Curing metastatic testicular cancer Lawrence H. Einhorn*
Indiana University Medical Center, 535 Barnhill Drive, RT 473, Indianapolis, IN 46202-5289
Contributed by Lawrence H. Einhorn, February 5, 2002
This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on May 1, 2001. Our initial studies with cisplatin ؉ vinblastine ؉ bleomycin began
and death after an initial clinical response. The strategies of
27 years ago in 1974, changing the cure rate for disseminated
combination chemotherapy, then and now, remain the same:
disease from 5 to 60%. Subsequently, through random prospective
(i) use drugs with known single-agent activity;
clinical trials, we have modified the treatment regimen to reduce
(ii) use drugs with nonoverlapping toxicity. Because the major
both the duration and dosages of the chemotherapy drugs. Cis-
dose-limiting toxicity for most drugs is myelosuppression, non-
platin ؉ etoposide was first used at Indiana University as salvage
myelosuppressive antineoplastic agents are of particular value;
chemotherapy in 1978, representing the first time that a solid
(iii) the cytolytic agents should have unique and separate
tumor had been cured with second-line chemotherapy. We next did a clinical trial comparing bleomycin ؉ etoposide ؉ cisplatin
(iv) develop combinations demonstrating a synergistic rather
(BEP) to cisplatin ؉ vinblastine ؉ bleomycin. The BEP regimen was proven to have less toxicity and a higher cure rate and therefore,
Although there was some success with single antineoplastic
since 1984, has been standard chemotherapy. More recent studies
agents such as cyclophosphamide for Burkitt’s lymphoma, or
have evaluated the use of lesser chemotherapy to maintain the
methotrexate for gestational choriocarcinoma, the more dra-
same cure rate for patients with good-prognosis disease. Standard
matic improvements in survival and cure were the result of
therapy for these patients is either three courses of BEP or four
combination chemotherapy. Hematologic malignancies such as
courses of EP, and over 90% of these patients will be cured of their
childhood acute lymphoblastic leukemia and Hodgkin’s and
disease. Patients who are not cured with their initial BEP chemo-
non-Hodgkin’s lymphoma were the initial beneficiaries of this
therapy are usually treated with salvage chemotherapy. Approx-
approach. At about the same time (30 years ago), clinical trials
imately 50% of these testicular cancer patients will subsequently
became a powerful tool for hypothesis generation and proof of
be cured with salvage chemotherapy with tandem transplant of
principle through random prospective phase III studies. This led
high-dose chemotherapy with peripheral stem cell rescue. Testic-
to dramatic improvements in survival of pediatric cancers such
ular cancer has become a model for a curable neoplasm. In the early
as rhabdomyosarcoma, Ewing’s sarcoma, osteosarcoma, etc. 1970s, metastatic testicular cancer was associated with only 5% Early Chemotherapy Studies survival. Today, with modern chemotherapy and surgery tech- niques, 80% of patients will survive their disease.
Before the usage of cisplatin combination chemotherapy, stan-
dard chemotherapy for disseminated testicular cancer consisted
Germ cell tumors are relatively uncommon, accounting for ofdactinomycin,aloneorincombinationwithmethotrexateand
only 1% of male malignancies in the United States. The
chlorambucil. Thirty years ago, M. C. Li and colleagues at
highest worldwide incidence is in Scandinavian countries; by
Memorial Sloan Kettering Hospital (New York) recognized that
contrast, testicular cancer is rare in African Americans. The
testis cancer was chemosensitive, with a 50% objective response
primary age group is 15–35 for nonseminomatous tumors and a
rate including 10–20% complete remission and a 5–10% cure
rate (1). M. L. Samuels and colleagues at M. D. Anderson
In 2001, there were Ϸ8,000 newly diagnosed cases in the
Hospital (Houston) later evaluated vinblastine ϩ bleomycin, a
United States, contrasting sharply with the 190,000 cases of
synergistic regimen in preclinical studies, and achieved a 25%
prostate cancer, the most common male malignancy.
