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Dose-Dense Chemotherapy in Advanced Ovarian Cancer:
Old Idea, New Perspectives
Vlad Manolescu1,2, Viorica Nagy1,2
1) Institute of Oncology Prof. Dr. I. Chiricuta Cluj Napoca; 2) The “Iuliu Hatieganu” University of Medicine and
Pharmacy Cluj Napoca
The current standard of care in advanced ovarian cancer consists of maximum cytoreductive surgical effort followed by chemotherapy - 6 cycles of
Paclitaxel 175mg/m2 (iv, 3 hours) plus carboplatin AUC 5-7 every 21 days, leading to excellent response rates but also to frequent relapses. Several
methods of improving outcomes were intensively studied: addition of a third agent to chemotherapy, addition of anti-angiogenesis drugs – Bevacizumab,
intraperitoneal chemotherapy, dose dense chemotherapy. Dose dense chemotherapy regimens rationale is the Norton-Simons model of growth according
to which the increasing of dose density of chemotherapy will increase efficacy by minimizing the opportunity for regrowth of tumor cells between cycles
of chemotherapy. Several clinical studies using DD regimens were first developed for breast cancer treatment in the neoadjuvant, adjuvant and metastatic
disease setting. Taking into account the promising findings of breast cancer clinical trials, the DDC principles were applied in advanced ovarian cancer
chemotherapy in the first and second line treatment setting clinical studies. Several regimens including weekly paclitaxel + cisplatin or weekly paclitaxel
+ carboplatin were investigated with results that proved that dose-dense weekly platinum is an effective therapy in platinum-sensitive as well as in
platinum resistant patients. The Japanese Gynecology Oncology Group (JGOG) was the first to demonstrate the survival advantage of dose dense weekly
administration of paclitaxel in 2009. Patients were randomly assigned to receive six cycles of either paclitaxel (180mg/m2; 3 hours intravenous infusion)
plus carboplatin (area under the curve [AUC] 6 mg/ml per min) given on day 1 of a 21 day cycle – conventional regimen arm with 320 patients) or dose
dense (DD) paclitaxel (80mg/m2; 1 hour infusion) given on days 1, 8 and 15 plus carboplatin given on day 1 of a 21-day cycle (dose dense regimen arm
with 317 patients). Statistical analysis showed that median progression-free survival was longer in the DDC group (28 months, 95% CI 22.3-35.4) than in
the conventional treatment group (17.2 months, 15.7-21.1; hazard ratio [HR] 0.71; 95% CI 0.58-0.88; p=0.0015). Moreover, the 3 years overall survival
was higher in the dose-dense regimen group (72.1%) than in the conventional treatment group (65.1%; HR 0.75,0.57-0.98; p=0.03). Hematologic toxicities
– neutropenia and severe anemia were higher in the dose dense group but peripheral neuropathy was similar in the two study arms. The ongoing trials
for treatment of advanced ovarian cancer include dose-dense chemotherapy arms. Although new biological therapies (bevacizumab) showed its efficacy
in ovarian cancer, it is still used in combination with chemotherapeutic agents such as paclitaxel. Such approaches as dose dense administrations are
intensively investigated in ongoing trials and the right dosing, frequency is to be established after publication of new emerging data.
Key words: ovarian cancer, dose dense chemotherapy, paclitaxel, carboplatin
Background
It is well known that ovarian cancer is the most lethal
disease in the gynecological malignancies group (1). At this
moment there is no efficient screening method for ovarian
cancer and most of the patients with epithelial ovarian cancer
are diagnosed in advanced stages.
The current standard of care in advanced ovarian cancer
consists of maximum cytoreductive surgical effort followed
by chemotherapy. Standard chemotherapy for advanced
ovarian cancer consists of 6 cycles of Paclitaxel 175mg/m2
(iv, 3 hours) plus carboplatin AUC 5-7 every 21 days (2).
Journal of Radiotheraphy & Medical Oncology
June 2013 Vol. 19 No 1: 11-16
Address for correspondence:
Vlad Manolescu
Institute of Oncology “Prof. dr. I. Chiricuta”, Cluj-Napoca
34-36, Republicii Str, 400015
Cluj-Napoca, Romania
Email: [email protected]
This recommendation is supported by level 1 evidence from
two large randomized trials, the Gynecologic Oncology
group (GOG) study and the Canadian-European Intergroup
study that showed the paclitaxel /platinum combination to
be superior to the cyclofosfamide/cisplatin combination in
terms of survival (3-5) . Despite excellent response rates
to standard chemotherapy, in 75% of the complete clinical
responses the disease will relapse and most of the patients
will die due to progressive disease (4).
