close

Вход

Забыли?

вход по аккаунту

?

207

код для вставкиСкачать
Int. J. Cancer: 83, 848–851 (1999)
r 1999 Wiley-Liss, Inc.
Publication of the International Union Against Cancer
Publication de l’Union Internationale Contre le Cancer
TREATMENT OF PATIENTS WITH CISPLATIN-REFRACTORY TESTICULAR
GERM-CELL CANCER
Carsten BOKEMEYER1*, Christian KOLLMANNSBERGER1, Andreas HARSTRICK2, Jörg BEYER3, Arthur GERL4, Jochen CASPER5,
Bernd METZNER6, Jörg T. HARTMANN1, Hans-Joachim SCHMOLL8 and Lothar KANZ1
for the GERMAN TESTICULAR CANCER STUDY GROUP (GTCSG)
1Department of Internal Medicine, University of Tuebingen Medical Center, Tuebingen, Germany
2Department of Internal Medicine, Westdeutsches Tumorzentrum, University of Essen, Essen, Germany
3Department of Internal Medicine, Virchowklinikum, University of Berlin, Berlin, Germany
4Department of Internal Medicine, Klinikum Grosshadern, University of Munich, Munich, Germany
5Department of Internal Medicine, University of Rostock Medical Center, Rostock, Germany
6Department of Internal Medicine, Städt. Kliniken Oldenburg, Oldenburg, Germany
7Department of Internal Medicine, Klinik Bad Triss, Oberandorf, Germany
8Department of Internal Medicine, University of Halle-Wittenberg Medical Center, Halle, Germany
With the use of cisplatin-based combination chemotherapy, metastatic testicular germ-cell tumors can be cured in
70% to 80% of patients. The combination of cisplatin, etoposide and bleomycine (PEB) is considered standard therapy.
Patients refractory to cisplatin-based chemotherapy have a
markedly poor prognosis. Several chemotherapeutic agents
have been evaluated in intensively pre-treated or cisplatinrefractory patients. Neither the anthracyclines nor vinorelbine, topotecan or biological agents such as suramin and
retinoic acid have demonstrated clinical activity. Paclitaxel
has been evaluated at different doses and schedules and
yielded a response rate of 21% (range 11–30%), with single
patients achieving complete remissions. This has led to the
inclusion of paclitaxel in salvage regimens in combination
with cisplatin and/or ifosfamide. Two studies have evaluated
gemcitabine in refractory germ-cell tumors and demonstrated a response rate of 17% (95% CI 7–28%) in 52 intensively pre-treated patients, two-thirds of whom had relapsed
after previous high-dose chemotherapy plus autologous stemcell transplantation. The non-hematological toxicity of weekly
gemcitabine at doses of 1,000 to 1,250 mg/m2 was tolerable,
and hematological side effects included thrombocytopenia in
approximately 20% of patients. Ongoing studies in refractory
germ-cell tumors performed by the German Testicular Cancer Study Group are evaluating bendamustine, an alkylating
agent with activity in breast and small-cell lung cancer, and
oxaliplatin, a platinum derivative with incomplete crossresistance to cisplatin. Future trials combining new active
agents may examine alternating treatment strategies in
patients with poor-prognostic disease or as salvage treatment. Int. J. Cancer 83:848–851, 1999.
r 1999 Wiley-Liss, Inc.
Platinum-based combination chemotherapy, such as PEB (platinum, etoposide, bleomycine) or PEI (platinum, etoposide, ifosfamide), is considered standard treatment for patients with metastatic
testicular cancer, achieving long-term cure rates of approximately
70% to 80% (Bokemeyer, 1998). Patients relapsing after conventional chemotherapy are currently included in clinical trials using
high-dose chemotherapy plus autologous stem-cell transplantation.
However, patients relapsing after high-dose salvage chemotherapy
or progressing during cisplatin-based first-line chemotherapy have
an extremely poor prognosis, particularly those with disease totally
refractory to platin-based regimens (Beyer et al., 1996). For these
patients, identifying new agents with significant anti-tumor activity
in germ-cell cancer remains a priority. Treatment of these patients
must take into account both potential activity and the avoidance of
severe side effects. With most patients now being pre-treated with
high-dose chemotherapy plus autologous stem-cell transplantation,
the tolerability of new agents after this treatment strategy requires
further evaluation.