long-term disease-free survival (2). This was a higher success
Despite the paucity of cases, this tumor has become an
rate than would have been predicted from the modest 5% cure
extremely important oncological disease. First, it is the most
rates of these drugs as single agents and appeared to validate the
common carcinoma in young men ages 15–35 and thus has the
preclinical studies of this synergistic two-drug regimen. How-
potential to greatly shorten productive years of life. Second,
ever, the drug that revolutionized the cure rate for patients with
available serum markers (alphafetoprotein and human chorionic
metastatic testicular cancer was cisplatin. Cisdiamminedichlo-
gonadotropin) allow the clinician to make important and accu-
roplatinum (cisplatin) was the first heavy metal to be evaluated
rate treatment-related decisions. Third, testicular cancer has
as an anticancer therapy and resulted from the serendipitous
been a model for multidisciplinary care, as surgical resection of
finding and subsequent intellectual acumen of Barnett Rosen-
postchemotherapy radiographically persistent disease can im-
berg in the Department of Biophysics at Michigan State Uni-
versity (3). In 1973, cisplatin was first evaluated in early phase
prove the cure rate. Fourth, germ cell tumors have become an
I–II clinical trials. Included among the patients in these studies
excellent testing ground for active experimental drugs (e.g.,
were men with testicular cancer who had failed prior chemo-
cisplatin, etoposide, and ifosfamide, all of which were approved
therapy (usually dactinomycin) (4). There is enthusiasm when
by the Food and Drug Administration primarily on the basis of
novel agents are capable of achieving a modest partial remission
data in testicular cancer). The goal of chemotherapy in germ cell
rate in refractory carcinomas. However, cisplatin attained not
tumors is never merely palliation or prolongation of survival,
only three partial but also three complete remissions in 11
patients with refractory testicular cancer (4). Furthermore,
despite initial severe nausea, vomiting, and nephrotoxicity, this
Combination Chemotherapy and Clinical Trials Combination chemotherapy began to be used in patients with
malignant diseases 30 years ago. The principle was that malig-
Abbreviations: PVB, cisplatin ϩ vinblastine ϩ bleomycin; BEP, etoposide ϩ bleomycin; NED,
nant clones of cells would rapidly develop drug resistance to a
single cytolytic agent, thereby permitting disease progression
4592– 4595 ͉ PNAS ͉ April 2, 2002 ͉ vol. 99 ͉ no. 7
drug was relatively nonmyelosuppressive, leading to inclusion as
PVB Versus Cisplatin ؉ Etoposide ؉ Bleomycin (BEP)
a component of combination chemotherapy. Subsequent im-
Etoposide (VP-16) is an epipodophyllotoxin derivative with
provements in supportive care have greatly mitigated the neph-
demonstrated single-agent activity in refractory testicular cancer
rotoxicity and emesis. This remains a dramatic example of the
(7). In 1978, we began our initial salvage chemotherapy studies
value, for patients and scientists, of clinical trials with novel
with cisplatin ϩ etoposide in patients who were not cured with
PVB or similar induction therapy. Schabel et al. demonstrated
With this background, in August 1974, we began our initial
remarkable synergism with cisplatin ϩ etoposide in numerous
cisplatin ϩ vinblastine ϩ bleomycin (PVB) study at Indiana
preclinical models (8). We confirmed the remarkable synergism
University, using the established two-drug synergistic regimen of
of these two active agents, as we achieved a 25% cure rate in
vinblastine ϩ bleomycin and simply adding the then experimen-
patients who were not cured with their initial cisplatin combi-
tal promising drug cisplatin (5). The PVB regimen fulfilled the
nation chemotherapy (9). This represented the first time an adult
requirements for a successful combination chemotherapy regi-
solid tumor was cured with second-line chemotherapy.
men: single-agent activity for each component of the PVB
From 1981 through 1984, the Southeastern Cancer Study
regimen, different and unique mechanism of action for the three
Group conducted a randomized prospective study comparing
agents, separate and nonoverlapping toxicity, allowing admin-
PVB and BEP as initial induction chemotherapy (10), based on
istration of each drug in full dosage, and evidence of preclinical
the promising results of cisplatin ϩ etoposide as second-line
synergism (vinblastine ϩ bleomycin).
therapy and the expectation for reduced neuromuscular toxicity
with etoposide compared with vinblastine. No maintenance
therapy was given in either arm. Postchemotherapy residual
From 1974 to 1976, we initiated and completed our first PVB
disease was resected if anatomically feasible. Two additional
study (5).† As was traditional in the mid-1970s, induction therapy
courses of the original induction regimen were given, deleting
was followed by maintenance chemotherapy (vinblastine 0.3
bleomycin, if carcinoma was found in the resected specimen.
