Download Chemotherapy versus hormonal treatment in platinum

Original article
Annals of Oncology 13: 251–257, 2002
DOI: 10.1093/annonc/mdf038
Chemotherapy versus hormonal treatment in platinum- and
paclitaxel-refractory ovarian cancer: a randomised trial of the
German Arbeitsgemeinschaft Gynaekologische Onkologie
(AGO) Study Group Ovarian Cancer
A. du Bois1,2*, W. Meier3,4, H. J. Lück5, G. Emons6,7, V. Moebus 8,9, W. Schroeder10,11, S. Costa12,
T. Bauknecht13,14, S. Olbricht15, C. Jackisch16, B. Richter17 & U. Wagner18
1
Department of Gynecology & Gynecologic Oncology, Dr-Horst-Schmidt-Kliniken Wiesbaden; 2Department of Gynecology & Obstetrics, St Vincentius
Krankenhaus Karlsruhe; 3Department of Gynecology & Obstetrics, ev. Krankenhaus Düsseldorf; 4Universitaetsfrauenklinik München-Grosshadern;
5
Department of Gynecologic Oncology, Universitaetsfrauenklinik Hannover; 6Universitaetsfrauenklinik Göttingen; 7Universitaetsfrauenklinik Marburg;
8
Department of Gynecology & Obstetrics, Städtische Kliniken Frankfurt-Höchst; 9 Universitaetsfrauenklinik Ulm; 10Department of Gynecologic Oncology,
Zentralkrankenhaus Bremen; 11Universitaetsfrauenklinik Aachen; 12 Universitaetsfrauenklinik Frankfurt; 13Universitaetsfrauenklinik Bonn;
14
Universitaetsfrauenklinik Freiburg; 15Universitaetsfrauenklinik Magdeburg; 16 Universitaetsfrauenklinik Münster; 17Universitaetsfrauenklinik Dresden;
18
Universitaetsfrauenklinik Tübingen, Germany
Received 30 April 2001; revised 8 August 2001; accepted 24 August 2001
Background: The majority of patients with ovarian cancer are not cured by first-line treatment.
Until now, no study could demonstrate any substantial benefit when exposing ovarian cancer patients to
second-line chemotherapy. However, most treatment regimens induce toxicity, thus negatively influencing the quality of rather limited life spans. Here we evaluate whether a second-line chemotherapy
can offer any benefit compared with a less toxic hormonal treatment.
Patients and methods: Patients with ovarian cancer progressing during platinum-paclitaxel containing first-line therapy or experiencing relapse within 6 months were eligible. Patients were stratified for
response to primary treatment (progression versus no change/response), and measurable versus nonmeasurable disease. Treatment consisted of either treosulfan 7 g/m2 infused over 30 min or leuprorelin
3.75 mg injected subcutaneously or intramuscularly. Both regimens were repeated every 4 weeks.
Results: This study began in late 1996, and after 2.5 years accrual an interim analysis was performed
when several investigators reported their concern about a suspected lack of efficacy. Following this
analysis the recruitment was stopped early and the 78 patients already enrolled were followed up. The
majority of patients received treatment until progressive disease was diagnosed or death occurred.
Treatment delay was observed rarely and dose reduction was performed only in the treosulfan arm in
5% of 150 courses. Overall, both treatment arms were well tolerated. No objective responses were
observed. The median survival time was 36 and 30 weeks in the treosulfan and leuprorelin arms,
respectively. Overall survival did not differ between patients with relapse 3–6 months after first-line
chemotherapy compared with patients with progressive disease within 3 months.
Conclusions: The selected patient population represents a subgroup with extremely poor prognosis.
Accordingly, results were not impressive. Both treatment arms showed favourable toxicity data, but
failed to show remarkable activity, thus adding only limited evidence to the issue of whether patients
with refractory ovarian cancer might benefit from second-line chemotherapy. Even stratified analysis
did not identify any subgroup of patients in whom the administration of second-line chemotherapy
could demonstrate a clinically relevant survival benefit.