Several approaches for improving outcomes of primary
treatment for advanced ovarian cancer have been studied.
The addition of a third chemotherapeutic agent to the
platinum and taxane regimen was the first approach to be
investigated but no improvement in survival was realised.
Moreover, a third agent brought little else but more severe
toxicities (6). The year 2010 was a turning point for ovarian
cancer treatment: bevacizumab was proved to improve the
survival of patients with ovarian cancer (7, 8). Other justified
attempts were intraperitoneal chemotherapy, maintenance
chemotherapy and dose-dense chemotherapy.
12
Basic principles of Dose-Dense Chemotherapy
Dose-dense chemotherapy (DDC) is a chemotherapy
administration concept that is being investigated more and
more. In order to achieve maximum tumor kill, dose-dense
regimens increase the rate of chemotherapy delivery by
reducing the interval between each dose, not by increasing
the dosage.
Understanding DDC requires the knowledge of tumor
cell replication and growth models better known as the
Gompertzian growth curve, which is based on Norton
Simon’s hypothesis (Fig.1). According to the Gompertzian
theory, tumor growth tends to follow a mathematically
predictable growth curve, with rapid initial growth
succeeded by slower, leveled growth (Fig.2) (9). It is well
known that rapidly dividing cells contained by smaller,
early stage tumors are more sensitive to chemotherapy.
The Norton–Simon model considers that increasing the
dose density of chemotherapy will increase efficacy by
minimizing the opportunity for the regrowth of tumor cells
Fig. 1. Norton-Simon Hypothesis. The aim of dose-dense treatment
is to hit cancer cells when they are most vulnerable, killing them
before they can give rise to drug-resistant descendants (9).
Manolescu & Nagy
between cycles of chemotherapy. This is the main principle
-of DDC with the Gompertzian curve, hitting the tumor cells
at the time they are just beginning to grow rapidly again
– “hit them while they are down” (10).
Accelerating the chemotherapy administration has its
maximal impact in the early (faster growing part of the
growth curve). Consequently, delays or interruptions in
chemotherapy result in lesser efficacy as the drug acts in
the later (flat) part of the gompertzian growth curve. Both
intrinsic kinetics of cancer cell growth and the potential
effect on tumor blood vessels (inhibition of angiogenesis)
contribute to reduce the tumor regrowth.
At the same time, heterogeneity of chemotherapy
sensitivity of cancer clones that reflects the evolutionary
diversity of any individual cancer is a variable that biases
the Norton-Simon mathematical model. This heterogeneity
predicts that resistant cancer clones are growing even as
sensitive clones are responding to chemotherapy.
Dose-Dense Chemotherapy in Breast Cancer
– first positive results
Several clinical studies using DD regimens were first
developed for breast cancer treatment in the neoadjuvant,
adjuvant and metastatic disease setting. Despite the fact that
the theory seems logical, practice showed that the results
of DDC regimens in the breast cancer treatment were
promising, but not that convincing (11) .Clinical studies
in women with node-positive breast cancer did not find a
statistically significant difference in survival or recurrence
rates between DD and classical chemotherapy regimens.
However, statistical analysis showed a slightly improved
survival and fewer recurrences. Consequently, researchers
drew the conclusion that certain subgroups of high risk
women with breast cancer (under 50 years old, with ER
negative status and/or HER2 positive tumors) would benefit
the most from DDC (12). Furthermore, two randomized
phase three trials on breast cancer showed improved survival
benefit by administering paclitaxel weekly compared with
every 21 days administration (12, 13).
Dose-Dense Chemotherapy in Advanced
Ovarian Cancer
Fig. 2. Gompertzian curve pattern of tumor growth. Initially the
tumor grows exponentially until crossing the inflection point at 2
whereupon its growth decelerates. As the tumor grows its core lacks
oxygen and becomes necrotic. When the rate of growth equals the
rate of death (necrosis) the tumor size remains constant (9).
Even if the prognosis of patients with advanced ovarian
cancer has improved significantly by the introduction
of paclitaxel/platinum combination chemotherapy and
interval debulking surgery, many patients still die of drug
resistant disease. Second line chemotherapy has an activity
in recurrent ovarian cancer and may result in prolonged
secondary remissions and improved quality of life with
good symptom control (14). The response to second line
chemotherapy is related to platinum sensitivity. Platinum
based re-challenge has 60% response rates in the case of
platinum sensitive tumors - progression free survival (PFS)
>6 month. The response rate falls below 10% in platinum
Dose-dense chemotherapy in advanced ovarian cancer: old idea, new perspectives
resistant patients (with progression during or within 6
months after last platinum chemotherapy) (15).