A total of 244 patients from 24 institutions entered this trial.
mg͞kg monthly for a total of 2 years of chemotherapy), in an
Of 121 patients treated with PVB, 74 (61%) had a complete
attempt to achieve total cell kill, as popularized with mainte-
remission (CR), and another 15 (13%) became disease-free after
nance chemotherapy in childhood acute lymphoblastic leukemia.
resection of teratoma (10 patients) or carcinoma (five patients).
Four courses of PVB induction chemotherapy were used. This
Among the 123 patients given BEP, 74 (60%) had a CR, and 28
number was chosen because of concern (in 1974) of cumulative
(23%) became free of disease after resection of teratoma (22
cisplatin-induced nephrotoxicity. We had a good early estimate
patients) or carcinoma (6 patients). Thus, 74% became disease-
of optimal duration of induction chemotherapy, as 25 years after
free after treatment with PVB and 83% after BEP. In the
completion of this original PVB trial, there is still no evidence
subgroup of advanced disseminated disease, there was a survival
to support the administration of more than four consecutive
advantage for BEP (P ϭ 0.02).
course of cisplatin combination chemotherapy.
Granulocytopenic toxicity, including granulocytopenic fever,
Thirty-three of 47 (70%) patients attained a complete remis-
was similar in the two arms. There was a major reduction in
sion, and an additional five patients (11%) were rendered
neuromuscular toxicity, as manifested by paresthesia, abdominal
disease-free by postPVB surgical resection of radiographically
cramps, ileus, and myalgias, favoring the BEP arm. This was
persistent disease. Fifty-three percent of patients were cured
significant not only statistically, but also clinically. On the basis
with PVB, representing a 1-logarithmic increase in the cure rate
of this study, which demonstrated a reduction in morbidity and
compared with contemporaneous dactinomycin chemotherapy.
superior survival, we have used BEP since 1984 as first-line
We next designed a series of phase III trials to answer clinically
therapy for disseminated testicular cancer and have abandoned
relevant questions. The first study addressed whether we could
reduce the significant neuromuscular and myelosuppressive
toxicity of vinblastine by reducing the dosage from 0.4 to 0.3
Subsequent Studies with BEP
mg͞kg and still maintain therapeutic efficacy. As expected, the
Good Risk (Minimal–Moderate Disease). Several groups have de-
lower dose of vinblastine was associated with a reduction in
signed staging systems that attempt to discriminate good-risk
toxicity, but the complete remission and cure rates were similar
from poor-risk disease (11, 12). This would allow the study of less
toxic regimens in good-risk disease and more aggressive therapy
Our subsequent phase III PVB study challenged one of the
in those validated to have poor-risk testicular cancer. We began
basic tenets of oncology, the utilization of maintenance therapy
a phase III study in 1984, completed in 1987, evaluating the
to prevent relapse. Patients achieving a disease-free status with
standard four courses of BEP versus three courses (9 weeks) of
BEP in good-risk disease. One hundred eighty-four patients
PVB in this trial were randomized to a standard arm of 21
entered this study, and 97% achieved a NED status confirming
months of maintenance vinblastine (total of 2 years of chemo-
the accuracy of this definition of ‘‘good risk.’’ An identical 92%
therapy) versus an experimental arm of just 12 weeks of PVB
of patients on each arm are continuously NED (13). We have
with no further therapy. One hundred thirteen patients entered
updated this study for the 118 patients entered at Indiana
this study at Indiana University or participating institutions in
University (median followup 9 years). There remain no differ-
the Southeastern Cancer Study Group. The relapse rate was only
ences between the two arms, with only four deaths in each arm.