Key words: chemotherapy, hormonal treatment, ovarian cancer, relapse, second-line therapy
*Correspondence to: Department of Gynecology & Gynecologic Oncology, Dr Horst Schmidt Kliniken, Ludwig-Erhard-Strasse 100,
D-65199 Wiesbaden, Germany. Tel: +49-611-43-3203; Fax: +49-611-43-3205; E-mail: [email protected]
© 2002 European Society for Medical Oncology
252
Introduction
Despite the considerable progress that has been achieved in
the treatment of advanced ovarian cancer during the last decades, the majority of patients are still not cured by first-line
treatment. Therefore, development of effective second-line
treatment strategies remains a clinically relevant issue. Today
standard first-line regimens in many countries contain both
paclitaxel and a platinum analogue (e.g. cisplatin [1, 2] or
carboplatin [3–5]). There are only limited data available
reporting results gained from second-line therapy following
failure of this new first-line regimen. Until now, no guidelines
for the selection of second-line treatment regimens have
reached universal acceptance [6]. Furthermore, the definitions
of recurrent or relapsed disease according to the status of platinum resistance [7] were solely based on data from patients
who did not receive the actual standard first-line regimens
containing paclitaxel, and therefore have to be re-evaluated.
The treatment-free interval, which offers a chance of gaining a
benefit from re-treatment with paclitaxel and/or platinum,
remains to be defined. However, patients progressing during
or relapsing shortly after platinum-paclitaxel probably have a
poor prognosis and can be regarded as refractory to both of the
drugs they were exposed to. Until now, no study has demonstrated clearly any substantial benefit for these patients when
treating them with second-line chemotherapy. However, most
treatment regimens induce toxicity, thus negatively influencing
the quality of rather limited life spans in this strictly palliative
setting. Therefore, the AGO Study Group set about evaluating
whether a second-line chemotherapy could offer any benefit
compared with a less toxic hormonal treatment.
The decision to use an alkylating agent for second-line
chemotherapy was based on the assumption that these agents,
which had been part of first-line treatment of ovarian cancer
for decades, could offer some benefit as second-line agent
after removal from first-line regimens. Treosulfan (Ovastat®,
medac, Germany) was chosen as alkylating agent because it has
been registered and used frequently in older first-line regimens
in Germany, due to a more favourable non-haematological
toxicity profile compared with cyclophosphamide [8, 9]. The
published data for treosulfan as second-line treatment after
platinum failure had been partially contradictory. Two studies
using intravenous treosulfan reported response rates of up to
20% in 25 and 72 patients, respectively [10, 11]. The latter
trial included 43 patients with platinum refractory ovarian
cancer and showed a 21% response rate. Orally administered
treosulfan resulted in response rates of 3, 14 and 19% in 30, 22
and 16 platinum pre-treated patients, respectively [12–14].
The only study reporting results of oral treosulfan in platinum
refractory patients observed only one response in 30 patients.
Therefore, we decided to use intravenous treosulfan as standard chemotherapy arm in this trial.
Leuprorelin (leuproreline acetate; Enantone®, Takeda,
Germany), a gonadotropin-releasing hormone (GnRH) analogue, was selected as hormonal treatment in the experimental
arm of this study. It could be administered in a similar time
schedule as the chemotherapy regimen (monthly injections)
and had shown some activity in previously reported studies in
platinum pre-treated ovarian cancer. In these trials, leuprorelin had been used either as single agent [15–17] or in combination with megestrole acetate or tamoxifen [18, 19]. Overall,
nine responses have been reported in 46 platinum pre-treated
patients [cumulative odds ratio (OR) 19.6%; 95% confidence
interval (CI) 9% to 34%]. A retrospective review reported
higher efficacy for leuprorelin compared with goserelin, thus
providing further support for selecting leuprorelin in favour of
other GnRH analogues [17]. However, platinum resistance
had been reported inconsistently in all these studies, thus leaving some questions unanswered regarding efficiency in this
particular group of patients. Toxicity profiles of leuprorelin
had been uniformely reported as being mild, making this
option potentially useful in this strictly palliative setting.