DRUGS WITH NO OR MINOR ACTIVITY IN REFRACTORY
GERM-CELL TUMORS
Several agents have been evaluated in patients with refractory
testicular cancer, but until recently no drugs with significant
anti-tumor activity had been identified. Table I summarizes the
phase II studies of these drugs. Anthracyclines, including mitoxantrone and epirubicin, at high doses have been evaluated in 3 clinical
trials (Williams et al., 1985; Harstrick et al., 1990; Stoter et al.,
1992). Myelosuppression, particularly following high epirubicin at
doses of 120 to 135 mg/m2, has been the major side effect. Among a
total of 48 patients reported in 3 trials, 1 patient with 2 prior
complete responses to cisplatin therapy of less than 4 months
duration each (early relapse) achieved a partial remission of lung
metastases lasting for 6 months (Harstrick et al., 1990). Overall,
these data do not demonstrate a significant clinical activity of
anthracyclines in platin-refractory testicular cancer.
Mitomycin C was evaluated in 7 pre-treated patients. Despite 2
responses, hematological and pulmonary toxicity prohibited further
evaluation of this drug (Hoskins et al., 1990). A phase I/II study of
vinorelbine in refractory testicular cancer was also prematurely
closed due to lack of responses and extensive myelotoxicity
(Bokemeyer et al., 1993). Topotecan, a novel topoisomerase-I
inhibitor with activity in ovarian cancer, has been evaluated in 14
patients with relapsed cisplatin-refractory germ-cell tumors. As
expected, myelosuppression was the major toxicity of topotecan,
but no responses were observed (Puc et al., 1995).
Recent trials have also investigated the use of biological agents
for the treatment of relapsed germ-cell tumors. Based on in vitro
results in 2 human teratocarcinoma cell lines, suramin was
evaluated in a phase II study in 14 intensively pre-treated patients.
Serum ␣-fetoprotein levels declined in 1 patient, but no complete
or partial response was observed. Suramin doses were based on a
normogram, allowing examination of individual therapeutic levels
(Motzer et al., 1993). The second biological agent evaluated in a
phase II trial was all-trans-retinoic acid. In vitro results showed
differentiation in response to retinoic acid in 6 human germ-cell
tumor cell lines. Subsequently, 16 patients were treated with
retinoic acid for an average of 7 weeks and responses were noted
(Moasser et al., 1995). It is unclear whether retinoids with
improved receptor selectivity or improved pharmacological dosing
achieve better results.
PACLITAXEL IN CISPLATIN-REFRACTORY DISEASE
Since the mechanisms of action of and resistance to paclitaxel
are different from those to DNA-damaging agents, such as cisplatin
*Correspondence to: Department of Medicine II, University of Tuebingen, Otfried-Mueller-Strasse 10, D-72076 Tuebingen, Germany. Fax: ⫹49
7071/ 29 36 75. E-mail: [email protected]
THERAPY IN CISPLATIN-REFRACTORY PATIENTS
849
TABLE I – AGENTS PREVIOUSLY EVALUATED IN CISPLATIN-REFRACTORY TESTICULAR GERM-CELL TUMORS WITH
MINOR OR NO ACTIVITY
Study
Number of Response
patients
rate
Agent
Williams et al. (1985)
Harstrick et al. (1990)
Stoter et al. (1992)
Hoskins et al. (1990)
Mitoxantrone
Epirubicin (high-dose)
Epirubicin (high-dose)
Mitomycin C
14
16
18
7
0/14
1/16
0/18
2/7
Bokemeyer et al. (1993)
Motzer et al. (1993)
Moasser et al. (1995)
Murphy et al. (1992)
Drasga et al. (1987)
Puc et al. (1995)
Vinorelbine
Suramin
All-trans retinoic acid
Iproplatin
Iproplatin
Topotecan
7
14
16
15
14
15
0/7
0/14
0/14
0/14
1/14
0/14
Toxicity/comments
—
Myelosuppression
Myelosuppression
Pulmonary toxicity and myelosuppression
No severe neurotoxicity
Individual dosing
Duration 7 weeks
—
Nausea/vomiting
Myelotoxicity
TABLE II – ACTIVITY OF SINGLE-AGENT PACLITAXEL IN RELAPSED/REFRACTORY GERM-CELL TUMOR
Study
Number of
patients
Paclitaxel dose
(mg/m2 )
Infusion
duration (hr)
Responses
Bokemeyer et al. (1994)
Motzer et al. (1994)
Nasario et al. (1995)
Bokemeyer et al. (1996)
Sandler et al. (1998)
Total
10
31
15
24
18
98
135–225
250 ⫹ G-CSF
250 ⫹ G-CSF
225
170–200
3
24
24
3
24
3 PR (30%)
3 CR, 5 PR (26%)
0 CR, 2 PR (13%)
2 CR, 4 PR (25%)
2 PR (11%)
5 CR, 16 PR (21%)
G-CSF, granulocyte colony-stimulating factor; CR, complete remission; PR, partial remission.