Several agents such as topotecan, gemcitabine, liposomal
doxorubicine, paclitaxel, docetaxel, etoposide were
investigated in the second line treatment of ovarian cancer
with response rates below 20% in the platinum resistant
patients. One distinct group is formed by the intermediate
sensitive patients (PFS between 6-12 months) that have
response rate raging from 20 to 35% to the chemotherapy
agents mentioned (16). Consequently, intensive efforts
were made in order to improve ovarian cancer management
including new treatment strategies
Taking into account the promising findings of breast
cancer clinical trials, the DDC principles were applied in
advanced ovarian cancer chemotherapy in the first and
second line treatment clinical studies.
Weekly paclitaxel and ciplatin
In vitro studies with paclitaxel suggested that fractionated
brief infusions might be more effective than the standard 3
hours infusion every three weeks. The main rationale of
dose dense weekly administration of paclitaxel is the larger
percentage of cancer cells to enter the vulnerable phase of
their cell cycle when cytotoxic paclitaxel concentrations are
present. Moreover, lower doses and the shorter the infusions
may lead to reduced myelosupresion and other toxicities
compared to the 3 hour infusion (17).
These assumptions were demonstrated in a dose
finding phase one study with paclitaxel administrated in
one hour, weekly in patients who were previously treated
with paclitaxel and cisplatin at conventional intervals.
This study demonstrated that the dose limiting toxicity
was reached at 100 mg/m2, defining a maximum tolerated
dose of 80mg/m2/week. 30% of the patients (4 out of 13
assessable patients) achieved partial responses. The toxicity
profile was much improved for the weekly administration:
no mucositis or grade 3 neuropathy was seen and the
hematologic toxicity was less pronounced compared to the
3-weekly schedule (18). These results, combined with later
studies that confirmed the feasibility and activity of the
weekly paclitaxel offered the rational to combine weekly
paclitaxel with weekly platinum.
FE de Jongh from the University Medical Center
Rotterdam performed a phase I/II study in order to investigate
the combination of dose dense cisplatin combined with
paclitaxel. Weekly cisplatin 70mg/m2 (days 1,8,15 and
29,36,43) was combined with escalating doses of paclitaxel
either 4 weekly(135-225 mg/m2) or weekly (60-100 mg/m2),
administered over 3h followed by 3 weekly paclitaxel/
platinum. The targeted population consisted of patients with
primary epithelial ovarian cancer with first line platinum–
based combination indication and patients with progressive
disease or relapse after therapy with first line platinum–based
combination without previous paclitaxel therapy. 50 patients
entered the study and 46 were evaluated : 21 chemo-naive
patients and 25 patients with a relapse after platinum–based
13
chemotherapy. Apart from 4 patients that were discontinued
due to grade 4 toxicities: neurotoxicity, renal toxicity, cardiac
event and one adverse event not related to the therapy, all
other patients (24 in the weekly paclitaxel arm and 22 in
the 4 weekly paclitaxel arm) received the two dose dense
induction cycles. 122 cycles of 4 weekly paclitaxel (arm A)
and 134 cycles of weekly paclitaxel/cisplatin (arm B) were
administered. Hematologic toxicity consisted of neutropenia:
24% in arm A versus 19% in arm B; thrombocytopenia in
2.4% versus 4.5%. Other evaluated toxicities were nausea
and vomiting in 1% of the cases for arm A compared to 6%
in arm B. Response rates were high and similar for both
regimes; 95% of the non pretreated patients responded to
chemotherapy and 71% achieved complete response. For
patients with recurrent disease previously treated with
platinum based chemotherapy, the response rate was 85%,
with 32% of the cases being complete responses. Median
PFS was 24 months for chemotherapy naïve patients and 12
months for recurrent disease. Median survival was 76 and 25
months, respectively. The authors investigated 2 schedules
that both doubled the dose intensity of paclitaxel compared
to standard 3 weekly paclitaxel/cisplatin cycles. Since the
highest dose intensity of paclitaxel in combination with
weekly cisplatin was reached with weekly paclitaxel 90mg/
m2, this was the scheduled recommended by the authors for
further studies (19).