Tamoxifen, another hormonal treatment with an 11% overall
response rate reported in a meta-analysis in recurrent ovarian
cancer [20], was not selected for this study, because the study
group felt that the different mode of application could hamper
comparability.
Patients and methods
This study was performed according to the Good Clinical Practice guidelines and was registered and certified by the German Cancer Society. It
gained acceptance from ethics committees in each state of Germany and
patients were only enrolled after giving written informed consent. Study
procedures followed the AGO Standard Operating Procedures including
central randomisation, regular on-site monitoring and double data entry.
Patients with epithelial ovarian cancer and progressing during platinumpaclitaxel containing first-line therapy or experiencing relapse within the
first 6 months following one platinum-paclitaxel containing regimen were
eligible. Elevated CA 125 as the only marker of progressive disease was
not accepted as a criterion for inclusion or for defining progression in this
study. Further inclusion criteria were an Eastern Collaborative Oncology
Group (ECOG) performance status of <3, a life expectancy of >12 weeks,
being at least the age of consent, and adequate haematologic function
[white blood cell (WBC) count 3000/mm 3, platelet count 100 000/mm3),
liver function (bilirubin 1.25 × upper limit) and renal function (serum creatinine 1.25 × upper limit, glomerular filtration rate 40 ml/min estimated
according to Jeliffe [21]). Exclusion criteria were: more than one prior
chemotherapy regimen, one prior chemotherapy regimen not including
platinum and paclitaxel, borderline tumours, Brenner tumours, known
allergy to one of the treatment arms, disabling concomittant disease, bowl
obstruction and second malignancies, except surgically controlled basal
skin cancer or carcinoma in situ of the uterine cervix. Patients were stratified for response to primary treatment (progression during first-line chemotherapy versus no change/response), and bi-dimensionally (measurable
versus non-measurable disease). Treatment consisted of either treosulfan
7 g/m2 infused over 30 min on day 1 or leuprorelin 3.75 mg injected s.c. or
i.m. Both regimens were repeated every 4 weeks until progression or
unacceptable toxicity occurred, or until the patient decided to end treatment. Reductions of treosulfan dose to 5 g/m2 was allowed for myelosuppression, and the administration of subsequent treatment courses was
not allowed within 6 weeks. Patients were followed up until death at
253
3-monthly intervals. Toxicity was recorded for each treatment course and,
in addition, patients with measurable disease were staged after every three
Results
courses using the methods that were appropriate for tumour measurement
This study (AGO protocol OVAR-2.1) began in late 1996, and
recruitment was slower than expected. After 2.5 years accrual
an interim analysis was performed when several investigators
reported their concern about a suspected lack of efficacy. A
discussion among the study coordination group revealed that
no significant response had been observed. The principal
investigator decided not to continue further patient recruitment until there was clarification. Therefore, this initially
unplanned interim analysis was performed. Following this
analysis the recruitment was stopped early and patients
already enrolled were followed up until this final analysis. Up
to that time, 78 patients had been enrolled, of whom five were
found to be ineligible. Three of these patients had been randomised to the chemotherapy arm. Reasons for ineligibility
were withdrawal of consent (one patient), ECOG performance
status of 3 (one), no proven progression after first-line therapy
(one), prior treatment with platinum but without paclitaxel
(one), relapse later than 6 months after completion of prior
at baseline. The same evaluation methods were performed every 3 months
during follow-up. The minimum requirements for evaluation in patients
without measurable tumours included physical examination, bi-manual
gynaecological examination and vaginal ultrasound. Responses were
classified according to the WHO standard criteria [22]. The primary endpoint was survival; secondary end-points were progression-free survival,
response in patients with measurable disease, and toxicity rates (NCI
Common Toxicity Criteria). Patient number calculations were based on
the assumption that treosulfan results in 60% survival after 6 months. A
difference of 20% survival after 6 months (40% 6 month survival) should
be detected with an 80% power and an error of 5%; thus, 58 patients
needed to be enrolled per arm. Statistical analysis and data management
were performed with SAS, FoxPro, East, Report/Dialog/Testimate/Topograph/N /Nsurv (IDV software). Primary end-point comparison was
carried out utilising the Kaplan–Meier life-table method and the log-rank
and Wilcoxon tests. The impact of treatment-free interval on results was
analysed by bi-factorial univariate analysis.