and ifosfamide, the role of paclitaxel in platinum-resistant tumors
remains an important clinical issue. Paclitaxel has demonstrated
significant clinical tumor activity in breast and ovarian cancer, with
neurotoxicity as the main limiting side effect. The German
Testicular Cancer Study Group (GTCSG) evaluated paclitaxel in a
phase I/II study at doses of 135 to 225 mg/m2 given as 3 hr
infusions every 3 weeks in patients with intensively pre-treated
testicular cancer (Bokemeyer et al., 1994). A dose of 225 mg/m2 ⫻
3 weeks was used for the consecutive phase II study, which
revealed 6 responders among 24 patients (25%) (Bokemeyer et al.,
1996). Despite intensive pre-treatment with a median of 7 (3–12)
previous cisplatin-based regimens, peripheral neuropathy was
tolerable, with 29% ⱖ WHO grade II. Other side effects included
granulocytopenia WHO grade III/IV in 12 patients (50%) and
thrombocytopenia in 4 patients (16%). Other investigators have
used even higher dose of 250 mg/m2 but with routine application of
G-CSF (Sandler et al., 1998; Motzer et al., 1994). These phase II
studies, including 31 and 15 patients, revealed response rates of
26% and 13%, respectively. The available phase II studies on
single-agent paclitaxel are summarized in Table II. In total, among
98 patients, a response rate of 21% (range 11–30%) was observed.
Interestingly, single patients pre-treated with high-dose chemotherapy plus autologous stem-cell transplantation responded to paclitaxel. Moreover, even single patients with absolutely platinumrefractory disease responded to paclitaxel (Bokemeyer et al.,
1996), which was already observed in in vitro experiments with
chemotherapy-resistant testicular cancer cell lines.
More recent trials have evaluated paclitaxel in combination with
cisplatin and/or ifosfamide as first-line salvage in patients with
favorable or unfavorable prognostic criteria at relapse. The GTCSG
has used a regimen of paclitaxel, ifosfamide and cisplatin (TIP)
given for 3 cycles and followed by high-dose chemotherapy with
thiotepa, etoposide and carboplatin (TEC) for patients with relapsed disease (Beyer et al., 1998). The EORTC has started a study
which includes paclitaxel in combination with PEB chemotherapy
as first-line treatment in patients with intermediate-prognosis
germ-cell tumors. These and other ongoing investigations should
shed more light on the question of whether paclitaxel adds to the
cure rates achievable in patients with metastatic germ-cell tumors.