Weekly paclitaxel and carboplatin
Taking into account the 3 randomised studies that showed
that 3-weekly paclitaxel / carboplatin was as effective and
better tolerated as
3 weekly paclitaxel /cisplatin, paclitaxel/carboplatin
combination therapy has become the standard regimen
in ovarian cancer (20, 21, 22). M.E.L. van der Burg
demonstrated that weekly paclitaxel 90mg/m2 can be safely
combined with weekly carboplatin area under the curve
4. The study enrolled 62 patients with recurrent epithelial
ovarian cancer after at least one platinum-based combination
therapy. Median PDI (progression free interval) was 8
months (0-81). 23 patients had a PFI of less than 6 months,
19 patients had a PFI of 6-12 months and 20 patients had
a PFI more than 12 months. The median number of prior
therapies was 2 (range 1-8). Thirty eight patients had prior
treatment with topotecan and 22 patients had at least one
prior weekly cisplatin based combination chemotherapy with
etoposide paclitaxel ot topotecan. The weekly paclitaxel/
carboplatin regimen was well tolerated. Toxicity of 360
administrations included grade 3 or 4 trombocytopenia in
8%, neutropenia in 40% and febrile neutropenia in 1.1%.
Treatment was delayed with a median of 1 week (range 1-5
weeks) in 16% of the administrations. No nausea/vomiting
or neurotoxicity grad 3 or 4 were observed. Using the weekly
paclitaxel/carboplatin regimen led to early responses: 61%
of the patients had a response at the completion of the sixth
week of the cycle. Taking into account the fact that the study
14
population was a heavily pretreated one, the overall response
rate is 74% and median PFS was 11 months. Consequently,
the weekly paclitaxel/carboplatin regimen appears to be very
active and is well tolerated.
These two studies presented above show that dosedense weekly platinum is an effective therapy in platinumsensitive as well as in platinum resistant patients. Both
weekly cisplatin/paclitaxel and carboplatin/paclitaxel lead
to responses ranging from 46% to 64% in platinum resistant
patients.
Various schedules based on dose-dense paclitaxel/
carboplatin were investigated. The “Leuven” dose-dense
paclitaxel/carboplatin regimen consisting of six courses of
paclitaxel (90mg/m2) and carboplatinum (AUC 4) on day
1 and 8 every 3 weeks was investigated in 33 patients with
recurrent platinum resistant and platinum sensitive ovarian
cancer. Median PFS was 9 months; median OS was 18 months.
Median PFS was 6.75 months for the platinum resistant and
10.5months for the platinum sensitive group. These results
published by Isabelle Cadron in the Department of Obstetrics
and Gynecology, University Hospital, Leuven confirms that
dose dense paclitaxel and carboplatin offers a well tolerated
regimen with high response rates even in heavily pre-treated
and platinum–resistant ovarian cancer (24).
Dose dense paclitaxel/carboplatin as front
line treatment in advanced ovarian cancer
after cytoreductive surgery?
The Japanese Gynecology Oncology Group (JGOG)
was the first to demonstrate the survival advantage of dose
dense weekly administration of paclitaxel in 2009 (25).The
clinical protocol JGOG3016 enrolled 637 patients with stage
II to IV epithelial ovarian cancer, fallopian tube cancer or
primary peritoneal cancer. Patients were randomly assigned
to receive six cycles of either paclitaxel (180mg/m2; 3 hours
intravenous infusion) plus carboplatin (area under the curve
(AUC) 6 mg/ml per min) given on day 1 of a 21 day cycle
– conventional regimen arm with 320 patients) or dose
dense (DD) paclitaxel (80mg/m2; 1 hour infusion) given
on days 1, 8 and 15 plus carboplatin given on day 1 of a
21-day cycle (dose dense regimen arm with 317 patients).
The results published by Dr. Noyuri Katsumata were more
than promising. Statistical analysis showed that median
progression-free survival was longer in the DDC group
(28 months, 95% CI 22.3-35.4) than in the conventional
treatment group (17.2 months, 15.7-21.1; hazard ratio
(HR) 0.71; 95% CI 0.58-0.88; p=0.0015). Moreover,
the 3 year overall survival was higher in the dose-dense
regimen group(72.1%) than in the conventional treatment
group (65.1%; HR 0.75,0.57-0.98; p=0.03). Despite the
bright side of achieving the primary endpoint of the study
– PFS, treatment toxicities were carefully analyzed. 165
patients assigned to the DD regimen and 117 assigned to
the conventional regimen discontinued treatment early.
