documented. Only 35% of patients (n=7)
exhibited neutropenia of grade III-IV drug-related adverse events. Moreover, 25% of patients
displayed platinum hypersensitivity; however, they progressed with successful treatment
through administration of a carboplatin desensitization procedure. The study concluded that a
regimen of weekly paclitaxel plus monthly carboplatin is effective and potentially safe in patients
with recurrent platinum-sensitive EOC. Large-sized multicenter study is warranted.

In 2010, Bafaloukos and colleagues [25] (phase II clinical trial, Hellenic Cooperative Oncology
Group study) randomized 189 patients with recurrent platinum-sensitive EOC to receive either
PLD (45 mg/m2 once every 28 days) plus carboplatin (AUC of 5) [Group A, n=93] or paclitaxel
(175 mg/m2 once every 21 days) plus carboplatin (AUC of 5) [Group B, n=96]. There were no
statistically significant differences between both groups regarding ORR (51 vs 58%), CR rate (23
vs. 34%), median OS (24.7 vs. 29.4 months), and median TTP (11.8 vs. 10.8 months). Although
there was no drug-related fatality reported, termination of treatment was statistically significantly
higher in Group B than Group A (13.5 vs. 3%, p=0.016). For both groups, neutropenia was the
most frequently documented side effect (Group A vs. Group B: 35 vs. 30%). Group A had higher
statistically significant rates of the following side effects than group B: severe thrombocytopenia
(11 vs. 2%, p=0.016) and grade II palmar-plantar erythrodysesthesia (38 vs. 9%, p<0.001).
Conversely, Group B had higher statistically significant rates of the following side effects than
group A: grade III neurotoxicity (7 vs. 0%, p=0.029) and grade III alopecia (20 vs. 5%, p=0.003).
The study concluded that PLD plus carboplatin is an active treatment in patients with recurrent
platinum-sensitive EOC with low associated frequencies of alopecia and neurotoxicity side
effects. A phase III clinical trial is deemed necessary to further assess the efficacy and safety of the
combination regimen.

In 2010, Pujade-Lauraine and colleagues [26] (multicenter, non-inferiority, CALYPSO phase


III clinical trial) randomized 976 patients with recurrent platinum-sensitive EOC into 2 groups,
namely, group A and group B. Group A (n=467) received PLD (30 mg/m2) plus carboplatin (AUC of
5) every 28 days, whereas group B (n=504) received paclitaxel (175 mg/m2) and carboplatin (AUC
of 5) every 21 days for at least 6 cycles. The median follow-up was 22 months. Group A achieved
a higher statistically significant PFS (11.3 vs. 9.4 months, p=0.005) than Group B. Despite the OS
data insufficient for final analysis, a sum of 334 patients passed away during treatment. Grade
II-III hand-foot syndrome (12.0 v 2.2%), nausea (35.2 vs. 24.2%) and grade II/III mucositis (13.9
vs. 7%) were noticed more frequently in Group A than Group B. Conversely, non-blood related

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adverse side effects (36.8 vs. 28.4%), ≥ grade II alopecia (83.6 vs. 7%), hypersensitivity reactions
(18.8 vs. 5.6%) and sensory neuropathy (26.9 vs. 4.9%) were noticed more frequently in Group
B than Group A. The study concluded that the regimen of PLD plus carboplatin is superior to the
regimen of paclitaxel plus carboplatin in terms of PFS and safety profile.

In 2011, Joly et al. [27] monitored the rate of hypersensitivity reactions (HSRs) in the above-
mentioned CALYPSO phase III clinical trial [26]. Data available for 466 and 502 patients in Group
A and Group B, respectively. It was noted that Group A had a higher rate of HSRs than Group B
within the first chemotherapeutic schedule (46 vs. 16%). However, overall, Group B experienced a
higher statistically significant rate of HSRs than group A (33.1 vs. 15.5%, p<0.001). Chemotherapy
regimen and age were sub-analyzed as multivariate predictors of allergy. At the conclusion of the
study, it was reported that the combination PLD plus carboplatin as well as older age ≥ 70 years
old were associated with a low frequency of HSRs in patients with recurrent platinum-sensitive
EOC.