GEMCITABINE IN RELAPSED DISEASE
Only 20% to 40% of patients undergoing high-dose chemotherapy plus autologous stem-cell transplantation for relapse will be
cured. Thus, there is considerable need for the development of less
toxic and effective palliative treatment after high-dose chemotherapy. Pont et al. (1997) have evaluated data on 47 evaluable patients
from 9 centers receiving chemotherapy at progression after highdose chemotherapy for germ-cell cancer. On multivariate analysis,
the interval since high-dose chemotherapy treatment and the use of
ifosfamide and/or paclitaxel were favorable prognostic factors for
survival (Pont et al., 1997).This study clearly demonstrated that
chemotherapy is feasible after previous high-dose chemotherapy
with stem-cell transplantation. Two studies have evaluated the role
of gemcitabine in refractory germ-cell tumors based on the
rationales that, at present, most patients have already received
paclitaxel as part of their salvage therapy. In addition, gemcitabine
represents a nucleoside analogue with an overall low toxicity and
without cross-resistance to cisplatin. Inclusion criteria for these
study were refractory germ-cell cancer after at least 2 previous
standard-dose chemotherapy regimens, relapse after high-dose
chemotherapy or progressive disease despite adequate cisplatinbased therapy (Table III). The study aims were to define both the
activity and toxicity of single-agent gemcitabine as well as the
feasibility of its use after high-dose chemotherapy. Investigators at
Indiana University treated 21 patients on a schedule with 1,250
mg/m2 weekly for 28 days. They reported 1 complete and 2 partial
remissions, for an overall response rate of 15% (Einhorn et al.,
1999). The GTCSG included 31 patients in a protocol examining
gemcitabine at a dose of 1,000 mg/m2 weekly for 28 days. Six
patients (19%) achieved a response to gemcitabine, including 3 of
22 patients (17%) after previous high-dose chemotherapy, 3 of 19
patients (16%) previously treated with paclitaxel and 1 of 4 patients
(25%) with mediastinal germ-cell tumors (Bokemeyer et al., 1999).
The median progression-free interval was 4 months. However,
single patients have responded for almost 1 year to gemcitabine.
No patient with absolute refractory disease responded, but 3
patients with refractory disease had a marked decline of more than
90%. Combining toxicity data of 52 published patients to date,
thrombocytopenia was the main side effect. It occurred in 25% of
BOKEMEYER ET AL.
850
TABLE III – ACTIVITY OF SINGLE-AGENT GEMCITABINE IN RELAPSED/REFRACTORY GERM-CELL TUMORS
Study
Gemcitabine schedule (mg/m2 )
Total number
of patients
Bokemeyer et al. (1999)
Einhorn et al. (1999)
Total
1,000 on days 1, 8, 15 for 28 days
1,200 on days 1, 8, 15 for 28 days
31
20
51
Patients
Previous
HD-Ctx
DDP-refractory
Response
rate
Median survival
22 (71%)
11 (55%)
33 (65%)
17 (54%)
13 (65%)
30 (58%)
6 (19%)
3 (15%)
9 (17%)
6 months (2–23)
not given
HD-Ctx, high-dose chemotherapy; DDP, cis-Diammindichlorplatin.
patients followed by granulocytopenia in 12%. Non-hematological
toxicities were infrequent and not severe. Due to the thrombocytopenia, dose reductions were necessary in 13 patients (25%). For
future patients, a schedule modification to weekly applications at
day 1 and day 8 followed by retreatment at day 21 was suggested.
While it has been demonstrated that single-agent gemcitabine is an
effective palliative treatment in approximately one-fifth of patients
with refractory germ-cell tumors, no data are available on its
combination with either cisplatin derivatives or paclitaxel in this
disease.
ONGOING PROTOCOLS AND FUTURE PROSPECTS
With the identification of 2 new active agents, paclitaxel and
gemcitabine, interest in systematically exploring new agents in
cisplatin-refractory disease is growing. The GTCSG has started a
phase II study of relapsed testicular cancer to evaluate bendamustine, an alkylating agent with activity in lymphoma, breast cancer
and small-cell lung cancer. Currently, 7 patients have been treated
with bendamustine, 120 mg/m2 on days 1 and 2, repeated at 3-week
intervals. Preliminary analysis demonstrates that application of
bendamustine is associated with low, non-hematological toxicity.
Treatment was successfully performed according to the planned
schedule in 6 of the 7 patients. One patient had a temporary
response to bendamustine of 4 weeks duration only. Completion of
this study on 14 patients should fully determine the value of this
agent.
New platinum derivatives have been of long-standing interest in
patients with cisplatin-refractory disease. Phase II studies performed in the late 1980s, which used iproplatin (CHIP), did not
identify significant activity of this agent (Murphy et al., 1992).
However, oxaliplatin, a diaminocyclohexane complex, has been
developed for anti-cancer therapy, particularly for colon cancer. In
vitro data on non-seminomatous germ-cell tumor cell lines indicate
incomplete cross-resistance between cisplatin and oxaliplatin (Dunn
et al., 1997). The second ongoing protocol of the GTCSG evaluates
oxaliplatin at 60 mg/m2 once weekly for 4 weeks (repeated at day
36) in patients with intensively pre-treated testicular cancer.