Table 1. Patients characteristics
Treosulfan
Leuprorelin
All
39
39
78
3
2
5
No. eligible patients
36
37
73
Age, years: mean (range)
58.0 (36–75)
59.5 (27–75)
58.8 (27–75)
ECOG 0
14
11
25
ECOG 1
16
19
35
ECOG 2
5
6
11
No. randomised patients
No. ineligible patients
Performance status
Unknown
1
1
2
19
19
38
25
24
49
Cisplatin–paclitaxel
9
6
15
Epirubicin–carboplatin–
paclitaxel
2
7
9
0–13 weeks
22
13
35
13–26 weeks
14
24
38
Measurable disease
First-line regimen
Carboplatin–paclitaxel
Treatment-free interval
Stage at initial diagnosis
FIGO II
1
2
3
FIGO III
24
22
46
FIGO IV
10
13
23
<1 cm tumour residuals
13
10
23
1–2 cm tumour residuals
5
5
10
>2 cm tumour residuals
18
20
38
Status after initial surgery
254
therapy (one). Therefore, 73 patients were included in this
analysis, of whom 36 received treosulfan and 37 received leuprorelin. One further patient was lost after receiving one treatment course and was classified as not evaluable for efficacy.
The treatment groups were well balanced regarding patient
characteristics and treatment history (Table 1). In contrast,
treatment-free intervals differed between both study arms in
favour of the leuprorelin arm. The latter included more
patients with treatment-free intervals exceeding 13 weeks
(63% versus 37% comparing leuprorelin with treosulfan).
The median observation period was 22.5 months for all
patients. The early termination of recruitment resulted in a
statistical power of 80% to detect a 20% survival difference
(50% versus 69.9%) after 6 months with two-sided testing and
an α error of 0.05.
Treatment and tolerability
leuprorelin arm. Hot flushes were reported by one patient in
each arm. Three further patients in the treosulfan arm reported
grade 3 pain (two patients) and neurotoxicity (one). The latter
was due to remaining toxicity from prior platinum-paclitaxel.
Alopecia was common but was due to prior treatment. Regrowth of patients’ hair took longer in the treosulfan arm than
in the leuprorelin arm. About one-third of patients still had
alopecia after treatment with treosulfan compared with 11% in
the leuprorelin arm. Fatigue was reported more frequently in
the chemotherapy arm (eight of 36 patients versus one of 37
patients, treosulfan versus leuprorelin; P = 0.014, Fisher’s
exact test). Overall, both treatment arms were relatively well
tolerated resulting in only one treatment cessation due to
toxicity.
Efficacy
The majority of patients received treatment until progressive
disease was diagnosed or death occurred. The mean and
median treatment periods, respectively, were 18 and 16 weeks
in the treosulfan arm, and 13 and 10 weeks in the leuprorelin
arm. Treatment delay was observed rarely and median intervals per course were 30.8 and 28.6 days in the treosulfan and
leuprorelin arms, respectively. Dose reduction was performed
only in the treosulfan arm in eight of 150 courses (5%)
because of myelosuppression.
Overall, 150 chemotherapy courses and 122 hormonal treatment courses were evaluable for toxicity. Haematological toxicities higher than grade 2 were observed in only a few patients.
Thrombocytopenia grade 3/4 occurred in four and one courses
in the treosulfan and leuprorelin arms, respectively. Neutropenia grade 3/4 was only observed in one course in each arm
and no infections or neutropenic fever was reported. Anaemia
greater than grade 2 was observed after seven courses in the
treosulfan arm and after two courses in the leuprorelin arm.