In 2012, Wagner et al. [28] released the final OS analysis of the CALYPSO phase III clinical
trial [26]. The median follow-up was 49 months. There was no statistically significant difference
of OS between Group A and Group B (30.7 vs. 33 months, p=0.94). The study concluded that PLD
plus carboplatin is associated with postponed disease progression and equivalent OS outcomes to
paclitaxel plus carboplatin regimen in patients with recurrent platinum-sensitive EOC.

Carboplatin plus pegylated liposomal doxorubicin (PLD)


In 2007, Ferrero and colleagues [29] (retrospective GINECO phase II clinical trial) administered
carboplatin (AUF of 5) plus PLD (30 mg/m2) every 4 weeks for a maximum of 9 cycles in 104
patients with recurrent platinum-sensitive EOC. The median PFS, OS and ORR were 9.4 months,
32 months and 63%, respectively. Non-hematologic drug-related adverse events were mostly of
grade I/II; grade III/IV neutropenia happened in 51% of patients whereas febrile neutropenia
happened in only 3% of patients. Alopecia and neurotoxicity were of low frequency. The study
concluded that carboplatin plus PLD is active and offers clinical benefits in terms of prolonged OS,
prolonged PFS and well-endured safety profile.

In 2009, Weber and colleagues [30] (prospective GINECO phase II clinical trial) administered
carboplatin (AUF of 5) plus PLD (30 mg/m2) every 4 weeks for a maximum of 6 cycles of occurrence
of disease progression, in 81 patients with recurrent platinum-sensitive EOC. The median PFS, OS
and ORR were 13.6 months, 38.9 months and 65.4%, respectively. Hematological drug-related
adverse events were more frequently reported than non-hematological ones. Neither drug-
related fatality nor cardiotoxicity were observed. The study concluded that carboplatin plus PLD
is an active treatment and well-endured in patients with recurrent platinum-sensitive EOC.

In 2010, a study was conducted by Bafaloukos and colleagues [25]. This study is reported
earlier.

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Also, in 2010, another study was conducted by Pujade-Lauraine and colleagues [26]. This
study is reported earlier.

In 2011, a study was conducted by Joly et al. [27]. This study is reported earlier.

In 2012, a study was conducted by Wagner et al. [28]. This study is reported earlier.

Carboplatin plus gemcitabine (GEM)


In 2006, Pfisterer and partners [31] (phase I/II trial, an intergroup trial of the AGO-OVAR, the
NCIC CTG, and the EORTC GC) randomized 356 patients with recurrent platinum-sensitive EOC
to receive either a single-agent carboplatin (n=178) or combination carboplatin plus gemcitabine
(n=178) every 21 days. A median of 6 cycles was reported in both groups. With a median follow up
of 17 months, the combination carboplatin plus gemcitabine group achieved higher statistically
significant PFS (8.6 vs. 5.8 months, p=0.0031) and ORR (47.2 vs. 30.9%, p=0.0016) than the single-
agent carboplatin group. There were no statistical differences among both groups with respect
to median OS and quality of life (QoL) scores. Myelosuppression was substantially more frequent
in the combination regimen; however, without subsequent increase in myelosuppression-related
complications, for example, infections and fever-related neutropenia. The study concluded
that combination regimen of carboplatin plus gemcitabine is associated with enhanced clinical
outcomes such as PFS and ORR without incurring deleterious effects on QoL in patients with
recurrent platinum-sensitive EOC.