Oxaliplatin is associated with low hematotoxicity and neuropathy,
including both cold sensitivity, and paresthesias is the dose-limiting
side effect. Six patients are currently enrolled in this protocol, and 1
patient achieved partial remission of his lung metastases and a
marked fall of ␣-fetoprotein values from 20,000 to 50 ng/ml.
Oxaliplatin was applied to patients after high-dose chemotherapy
without cumulative hematotoxicity.
New drugs for testicular cancer have currently been developed
only in intensively pre-treated patients. Two new agents, paclitaxel
and gemcitabine, have demonstrated activity in approximately 20%
of patients with refractory disease. The identification of these new
agents may allow alternating treatment strategies in patients with
advanced or relapsed disease using these agents as an early line of
therapy. Furthermore, combinations of gemcitabine and paclitaxel
or gemcitabine with platinum derivatives should be interesting.
Cooperative efforts using common palliative treatment protocols of
new drugs have allowed development of new treatment strategies
in patients with testicular cancer. Ongoing research in this area may
not only improve the treatment of patients with refractory and
relapsed disease but also allow further insight into mechanisms of
drug resistance and the possibility of combining novel agents.
These efforts may allow development of treatment strategies
applicable to a broad range of solid tumors.
REFERENCES
BEYER, J., BOKEMEYER, C., RICK, O., METZNER, B., CASPER, J., WANDT, H.,
HARTMANN, F., SCHMOLL, H.J., KANZ, L., HUHN, D. and SIEGERT, W.,
Salvage treatment in germ-cell tumors using taxol, ifosfamide, cisplatin
(TIP) followed by high-dose carboplatin, etoposide, and thiotepa (HDCET):
first results. Proc. Amer. Soc. clin. Oncol., 17, 322a (1998).
BEYER, J. AND 12 OTHERS, High-dose chemotherapy as salvage treatment in
germ cell tumors: a multivariate analysis of prognostic variables. J. clin.
Oncol., 14, 2638–2645 (1996).
BOKEMEYER, C., Current trends in chemotherapy for metastatic nonseminomatous testicular germ cell tumors. Oncology, 55, 177–188 (1998).
BOKEMEYER, C., BEYER, J., METZNER, B., RÜTHER, U., HARSTRICK, A.,
WEISSBACH, L., KÖHRMANN, U., VERBEEK, W. and SCHMOLL, H.J., Phase II
study of paclitaxel in patients with relapsed or cisplatin-refractory testicular
cancer. Ann. Oncol., 7, 31–34 (1996).
BOKEMEYER, C., DROZ, J.P., HANAUSKE, A., SCHRÖDER, M., QUEISSER, W.
and SCHMOLL, H.J., Treatment of relapsed nonseminoma germ cell tumors
with vinorelbine: a trial of the phase I/II study group of the Association of
Medical Oncology of the German Cancer Society. Onkologie, 16, 29–31
(1993).
BOKEMEYER, C., GERL, A., SCHÖFFSKI, P., HARSTRICK, A., NIEDERLE, N.,
BEYER, J., CASPER, J., SCHMOLL, H.J. and KANZ, L., Gemcitabine in patients
with relapsed or cisplatin-refractory testicular cancer. J. clin. Oncol., 17,
512–516 (1999).
BOKEMEYER, C., SCHMOLL, H.J., NATT, F., KNOCHE, M., BEYER, J. and
SOUCHON, R., Preliminary results of a phase I/II trial of paclitaxel in
patients with relapsed or cisplatin-refractory testicular cancer. J. Cancer
Res. clin. Oncol., 120, 754–757 (1994).
DRASGA, R.E., WILLIAMS, S., EINHORN, L.H. and BIRCH, R., Phase II
evaluation of iproplatin in refractory germ cell tumors: A Southeastern
Cancer Study Group trial. Cancer Treat. Rep., 71, 863–864 (1987).
DUNN, T.A., SCHMOLL, H.J., GRÜNWALD, V., BOKEMEYER, C. and CASPER, J.,
Comparative cytotoxicity of oxaliplatin and cisplatin in non-seminomatous
germ cell lines. Invest. New Drugs, 15, 109–114 (1997).
