Mitoxantrone Combined with Paclitaxel as Salvage Therapy ...TDC) with 0.6 p.g/ml mitoxantrone and 13.6 pg/ml paclitaxel as 100% TDC (14, 24). Each TDC was tested in triplicate. Addi-tionally,
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Vol. 3, 1527-1533, September 1997 Clinical Cancer Research 1527
Mitoxantrone Combined with Paclitaxel as Salvage Therapy for
Platinum-refractory Ovarian Cancer: Laboratory Study and
Clinical Pilot Trial1
Christian M. Kurbacher,2 Howard W. Bruckner,
Ian A. Cree, Jutta A. Kurbacher,3
Lucas Wilhelm, Gerald P#{246}ch,Dorit Indefrei,
Peter Mallmann, and Peter E. Andreotti
Department of Gynecology and Obstetrics, University of CologneMedical Center, D-5093l Cologne, Germany [C. M. K., L. W., P. M.];Division of Neoplastic Diseases, Derald H. Ruttenberg Cancer Center,Mount Sinai School of Medicine, New York, New York 10029[H. W. B.]; Department of Pathology, Institute of Ophthalmology,University College London, London EC1V 9EL, United Kingdom
[I. A. C.]; Department of Gynecology and Obstetrics, University ofBonn Medical Center, D-53105 Bonn, Germany [J. A. K., D. I.];Institute of Pharmacology and Toxicology, University of Graz,
A-8020 Gras, Austria [G. P.]; and Atlantic Scientific DevelopmentInc., Boca Raton, florida 33428 [P. E. A.]
ABSTRACT
This report describes preclimcal and early clinical in-
vestigations of the mitoxantrone/paclitaxel combination
(NT) for patients with platinum-refractory ovarian cancer.
The preclinical activity of NT was studied ex vivo, evaluating
native tumor specimens with the ATP tumor chemosensitiv-ity assay. Of 24 tumors tested, 20 (83%) were sensitive to
NT, whereas 7 (29%) responded to mitoxantrone and 8
(33%) responded to paclitaxel. In the majority of tumorsassayed (19 of 24), potentiating or major independent effects
between both agents were found. Subsequently, a clinical
pilot trial of NT was initiated for patients with platinum-
refractory ovarian cancer. Patients had failed one to four
(median, two) prior chemotherapy regimens. In 11 cases, NTwas administered every three weeks with 8 mg/rn2 mito-
xantrone and 180 mg/rn2 paclitaxel (NT-I). Seven patientswere treated biweekly with 6 mg/rn2 mitoxantrone andweekly with 100 mg/rn2 paclitaxel (NT-Il). During 92 NTcourses, myelosuppression with leucopenia, anemia, and
thrombocytopenia was the limiting toxicity, occurring morefrequently with NT-Il. No patient required hospitalization
Received 12/30/96; revised 5/15/97; accepted 5/17/97.The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby markedadvertisement in accordance with 18 U.S.C. Section 1734 solely to
indicate this fact.
‘ Supported in part by DCS Innovative Diagnostik Systeme, Hamburg,Germany.2 To whom requests for reprints should be addressed, at Department ofGynecology and Obstetrics, University of Cologne Medical Center,Kerpener Strasse 34, D-50931 Cologne, Germany. Phone: 49-221-478-4910; Fax: 49-221-478-4929.3 Present address: Department of Obstetrics and Gynecology,Johanniter-Krankenhaus, Johanniterstrasse 3-5, 53 1 1 3 Bonn, Germany.
due to any life-threatening complication. Five complete and
nine partial remissions were observed with both NT-I and
NT-Il, accounting for an overall 78% response rate, with a
median progression-free survival of 40 weeks. One patientshowed early progression during therapy. Currently, three
patients (NT-I, two; NT-H, one) have died due to progressive
relapsed ovarian cancer, so that the median overall survival
is not reached after a median follow-up of 40.5+ weeks.
Both schedules were found to be equal in terms of responserate and overall survival. NT is highly active and practical
for salvage treatment of ovarian cancer. NT-Il may be pre-ferred due to both clinical activity and patients’ acceptance.However, NT-I seems to be a less myelotoxic alternative.Both schedules warrant further clinical investigation.