Non-haematological toxicities grade 3 or 4 were reported in
only few patients in both arms. Treosulfan induced nausea and
emesis in 9% of patients compared with 6% of patients in the
No objective responses were observed in either of the treatment arms. Disease stabilisation lasting at least 4 weeks (no
change) was reported in nine and four patients in the chemotherapy and hormonal treatment arm, respectively. All but one
patient showed progressive disease within a median observation period of 22 months. Median progression-free survival
was 17 weeks for treosulfan and 10 weeks for leuprorelin (P =
0.035, Wilcoxon test). The difference between both treatment
arms remained significant in favour of treosulfan after adjusting for treatment-free interval before study entry (P = 0.028).
However, after 6 months only 23% and 14% of patients in the
treosulfan and leuprorelin arms had not progressed; corresponding figures for the 12 month observation period were 9%
and 5%, respectively (Figure 1).
At the time of this analysis, seven patients in the treosulfan
arm and eight patients in the leuprorelin arm are still alive with
disease [hazard ratio (HR) 0.98; 95% CI 0.58–1.67]. The differences observed between the treatment arms did not reach
statistical significance (P = 0.87, Wilcoxon test; Figure 2).
Again, adjusting for a treatment-free interval before study
entry did not alter results. The median survival time was 36 and
Figure 1. Progression-free survival (median 17 and 10 weeks for treosulfan
Figure 2. Survival (median 36 and 30 weeks for treosulfan and leupro-
and leuprorelin, respectively; P <0.05, log rank test; Kaplan–Meier curves).
relin, respectively; P = 0.87, log rank test; Kaplan–Meier curves).
255
30 weeks in the treosulfan and leuprorelin arm, respectively.
About one-third of patients in each arm were alive after 12
months.
The impact of time to treatment failure after first-line chemotherapy on second-line therapy efficacy was analysed bicategorially. The cut-off was set at 13 weeks, thus comparing
patients with progression under first-line therapy or early relapse
within 3 months with patients who relapsed 3–6 months after
completion of first-line chemotherapy. Overall, the difference
between the groups with respect to progression-free survival
did not reach statistical significance. Median progression-free
survival was 11 and 12 weeks, respectively, for the two groups
(P = 0.46, log rank test; HR 0.83; 95% CI 0.51–1.35). Furthermore, overall survival did not differ significantly between
patients with relapse 3–6 months after first-line chemotherapy
compared with patients with progressive disease within 3
months (P = 0.34, log rank test; HR 0.77; 95% CI 0.46–1.31).
However, median survival was slightly superior in the group
with a longer progression-free interval after first-line therapy
(42 versus 25 weeks). The latter difference did not reach
statistical significance and the Kaplan–Meier curves almost
fell on top of each other shortly after 1 year of observation
(data not shown).
The presence of bi-dimensionally measurable disease had a
negative impact on treatment results. Patients with measurable
disease showed a median progression-free survival of 11 weeks
compared with 19 weeks in patients with non-measurable
disease (P = 0.0006, log rank test). Again, overall survival was
superior in the group of patients with non-measurable disease,
but this difference did not reach statistical significance
(median 47 versus 24 weeks; P = 0.18, log rank test). Only
29% of patients with measurable disease compared with 46%
of patients with non-measurable disease were alive after 12
months (HR 1.93; 95% CI 0.73–5.16).
Subsequent treatment
In the treosulfan arm, 15 patients received third-line treatments, of whom three were changed over to leuprorelin. The
remaining eight patients received: radiotherapy (one),
tamoxifen (one) or chemotherapeutic drugs [topotecan (six),
etoposide (one), liposomal doxorubicin (one), carboplatin
(one), carboplatin-paclitaxel (one)]. Furthermore, 14 patients
received fourth-line treatment, including tamoxifen (two),
MPA (one), etoposide (two), topotecan (two), and one patient
each idarubicin, gemcitabin or mitoxantrone i.p. Finally,
three patients received fifth-line cyclophosphamide (one),
etoposide (one) or radiotherapy (one). In the leuproreline arm,
almost all patients received third-line therapy. Sixteen patients
were crossed over to treosulfan, four received intraperitoneal
mitoxantrone, two had liposomal doxorubicin and one patient
each received etoposide, topotecan, carboplatin, paclitaxelmitoxantrone or carboplatin-paclitaxel. Two patients received
hormonal third-line treatment (one each received tamoxifen
and MPA). Fourth-line treatment was offered to seven
patients, including radiotherapy (one), topotecan (two), and
one patient each liposomal doxorubicin-etoposide, etoposide
or etoposide–5-fluorouracil (5-FU). Fifth-line treatment was
offered to three patients, including paclitaxel, gemcitabin and
5-FU–platinum. The considerable use of third-line therapies
after progression of disease might have hampered survival
analysis, which in fact showed no significant difference
between the treatment arms (although progression-free survival differed).