5%, with or without maintenance vinblastine (6). This random-
Furthermore, for patients with serum human chorionic gonad-
ized clinical trial benefited patients by reducing duration of
otropin less than 1,000 milliunits͞ml, there were only two deaths
therapy and toxicity as well as lessening the financial expenditure
out of 104 patients (14). Patients with good-risk metastatic
disease (e.g., small pulmonary metastases) have a 98% cure rate
with 9 weeks of chemotherapy, superior to surgical cure rates for
most clinically localized cancers. Therefore, we have greatly
ameliorated the toxicity and reduced the duration of therapy
†PVB: cisplatin, 20 mg͞m2 days 1 to 5; vinblastine, 0.2 mg͞kg, days 1–2; bleomycin, 30 units,
from the original PVB study in 1974 to the completion of this
days 2, 9, and 16. (i) Courses were repeated every 3 weeks for four courses; (ii) after PVBinduction, single-agent maintenance vinblastine (0.3 mg͞kg) every 4 weeks was utilized
clinical trial in 1987. We have demonstrated that we could reduce
for a total of 24 mo of chemotherapy.
vinblastine dosage, eliminate 20 months of maintenance vinblas-
PNAS ͉ April 2, 2002 ͉ vol. 99 ͉ no. 7 ͉ 4593 Table 1. Poor–risk disease (all nonseminomatous patients)
variable was the cisplatin dosage (20 mg͞m2 ϫ 5 versus 40 mg͞m2
ϫ 5) with BEP in both arms. One hundred fifty-three patients
Lactic dehydrogenase Ͼ 10 times upper limit of normal; human
were evaluable. As expected, patients receiving double-dose
chorionic gonadotropin Ͼ 50,000 units͞ml, or
cisplatin experienced considerably more toxicity than standard
BEP. Unfortunately, there was no evidence of therapeutic
Any primary mediastinal nonseminomatous germ cell tumor
superiority for the high-dose cisplatin arm, with 62.2% contin-
Nonpulmonary visceral metastases (bone, liver, brain, etc.)
uously NED with high-dose and 63.6% with standard BEP (18).
tine, substitute etoposide for vinblastine with improved efficacy
Salvage Therapy. Our concept for salvage therapy has always been
to use cisplatin plus other active agents not previously used, as
and decreased toxicity, and finally, delete the fourth and final
long as there was no progression during cisplatin combination
course of BEP in good-risk patients. This resulted in the
elimination of the most toxic of the four courses because of
potential for cumulative toxicities (bleomycin pulmonary fibro-
salvage therapy after PVB (9). Our initial salvage therapy after
sis, cisplatin neurotoxicity, and ototoxicity). Also, during the
BEP had been vinblastine 0.11 mg͞kg day 1 and 2 ϩ ifosfamide
years of this phase III study (1984–1987), we did not have
1.2 grams͞m2 ϫ 5 ϩ cisplatin 20 mg͞m2 ϫ 5 every 3 weeks for
availability of effective antiemetics, and the cumulative toxicities
four courses. Between 1984 and 1989, 135 patients received this
of anorexia, nausea, and vomiting were also a formidable
regimen as second-line therapy. Sixty-seven patients (49.6%)
challenge for patients with their fourth courses of BEP.
achieved NED status, including 15 (11%) who were NED after
A larger European Organization for Research and Treatment
postchemotherapy resection of teratoma and 10 (7.4%) NED
of Cancer phase III study randomized 812 good-risk patients to
after postchemotherapy resection of carcinoma. Thirty-
BEP ϫ 3 versus BEP ϫ 3 with a fourth course of EP. This study
two (23.7%) are continuously NED with minimal followup of 5
was performed to attempt to detect a 5% difference favoring
four courses. The results were again identical, with 90.4% (three
High-dose therapy, with carboplatin and etoposide and au-
courses) versus 89.4% progression-free survival (15).