INTRODUCTION
Primary ovarian carcinomas frequently respond to chemo-
therapy. Remission rates of 60-70% have been observed after
platinum-based first-line therapy, reducing the relative risk of
progression and death to 0.7 (1, 2). Nevertheless, the majority of
patients with advanced disease will relapse, resulting in an
overall 5-year survival of only 20% ( 1 , 2). The likelihood of
relapsing patients to respond to either second-line platinum or
nonplatinum regimens strongly depends on the disease-free in-
terval after completion of initial chemotherapy (2-6). The prob-
ability that platinum-refractory patients (i.e., those presenting
with primary progression or recurrence after �6 months) will
benefit from salvage chemotherapy is limited (2, 3, 6, 7). Pa-
clitaxel (Taxol#{174}), ifosfamide, and altretamine are considered to
be the most active single agents in this setting, but at conven-
tional dosages, they produce RRs4 of no more than 30% (2, 6,
7). Unfortunately, higher RRs achieved with dose-escalated
paclitaxel do not translate into improved PFS and OAS, respec-
tively (6, 8, 9). Introduction of paclitaxel into first-line therapy
of ovarian cancer (10) may even create more problems with
recurrent disease. Recently, altretamine and topotecan have
been considered the most effective agents in this setting (1 1,
12), whereas modest activity was demonstrated for gemcitabine
and reinduction with either carboplatin or paclitaxel (13-15).
Therefore, the search for new salvage regimens remains an
important goal to improve treatment for patients with platinum-
refractory ovarian cancer.
Paclitaxel exhibits synergistic cytotoxicity with a number
4 The abbreviations used are: RR, response rate; ATP-TCA, AlP tumorchemosensitivity assay; CR, complete response; G-CSF, granulocyte
colony-stimulating factor; MI, maximum inhibition; NC, no change;NT, mitoxantrone/paclitaxel; OAS, overall survival; PD, progressivedisease; PFS, progression-free survival; PR, partial response; SI, sensi-tivity index; TDC, test drug concentration.
C. B. 43 aCP, EPI, aCC Pelvis, abdomen I 6 CR 88+M. C. 48 CC, CP Pelvis, abdomen I 6 CR 76+M. E. 55 CP, VP-l6 Pelvic, paraaortic LNS I 3 NC 65+B. F. 67 CP Pelvis, abdomen, lung I 2 PD - (alive)P. F. 63 CC Abdomen, abdominal wall, subhepatic LNS I 6 NC 55 (dead)K. 0. (a) 45 CP Pelvis, subhepatic LNS I 6 PR 50 (alive)
K. 0. (b) 46 CP, NT-I, Pelvis, liver, spleen capsule II 6 PR 28K. G. (c) 46 CP, NT-I, NT-Il Pelvis, spleen II 6 PR 16E. K. 63 CC Pelvis, abdomen II 4 NC 10+
M. J. (a) 67 CC, PTX Subhepatic and paraaortic LNS II 4 PR 28
M. J. (b) 68 CC, PTX, NT Subhepatic, retroperitoneal, sigma II 6 PR 20+
R. R. 64 CC, PTX, CP Subhepatic and paraaortic LNS II 6 PR 15+B. R. 35 CC, CI, ICE (high dose) Pelvis, pelvic and paraaortic LNS, bursa omentalis I 6 CR 40 (alive)U. R. 55 CP, TREO Pelvis, abdomen, paraaortic LNS I 2 PR 36+
T. S. 49 CC Pelvis, abdomen I 6 CR 20+M. S. 55 CP Pelvis, paraaortic LNS I 6 CR 23 (dead)R. T. 58 CP, CC, VP-l6, P1 Pelvis, pelvic LNS I 6 PR 20+P. U. 40 CC, aCP, CPA, AT Pelvis, perihepatic and paraaortic LNS, spleen II 4 PR 22 (dead)
a The abbreviations used are: aCC, cytosine arabinoside/carboplatin; aCP, cytosine arabinoside/cisplatin; AT, doxorubicin-paclitaxel; CC,
Fig. 2. Kaplan-Meier plots for 15 patients with platinum-refractory
ovarian cancer receiving a total of 18 blocks of salvage chemotherapywith NT. A, OAS estimated for 15 patients treated. B, PFS estimated for18 NT treatments administered.
Clinical Cancer Research 1531
was discontinued after two cycles. Three patients (NT-I, two
patients; NT-Il, one patient) have died due to progressive recur-
rent tumor at 32, 37, and 62 weeks from the start of NT. The
remainder are still alive, and nine are even progression-free
(NT-I, six patients; NT-Il, three patients).
DISCUSSION
Taxanes such as paclitaxel are considered the most active
agents in platinum-refractory recurrent ovarian cancer, produc-
ing a 25-30% RR and a median PFS of6 months (2, 6-8, 22, 36).
Increasing the paclitaxel dose may increase the RR, but this,
unfortunately, did not improve survival (8, 9, 37).