Discussion
This study represents a prospectively randomised trial in a
very homogenous population. Only patients who were refractory to the standard first-line treatment of advanced ovarian
cancer (i.e. platinum plus paclitaxel) were recruited. This
selection represents a patient group with an extremely poor
prognosis. At the moment, there is only limited evidence that
these patients benefit from second-line chemotherapy at all,
and more studies in this subgroup are necessary before any
recommendations or guidelines can be established.
A randomised trial of the National Cancer Institute of Canada has shown an advantage for one arm over another when
comparing 3-weekly topotecan days 1–5 to weekly topotecan
in 78 patients, of whom 60% had received prior paclitaxel,
and 60% were platinum refractory [23]. This advantage was
limited to overall response (23% versus 8%). Progression-free
survival differed only at a non-significant level (8 versus 13
weeks), and overall survival did not differ at all. Our trial
showed a statistically significant advantage of one arm (treosulfan) with respect to progression-free survival, but failed to
show any difference in overall survival. In addition, no differences with respect to response rates were observed. In fact, we
did not observe any objective response. The latter could indicate a lack of activity of both study drugs, treosulfan and
leuprorelin. However, even higher response rates as reported
in the literature did not translate to longer progression-free and
overall survival. A prospectively randomised trial comparing
liposomal doxorubicin with topotecan included 254 platinum
refractory patients; in addition, about two-thirds had received
paclitaxel as part of prior therapy [24]. No significant differences were observed in the refractory subgroup: response
rates were 7% and 12%, median progression-free survival was
9 and 14 weeks, and median survival was 33 and 37 weeks,
respectively. Our observations of median progression free
survival of 11 and 17 weeks and median survival of 30 and 36
weeks fit well with the reported data in this poor prognostic
subgroup, although we did not observe any objective
responses. Another randomised trial in 81 platinum refractory
patients comparing paclitaxel with paclitaxel–epirubicin
reported response rates of 17% and 34% translating to 2-year
survival of 10% and 18% [25]. The corresponding 2-year survival in our trial was 19% and 22%, thus indicating the limited
value of objective response rates as predictors for survival or
256
progression-free survival in this poor prognostic subgroup of
patients with truely refractory ovarian cancer.
Nevertheless, achieving an objective response might be
beneficial in this palliative setting, especially if bulky tumours
induce symptoms such as pain or bowl obstruction. However,
objective response rates might not sufficiently reflect this
potential benefit. Therefore, different response criteria that
better reflect the palliative approach in these patients should
be evaluated prospectively (e.g. symptom relief, reduction of
pain medication or ability of enteral food intake). The development of better tools for the evaluation of genuine second-line
chemotherapies becomes even more necessary when taking
into account the fact that ovarian cancer becomes more of a
chronic disease: mortality does not change substantially, but
median and 5-year survival improves, thus indicating a growing need for efficient second-line and higher treatment. These
therapies should allow tumour control and simultaneously
should not reduce life quality.
This study reports mild toxicity data for both treatment
arms, treosulfan and leuprorelin acetate, but, due to the very
poor activity levels observed in both arms, adds only limited
evidence to the issue of whether patients with refractory ovarian cancer benefit from second-line chemotherapy at all. Even
stratified analysis in patients with progressive ovarian cancer
versus patients experiencing relapse 3–6 months after firstline therapy, or patients with measurable versus non-measurable diseases, did not demonstrate any subgroup of patients in
whom the administration of treosulfan second-line chemotherapy could demonstrate a clinically relevant benefit.