Carboplatin plus epidoxorubicin


In 2001, Bolis and colleagues [32] (phase III clinical trial) randomized 190 patients with
recurrent platinum-sensitive EOC to receive either single-agent carboplatin (300 mg/m2 every
4 weeks for 5 cycles) [Group A, n=95] or carboplatin (300 mg/m2) plus epidoxorubicin (120
mg/m2) every 4 weeks for 5 cycles [Group B, n=95]. For the single-agent carboplatin group,
the DOR, CR and PR were 16 months, 36% and 20.2%, respectively. On the other hand, for
carboplatin plus epidoxorubicin group, the DOR, CR and PR were 20 months, 31.8% and 29.9%,
respectively. Among both groups, there were no statistical significance with respect to DOR, CR
and PR. The single-agent carboplatin group had a lower 3-year percentage of survival (29 vs.
42%, no statistical significance) than the carboplatin plus epidoxorubicin group. With respect
to drug-related adverse events, the single-agent carboplatin group had lower rates of grade III/
IV thrombocytopenia, leukopenia and anemia. Conversely, the carboplatin plus epidoxorubicin
group had a higher rate of grade III alopecia (around 90%). The study concluded that both
regimens did not exhibit noticeable therapeutic differences, and the hematological side effects
were more common in the combination regimen.

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Carboplatin plus cyclophosphamide
In 1991, van der Burg and partners [33] (phase II clinical trial) administered cyclophosphamide
(100 mg/m2orally on days 1-7) plus carboplatin (300 mg/m2 IV on day 8) in 30 patients with
platinum-sensitive EOC. Only 28 patients were eligible for response assessment. The ORR, CR,
PR, DS and DP rates were 32%, 18%, 14%, 53% and 14%, respectively. The median PFS and
OS were 8 and 12 months, respectively. Overall, the combination regimen was well-endured,
and thrombocytopenia was the most significant drug-related toxicity. The study concluded that
cyclophosphamide plus carboplatin should be considered for palliative purposes only.

Weekly cisplatin plus epirubicin or etoposide


In 1991, Zanaboni and colleagues [34] (retrospective study) administered weekly cisplatin
plus epirubicin or etoposide in 40 patients with platinum-sensitive EOC. The ORR, DOR and
median OS were 60% (CR: 25%), 7 months and 13.5 months, respectively. The drug-related side
effects were acceptable. The study concluded that weekly cisplatin plus epirubicin or etoposide
showed an evidence of effectiveness and was well-tolerated.

Non-platinum-based Combination Systemic Chemotherapy Regimens


There are a few studies that have explored the role of non-platinum-based doublets in the
management of patients with recurrent platinum-sensitive EOC.

Trabectidine plus pegylated liposomal doxorubicin (PLD)


In 2010, Monk and colleagues [35] (OVA-301, phase III clinical trial) randomized 672 patients
with recurrent platinum-sensitive and platinum-resistant EOC to receive either trabectidine (1.1
mg/m2 3-hour infusion) plus PLD (30 mg/m2 IV) every 21 days [Group A, n=337] or single-agent
PLD [Group B, n=335] every 28 days. For all patients, the trabectidine plus PLD group achieved
higher statistically significant median ORR (27.6 vs. 18.8%, p=0.0080) and median PFS (7.3 vs.
5.8 months, p=0.0190) than the single-agent PLD group. For patients with recurrent platinum-
sensitive EOC [n=431], similar outcomes were obtained; the trabectidine plus PLD group [n=218]
achieved higher statistically significant median ORR (35.3 vs. 22.6 %, p=0.0042) and median PFS
(9.2 vs. 7.5 months, p=0.0170) than the single-agent PLD group [n=213]. As for the platinum-
resistant EOC patients, there were no statistically significant differences between both groups
with regards to ORR and PFS. When compared to the single-agent PLD group, the trabectidine
plus PLD group had high frequencies of neutropenia and grade III/IV high transaminase levels,
and low frequencies of mucositis and hand-foot syndrome. The study concluded that combination
trabectidine plus PLD regimen is associated with clinical advantages in terms of ORR, PFS and
better drug-related safety profile in patients with recurrent platinum-sensitive EOC.

In 2011, Poveda and colleagues [36] (OVA-301 phase III clinical trial) reported the outcomes
of the OVA-301 study [35] for the 214 patients with platinum-sensitive EOC. The trabectidine plus

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PLD group achieved a higher statistically significant median PFS (7.4 vs. 5.5 months, p=0.0152;
35% reduction in the risk of DP) and median OS (23 vs. 17months, p=0.0015; 41% reduction
in the risk of death) than the single-agent PLD group. Both groups (76 and 77%, respectively)
were administered subsequent platinum-based therapy, and the trabectidine plus PLD group
had a higher statistically significant median OS (13.3 vs. 9.8 months, p=0.0357) than the single-
agent PLD group. The study concluded that trabectidine plus PLD yields clinical advantages
with respect to PFS and OS in the general population, generally, and in the platinum-sensitive
population, specifically.