In various preclinical studies, paclitaxel was shown to act
synergistically with a number of standard cytostatics. including
topoisomerase II inhibitors (16). In a clinical trial based on prior
ex viva evaluation of fresh tumor specimens ( I 8), we found
doxorubicin/paclitaxel to have well-tolerated activity in ovarian
cancer patients who had failed both platinum and single-agent
paclitaxel (21). Testing a limited number of human tumor cell
lines, GlOck et a!. (29) observed a strong synergism between
paclitaxel and mitoxantrone that compared favorably with other
paclitaxel-based combinations including doxorubicin, etopo-
side, cyclophosphamide, or platinum (29). Mitoxantrone is less
cardiotoxic and mucotoxic than doxorubicin, and lack of cross-
resistance has been demonstrated for various clinical tumors in
a considerable number of patients (25, 26, 38, 39). Both the
promising clinical activity of doxorubicin/paclitaxel and the
confirmed preclinical experiences provide evidence that NT
should be regarded as a logical next step in developing a
well-tolerated regimen for the treatment of platinum-refractory
recurrent ovarian carcinoma.
The ATP-TCA may be useful for ex vivo chemosensitivity
testing of clinical tumors and seems to be applicable to anthra-
cyclines and taxanes ( I 8, 27, 28). It possibly provides major
advantages over classical chemosensitivity assays in terms of
efficacy, reproducibility, robustness, and evaluability, with
promising clinical correlations reported for both ovarian and
breast cancers (1 7, 19, 20). This assay was thus considered a
suitable model to assess the preclinical activity of NT in native
platinum-refractory ovarian cancers.
Generally, the ex vivo results described herein show activ-
ity for both mitoxantrone and paclitaxel that is consistent with
clinical experience (8, 36, 40). The combination produced an
unexpectedly high rate of antineoplastic activity ex vivo. Seven
tumors with apparent resistance to both single agents were
sensitive to NT. Ex vivo resistance is a highly reliable predictor
of clinical resistance (41); thus, reversal of resistance as we
found here is a noteworthy success. The analysis of the effect of
the NT combination indicates potentiation or at least major
independent activity for both drugs in the majority of tumors.
Although the reasons for these effects are not clear at present,
our findings argue in favor of a real synergism between the
drugs.
Our first clinical results provide evidence that NT given at
either schedule has acceptable toxicity and produces exception-
ally high clinical efficacy in patients with platinum-refractory
ovarian cancer. Compared to clinical results with doxorubicin/
paclitaxel described by us and others (2 1 , 3 1 ), NT seems to be
a further improvement. Both the 78% RR and particularly the
response duration observed in this study compare favorably with
those achieved with other salvage therapies such as paclitaxel,
docetaxel, altretamine, ifosfamide, or topotecan (2, 6-8, 1 1, 12,
22, 36, 42). These findings therefore challenge the traditional
view that drug combinations have no advantage for salvage
therapy of ovarian carcinoma as compared to single agents (42).
Work in progress seeks the optimal dosage for NT-Il, which
may be preferred for future evaluation because this regimen
combines both high clinical activity and convenience for the
patients. However, NT-I seems to be a reasonable alternative to
NT-Il, particularly in patients with impaired bone marrow func-
tion or in those who are otherwise unable to undergo weekly
chemotherapy.
Responses in ovarian cancer patients failing both platinum
and paclitaxel are rare. In this setting, altretamine and topotecan
are the only drugs with proven major clinical activity (1 1, 12).
Therefore, the activity of NT that we have found in patients
pretreated with paclitaxel alone or in combination is of partic-
ular interest. Considering the published single-agent activities of
mitoxantrone (35) and paclitaxel (8, 22, 36), the results of this
pilot trial provide evidence for a clinical synergism between
these drugs that parallels our previous and current laboratory
experience (28). We made similar observations with platinum
and cytosine arabinoside even when both single agents were
completely inactive (43, 44). Moreover, it should be noted that
NT clearly produced a higher clinical activity than doxorubicin/
paclitaxel, although this was not expected from the preclinical
and clinical single-agent activities ( 1 8, 21 , 23, 25, 3 1 ). Modern
ex vivo test systems such as the ATP-TCA thus provide an
effective and time-saving method for the preclinical selection of
innovative chemotherapy regimens for further clinical use. In
conclusion, NT showed unusually promising anticancer activity
in heavily pretreated patients with platinum-refractory ovarian
cancer, without producing nontolerated toxicity. This combina-
tion should thus be considered for large-scale clinical trials.
ACKNOWLEDGMENTS
We thank H. HObner and R. Klasen for skillful technical assistance.
Special thanks are addressed to all colleagues and nurses of the onco-
logic staff of the Departments of Gynecology and Obstetrics, University
of Cologne and University of Bonn Medical Centers, for their engage-ment in care and treatment of the patients. This work was performedwithin the framework of the Preclinical Therapeutic Models Group of
the European Organization for Research and Treatment of Cancer.
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