Although a very short progression-free interval and the presence of bi-dimensionally measurable disease seemed to turn a
bad prognosis into a worse prognosis, none of the differences
between the strata showed a consistent and clinically relevant
difference in survival. Only progression-free survival was
influenced by these factors to some extent. Our data did not
indicate that patients with a progression-free interval of
>3 months but <6 months after first-line therapy have a better
prognosis than those patients progressing within 3 months.
Therefore, a progression-free interval of up to 6 months after
first-line chemotherapy remained the inclusion criteria in our
subsequent trials in this population.
However, results were disappointing in all subgroups. A
rather small benefit was traded for a higher rate of fatigue in
patients receiving chemotherapy. A gain of 6 weeks median
progression-free survival in the superior chemotherapy arm in
our study and some advantages with respect to response rates
in other trials do not convincingly answer the question of
whether second-line chemotherapy offers any benefit for
patients with refractory ovarian cancer. Further studies are
necessary to help to evaluate whether chemotherapy has a role
in this subgroup of patients with a very unfavourable prognosis. A randomised comparison between best supportive care
and the most active chemotherapy regimen available could
theoretically be an appropriate design for such a trial. How-
ever, the German AGO investigators did not even broadly
accept a randomisation between a hormonal treatment and a
chemotherapy arm, as measured by an extremely slow recruitment rate. Furthermore, this study had to be closed prematurely after an interim analysis indicated only very limited
activity in both treatment arms. A trial using best supportive
care as one treatment arm would probably not be accepted
either, although the above-mentioned efficacy data from
chemotherapy studies do not provide more optimistic results.
Treosulfan showed an acceptable toxicity profile and at
least some activity compared with leuprorelin acetate, thus
allowing continuation of clinical research with this alkylating
agent. Our subsequent trial in the refractory population compares treosulfan with topotecan (AGO protocol OVAR-2.3)
and recruitment is much better, indicating that investigators
more easily accept trials comparing two chemotherapy regimens. Quality of life evaluation was included in this protocol
in an attempt to improve understanding of the nature of potential gains from second-line therapy.
Besides treosulfan and topotecan, which are further evaluated by our group, several chemotherapy agents have shown
some activity in platinum- and paclitaxel-refractory ovarian
cancer, and could serve as comparators in pending further
trials: ifosfamide [26], hexamethylmelamine [27], gemcitabin
[28] and liposomal doxorubicin [23, 29]. The difficult task of
recruiting large homogenous patient populations to secondline trials supports the ongoing discussions and activities in
cooperative groups and networks, such as the worldwide
Gynecologic Cancer InterGroup (GCIG), which is already
planning and performing intergroup trials of second-line treatment of ovarian cancer.
Acknowledgements
The authors thank Dr Sheila De Liz for helping with the language, and the investigators contributing to this study: K.
Friese (Rostock), G. Batzke (Rottweil), H. J. Becker (Gardelegen), H. J. Bettex (Lüneburg), P. Richter (Plauen), O. Behrens
(Rendsburg), R. Blumenberg/D. Kramer (Pforzheim), G.
Deutsch (Karlsruhe), J. Felz-Süssenbach (Stadthagen), K.
Gössel (Leer), H. Gröger (Bad Neuenahr), G. Hasselbauer
(Aschersleben), L. Heilmann (Rüsselsheim), W. Herchenhein
(Herzberg), U. P. Hoyme (Erfurt), D. Kranzfelder (Würzburg), M. Lange (Riesa), K. V. Maillot (Aalen), W. Meinerz
(Paderborn), J. Meyer-Grohbrügge (Sigmaringen), H. Mickan
(Esslingen), W. Niedner (Moers), E. Petri (Schwerin), A.
Reichel (Burg), K. O. Reichl (Schorndorf), K. Robke (SteinfurtBorghorst), G. Stricker (Wipperfürth), T. Zeiser (HernstedtUlzburg). We also thank the pharmaceutical companies
Takeda and medac, Germany for supporting the infrastructure
of the AGO Study Group Ovarian Cancer. Furthermore, we
thank Takeda for providing the study drug leuprorelin (leuproreline acetate, Enantone®).
257
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