EINHORN, L.H., STENDER, M.J. and WILLIAMS, S.D., Phase II trial of
gemcitabine in refractory germ cell tumors. J. clin. Oncol., 17, 509–511
(1999).
HARSTRICK, A., SCHMOLL, H.J., WILKE, H., SCHÖBER, C., STAHL, M., KÖHNE
WÖMPNER, C., BOKEMEYER, C., DÖLKEN, G., BURK, K. and POLIWODA, H.,
High dose epirubicin in refractory or relapsed non-seminomatous testicular
cancer: a phase II study. Ann. Oncol., 1, 375–376 (1990).
HOSKINS, P., COPPIN, C.M. and MURRAY, N., Mitomycin is active against
refractory germ-cell tumors. A phase II study. Amer. J. clin. Oncol., 13,
35–38 (1990).
MOASSER, M.M., MOTZER, R.J., KHOO, K.S., LYN, P., MURPHY, B., BOSL,
G.J. and DMITROVSKY, E., All-trans retinoic acid for treating germ cell
tumors. In vitro activity and results of a phase II trial. Cancer, 76, 680–686
(1995).
MOTZER, R.J., BAJORIN, D., SCHWARTZ, L.H., HUTTER, H.S., BOSL, G.J.,
SCHER, H., LYN, P. and FISCHER, P., Phase II trial of paclitaxel shows
THERAPY IN CISPLATIN-REFRACTORY PATIENTS
antitumor activity in patients with previously treated germ cell tumors. J.
clin. Oncol., 12, 2277–2283 (1994).
MOTZER, R.J., DMITROVSKY, E., MILLER, W.H.J., TONG, W.P., BAJORIN, D.,
SCHER, H. and BOSL, G.J., Suramin for germ cell tumors. In vitro growth
inhibition and results of a phase II trial. Cancer, 72, 3313–3317 (1993).
MURPHY, B., MOTZER, R.J. and BOSL, G.J., Phase II study of iproplatin
(CHIP) in patients with cisplatin-refractory germ cell tumors; the need for
alternative strategies in the investigation of new agents in GCT. Invest. New
Drugs, 10, 327–330 (1992).
NASARIO, A., AMATO, R.J., HUTCHINSON, L., BUI, C., ELLERHORST, J. and
LOGOTHETIS, C., Paclitaxel in extensively pretreated nonseminomatous
germ cell tumors. Urol. Oncol., 1, 184–187 (1995).
PONT, J., BOKEMEYER, C., HARSTRICK, A., SELLNER, F., GREINIX, H. and
STOIBER, F., Chemotherapy for germ cell tumors relapsing after high-dose
chemotherapy and stem cell support: a retrospective multicenter study of
851
the Austrian Study Group on Urologic Oncology. Ann. Oncol., 8, 1229–
1234 (1997).
PUC, H.S., BAJORIN, D., BOSL, G.J., AMSTERDAM, A. and MOTZER, R.J.,
Phase II trial of topotecan in patients with cisplatin-refractory germ cell
tumors. Invest. New Drugs, 13, 163–165 (1995).
SANDLER, A.B., CRISTOU, A., FOX, S., WILLIAMS, S.D., NICHOLS, C.R.,
TURNS, M. and RSCROTH, B.J., A phase II trial of paclitaxel in refractory
germ cell tumors. Cancer, 82, 1381–1386 (1998).
STOTER, G., AKDAS, A., FOSSÅ, S.D., KAYE, S.B., VAN GROENINGEN, C.J.,
RENARD, J. and VAN GLABBEKE, M., High-dose epirubicin in chemotherapy
refractory non-seminomatous germ cell cancer: a phase II study. Ann.
Oncol., 3, 577–578 (1992).
WILLIAMS, S.D., BIRCH, R., GAMS, R. and IRWIN, L., Phase II trial of
mitoxantrone in refractory germ cell tumors: a trial of the Southeastern
Cancer Study Group. Cancer Treat. Rep., 69, 1455–1456 (1985).
Документ
Категория
Без категории
Просмотров
7
Размер файла
78 Кб
Теги
207
1/--страниц
Пожаловаться на содержимое документа