tologous bone marrow transplant, was first started at Indiana
University in 1986. Initially, this was used as a last attempt at
curative therapy (third-line or later or after progression during
Definition of Poor-Risk (Advanced) Disease. Poor-risk disease con-
sists of a more heterogeneous patient population and has been
cisplatin therapy). Six of these first 40 patients are 5ϩ years
defined based on tumor markers, volume of metastatic disease,
continuously NED (20). We now use peripheral stem cells and
and multiplicity of anatomic sites (11, 12). These patients will
granulocyte colony-stimulating factor, and we are able to safely
have a 40–60% cure rate with standard therapy. In this group,
administer carboplatin 700 mg͞m2 ϫ 3 ϩ etoposide 750 mg͞m2
the impetus has been to evaluate more aggressive chemotherapy
ϫ 3. We currently use this therapy as initial salvage chemother-
in phase II and III studies to try to improve the therapeutic
apy. Thirty-five of 65 (54%) are continuously disease-free for a
minimum of 2 years with this approach (21), demonstrating the
An international group was convened to develop a consensus
remarkable chemosensitivity and curability of testicular cancer.
classification for poor-risk (and good-risk) germ cell tumors.
Over 70% of patients with metastatic testicular cancer will be
Data were available on 5,862 patients, with a median followup
cured with BEP. Approximately half of patients who are not
time of 5 years. Only 14% of these patients comprised the
cured with their initial chemotherapy will still be cured with
poor-risk category, with a 41% 5-year disease-free survival and
overall 48% 5-year survival (16). The cure rate with standard
BEP is probably 10% higher, because the intergroup consensus
Future Studies. Testicular cancer has been a model for a curable
included older regimens that did not include etoposide. This new
neoplasm. We are currently exploring whether there are molec-
definition (Table 1) is now incorporated in the current American
ular as well as clinical differences that separate curable from
intergroup trial for poor-risk disease.
incurable disease. We will evaluate specific poor-risk subsets,
including salvage chemotherapy patients, primary mediastinal
Advanced Disease. The National Cancer Institute in the United
nonesminomatous germ cell tumors (22), transformation of
States randomized poor-risk patients to PVB versus an experi-
teratoma to primitive neuroectodermal tumors (23), and late-
mental regimen that used double-dose (40 mg͞m2 ϫ 5) cisplatin.
relapse patients (24). This latter group is particularly intriguing.
This phase III study revealed a statistically significant disease-
Metastatic testicular cancer grows very rapidly and is uniquely
free and overall survival favoring the double-dose cisplatin arm
curable with cisplatin combination chemotherapy. However,
(17). This study seemed to validate the concept of dose intensity.
2–3% of patients initially diagnosed with testicular cancer will
However, there were several flaws in the study methodology.
experience a late relapse beyond 2 years of last therapy. Most late
First, there was a very small sample size (n ϭ 57 with a 2:1
relapses occur beyond 5 years, with our latest relapse 32 years
randomization). Second, and most important, the experimental
after chemotherapy. Patients with late relapse may respond to
arm also included a fourth drug, etoposide, with PVB. BEP had
cisplatin combination chemotherapy but are rarely curable with
superior survival compared with PVB in advanced poor-risk
chemotherapy alone. We hope to identify an important molec-
disease, with standard-dose cisplatin on both arms (10). There-
ular mechanism and then be able to exploit it as a therapeutic
fore, we designed a study in advanced disease in which the only
1. Li, M. C., Whitmore, W. F., Golbey, R. & Grabstald, H. (1960) J. Am. Med.
7. Fitzharris, B. M., Kaye, S. B., Saverymuttu, S., Newlands, E. S., Barrett, A.,
Assoc. 174, 145–153.
Peckham, M. J. & McElwain, T. J. (1980) Eur. J. Cancer 16, 1193–1197.
2. Samuels, M. L., Lanzotti, V. J., Holoye, P. Y., Boyle, L. E., Smith, T. L. &
8. Schabel, F. M., Jr., Trader, M. W., Laster, W. R., Jr., Corbett, T. H. & Griswold,
Johnson, D. E. (1976) Cancer Treat. Rev. 3, 185–204.
D. P., Jr. (1979) Cancer Treat. Rep. 63, 1459–1473.
3. Rosenberg, B., VanCamp, L. & Krigas, T. (1965) Nature (London) 205, 678–699.
9. Williams, S. D., Einhorn, L. H., Greco, F. A., Oldham, R. & Fletcher, R. (1980)
4. Higby, D. J., Wallace, H. J., Albert, D. J. & Holland, J. F. (1974) Cancer 33, Cancer 46, 2154–2158.
10. Williams, S. D., Birch, R., Irwin, L., Greco, A., Loehrer, P. J. & Einhorn, L. H.
5. Einhorn, L. H. & Donohue, J. P. (1977) Ann. Int. Med. 87, 293–298.
(1987) N. Engl. J. Med. 316, 1435–1440.