In 2012, Monk and partners [37] reported the OS analysis of OVA-301 phase III clinical trial [35].
The study was powered to demonstrate a 33% increase in the OS after 520 deaths occurred. The
median follow-up was approximately 47.5 months. The trabectidine plus PLD group had a higher
statistically significant median OS (p=0.0285) than the single-agent PLD group; the platinum-
sensitive group had the most pronounced advantage of OS as opposed to the platinum-resistant
group (p=0.0027). The analysis included several unexpected outcomes and further secondary
analyses/hypotheses were generated. At the conclusion of the study, it was determined that the
final analysis of OS did not match the protocol-defined condition for statistical significance, and
the PFI influenced the OS, rendering the interpretation of results uncertain.

Gemcitabine plus topotecan


In 2009, Joly and partners [38] (a French multicenter phase II clinical trial) administrated
weekly gemcitabine (1000 mg/m2) plus topotecan (2.5 mg/m2) on days 1, 8, and 15 of a 28-day
cycle to 77 patients with platinum-sensitive and platinum-resistant EOC. A total of 66 patients
were evaluable for response, and 17% and 4% of patients developed grade III and IV neutropenia,
respectively. Around 60% of patients were administered the complete regimen of the combination
therapy as a result of developing moderate neutropenia and thrombocytopenia. For all patients,
the ORR was 14%. As compared to platinum-resistant (n=30), the platinum-sensitive (n=36) EOC
patients had higher ORR (20 vs. 7%), median DOR (6.4 vs. 4.9%), DS (69 vs. 63%) and median
OS (15.6 vs. 7.5 months). However, the platinum-resistant group had a higher decrease in the
rate of pain/symptomology (64 vs. 39%) than the platinum-sensitive group. The study concluded
that weekly administration of gemcitabine plus topotecan is associated with moderate ORR and
satisfactory quality of life (QoL) in terms of disease- and symptom-control.

CONCLUSIONS
• Epithelial ovarian cancer (EOC) remains a principal cause of cancer-related mortality in
women.

• In spite of the primary therapy (surgical cytoreduction and platinum-taxane combination


regimen), majority of patients (85%) with advanced-stage EOC will relapse and require an
additional systemic medical treatment.

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• The selection of systemic medical treatment is largely based on the response to the first-line
chemotherapy -that is, the platinum-free interval (PFI):

o Patients with a PFI ≤ 6 months are regarded as platinum-resistant.

o Patients with a PFI ≥ 6 months are regarded as platinum-sensitive.

• Patients with recurrent platinum-sensitive EOC should be considered for secondary


cytoreduction (whenever technically feasible) and re-treatment with a platinum-based
regimen.

• In patients with recurrent platinum-sensitive EOC, platinum-based regimens are recommended


over non-platinum-based regimens.

• Platinum-based combination chemotherapy is preferred over monotherapy as it is associated


with improved objective response rate (ORR), progression-free survival (PFS), and to some
degree, superior overall survival (OS).

• Recommended platinum-based combination regimens are carboplatin plus paclitaxel (first


priority), carboplatin plus gemcitabine, or carboplatin plus pegylatedliposomal doxorubicin
(PLD).

• The selection of the platinum-based combination regimen should be based on availability,


affordability, therapeutic efficacy and toxicity profile.

• Availability and affordability of novel molecularly targeted therapies, such as angiogenesis


inhibitors and poly-ADP ribose polymerase (PARP) inhibitors as a maintenance therapy,
remains a healthcare problem.

• Combination novel molecularly targeted therapy and systemic chemotherapy is an active and
exciting area for research.

• Future research should strive to explore molecular mechanisms of recurrence, and


subsequently recognize significant molecular targets for therapeutic interventions.

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