Manolescu & Nagy
Although most reasons for patient dropout were balanced
between the groups, withdrawal due to toxicity was much
higher in the DD regimen arm than in the conventional arm
(113 patients vs. 69 patients). Neutropenia was the most
common adverse event: in DD group 92% of the patients
developed neutropenic events grade 1-4 respectively 88%
in the conventional arm. Severe anemia (grade 3 and 4
CTCAE was more frequent in the DD arm compared
to the conventional arm (69% vs 44%; p<0.0001). The
frequency of neurotoxicity was similar in both groups.
Motor neuropathy affected 5% of the DD regimen group
patients compared to 4% in the conventional regimen group.
Sensorial neuropathy occurred in 7% of the DD arm versus
6% in the conventional arm (25). .
Strong points of the JGOC study :
1. It is the first study to show an improved progression
free survival in women with newly diagnosed, stage II to IV
ovarian cancer for the dose dense treatment with paclitaxel
and carboplatin.
2. Toxicities were accurately analyzed. As expected,
hematological toxicity (neutropenia and anemia) should
be a matter of concern especially in the dose dense group.
Fewer than half the patients assigned to the dose dense
regimen completed treatment according to the study
protocol (26).
Weak points of the JGOC study:
1. The study recruited patients only from Japan. Taking
into account that the biological features of ovarian cancer
might vary according to geographical area, the results
cannot be generalized unless a multinational multicentre
prospective study confirms the results.
2. The dose-dense chemotherapy regimen used in the
trial was also dose-intense. The study showed a survival
advantage with an increased total dose of 240mg/m2 given
in three divided doses during a 21 day cycle. It cannot be
established clearly if the dose density or dose intensity
or more probably both of them influenced the positive
results.
3. Effects of the two chemotherapy regimens on the
quality of life were not assessed.
4. Although the groups were balanced according
to routine clinical prognostic factors, reporting of the
proportion of patients with not visible (microscopic) residual
disease after cytoreductive surgery would have been useful,
because these data are a more robust predictor of clinical
outcomes than macroscopic residual disease.
5. It is not clear if the overall survival advantage will
be maintained since the 5 year survival rates have not been
published yet.
6. All the available results date from the pre – bevacizumab
era. How the monoclonal antibody influences the outcomes
when combined with dose dense regimens could be cleared
hopefully by further clinical trials.
Dose-dense chemotherapy in advanced ovarian cancer: old idea, new perspectives
Future perspectives opened by the JGOC3061 trial
The findings of the JCOG trial are important but they
did not change practice at once. It is clear that the results
of the Japanese trial have clearly influenced the design of
actual clinical trials.
Three major randomized trials in advanced ovarian
cancer are ongoing. The GOG262 trial, closed in early
2012, compares the same treatment arms as the Japanese
trial – conventional versus three weekly paclitaxel and
carboplatin in stage III and IV patients (27). The Multicenter
Italian Trials in Ovarian Cancer Group developed the
MITO7 study that compares the efficacy and toxicity of
weekly administration of carboplatin (AUC2) plus weekly
administration of paclitaxel (60mg/m2) (28). Finally, ICON8
–ENGOT OV-13 trial compares standard treatment (every
21 days administration on paclitaxel + carboplatin) with
dose dense weekly administration of paclitaxel and every 3
weeks administration of carboplatin and dose dense weekly
administration of both paclitaxel and carboplatin (29).
These three studies are meant as confirmatory studies for
the JGOC trial but they will also try to answer two major
questions: “Does dose dense carboplatin also contribute to
improve survival?” and “Will the simple division of total
dose of paclitaxel show similar efficacy with less toxicity?”.
The results are eagerly awaited.
Conclusions
The main rationale for weekly paclitaxel administration
in combination with platinum is the possibility of increasing
dose density. This dose dense schedule results in extensive
cumulative exposure that has the potential to increase the
drug efficacy against slow-growing tumours and reduces
the emergence of drug resistant clones. Furthermore, the
weekly moderate dosing of paclitaxel also reduces sideeffects compared with the 3 weekly high dosing schedule
and seems to be effective even in patients who no longer
respond to 3 weekly paclitaxel administration.
The ongoing trials for treatment of advanced ovarian
cancer include dose-dense chemotherapy arms. Although
new biological therapies (bevacizumab) has shown its
efficacy in ovarian cancer, it is still used in combination
with chemotherapeutic agents such as paclitaxel. Such
approaches as dose dense administrations are being
intensively investigated in ongoing trials and the right
dosing, frequency will be established after the publication
of new emerging data.
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