6. Einhorn, L. H., Williams, S. D., Troner, M., Greco, F. A. & Birch, R. (1981)
11. Birch, R., Williams, S. D., Cone, A., Einhorn, L. H., Roark, P., Turner, S. &
N. Engl. J. Med. 305, 717–731.
Greco, F. A. (1986) J. Clin. Oncol. 4, 400–407. 4594 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.072067999
12. Bosl, G. J., Geller, N. L., Cirrincione, C., Vogelzang, N. J., Kennedy, B. J.,
Weetlaufer, J., Miller, M. E., Bartolucci, A., Schacter, L. & Einhorn, L. H.
Whitmore, W. F., Jr., Vugrin, D., Scher, H., Nisselbaum, J. & Golbey, R. B.
(1991) J. Clin. Oncol. 9, 1163–1172.
(1983) Cancer Res. 43, 3403–3407.
19. Loehrer, P. J., Gonin, R., Nichols, C. R., Weathers, T. & Einhorn, L. H. (1998)
13. Einhorn, L. H., Williams, S. D., Loehrer, P. J., Birch, R., Drasga, R., Omura,
J. Clin. Oncol. 16, 2500–2504.
G. & Greco, F. A. (1989) J. Clin. Oncol. 7, 387–391.
20. Broun, E. R., Nichols, C. R., Jacob, J., Ostchega, Y. & Young, R. C. (1992) Ann.
14. Saxman, S., Finch, D., Gonin, R. & Einhorn, L. H. (1998) J. Clin. Oncol. 16, Intern. Med. 11, 7124–7128.
21. Bhatia, S., Cornetta, K., Broun, R., Nichols, C., Abnour, R. & Einhorn, L. H.
15. de Wit, R., Roberts, J. T., Wilkinson, P. M., de Mulder, P. H., Mead, G. M.,
(2000) J. Clin. Oncol. 18, 3346–3351.
Fossa, S. D., Cook, P., de Prijck, L., Stenning, S. & Collette, L. (2001) J. Clin. Oncol. 19, 1629–1640.
22. Ganjoo, K. N., Rieger, K. M., Kesler, K. A., Sharma, M., Heilman, D. K. &
16. International Germ Cell Cancer Collaborative Group (1997) J. Clin. Oncol. 15,
Einhorn, L. H. (2000) Cancer 88, 1051–1056.
23. Ganjoo, K. N., Foster, R. S., Michael, H., Donohue, J. P. & Einhorn, L. H.
17. Ozols, R. F., Ihde, D. C., Linehan, M., Jacob, J., Ostchega, Y. & Young, R. C.
(2001) J. Urol. 165, 1514–1516.
(1988) J. Clin. Oncol. 6, 1031–1040.
24. Baniel, J., Foster, R. S., Gonin, R., Messemer, J. E., Donohue, J. P. & Einhorn,
18. Nichols, C. R., Williams, S. D., Loehrer, P. J., Greco, F. A., Crawford, E. D.,
L. H. (1995) J. Clin. Oncol. 13, 1170–1176. SCIENCES
PNAS ͉ April 2, 2002 ͉ vol. 99 ͉ no. 7 ͉ 4595
Rezidivprophylaxe affektiver Störungen mit Lithium Synopsis 1. Bei der Langzeitbehandlung affektiver Störungen wird zwischenErhaltungstherapie (Verhinderung eines Rückfalls während der noch nichtvollständig abgeklungenen Krankheitsepisode) und Rezidivprophylaxe(Verhinderung von zukünftigen Phasen/Rezidiven) unterschieden. ZurErhaltungstherapie wird die in der depressiven bzw. manis
Replagal (agalsidase alfa) Prescribing Information : Please consult the Summary patient receiving Replagal. Extensive renal of Product Characteristics (SmPC) before Presentation: Concentrate solution for IV infusion. 1ml of concentrate for solution for infusion contains 1mg of agalsidase alfa. Indication: Long-term enzyme intracellular a-galactosidase activity. replacement therap