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VOLUME
32
䡠
NUMBER
28
䡠
OCTOBER
1
2014
JOURNAL OF CLINICAL ONCOLOGY
A S C O 50TH A N N I V E R S A R Y
Testicular Cancer: A Reflection on 50 Years
of Discovery
Nasser Hanna and Lawrence H. Einhorn, Indiana University School of Medicine, Indianapolis, IN
Introduction
The advances in the treatment of testicular cancer are among the
great achievements in medicine. Cancer researchers from around the
globe have asked and answered nearly every fundamental question
about the treatment of patients with testicular cancer. The results are
astonishing: cure in 95% of all patients; refined surgical techniques
that preserve sexual function; minimization of short-term and longterm toxicities of therapy; FDA approval of several agents due entirely
or in part from trials in testicular cancer including vinblastine in the
1960’s, bleomycin in 1973, cisplatin in 1978, etoposide in 1983, and
ifosfamide in 1988. This article will help the reader understand this
journey to a cure, which in many ways mirrors the history of drug
development and cancer management during the 20th century.
The basic tenets of cancer care were established, reinforced, or
challenged during the methodical study of testicular cancer. These
tenets include the use of randomized clinical trials to minimize
toxicity and maximize outcomes; the rational utilization of combination chemotherapy; and the integration of care involving medical and surgical specialties.
Early Challenges
Before the era of platinum combination chemotherapy, testicular
cancer was curable in its’ earliest stages with surgery and radiation, but
nearly uniformly fatal in patients with advanced disease. The lack of
convenient and accurate imaging techniques made effective management more challenging. A patient with testicular cancer was evaluated
by physical examination, and radiographic procedures which may
include chest x-ray, abdominal x-ray, urogram, venocavogram, or
lymph angiogram and many patients required surgical staging. The
ability to diagnose, stage, assess response, detect relapse, and estimate
prognosis took a major leap forward with the discovery of human
chorionic gonadotropin (hCG) and ␣-fetoprotein (AFP) in 1927 and
1956, respectively.1,2 The demonstration of hCG in the urine of patients with testicular cancer, first reported in 1937, significantly improved the accuracy of detecting advanced stage disease.3,4 By the late
1970s and early 1980s, surgical staging was no longer required with the
routine use of AFP, hCG, and computed tomography scans.5
In the years following World War II, the successful treatment of
testicular cancer included orchiectomy with retroperitoneal lymphnode dissection (RPLND), radiation, or both, regardless of histology.
Seminomas were more radiation-sensitive.6 Between 1920 and 1965,
414 cases of testicular cancer were reported from Roswell Park.7 For
patients with pure seminoma, orchiectomy was followed by RPLND
Journal of Clinical Oncology, Vol 32, No 28 (October 1), 2014: pp 3085-3092
or radiation to pelvic and para-aortic lymph nodes. Either approach
resulted in similar survival; therefore, postorchiectomy radiation became standard practice. Before 1949, if embryonal carcinoma was
present, higher doses of radiation were given. Given the relative
radiation-resistance of embryonal carcinoma, RPLND soon replaced
radiation if nonseminomatous germ cell tumors (NSGCT) were present. Each of these observations were confirmed from a series of patients (n ⫽ 510) with testicular cancer treated at Walter Reed Army
Hospital (Washington, DC) from 1940 to 1964.8 A 95% cure rate was
reported in patients with seminoma treated with orchiectomy and
radiation therapy. If distant metastases were found, radiation was
given to the abdomen, mediastinum, supraclavicular area and even to
lung metastases. In their series of 127 patients with NSGCT, no patients with lymph node involvement responded to radiation, and all
died within 2 years. RPLND replaced radiation for patients with stage
I or II NSGCT, achieving cures in nearly 50% of patients with nonmetastatic, lymph node (LN) –positive disease.
Further refinements in the management of patients with stage I
seminoma challenged the need for adjuvant radiation, reduced the
dose and fields of radiation for those receiving it, and broadened
the treatment options to include adjuvant chemotherapy. Today, the
treatment options for stage I seminoma following orchiectomy include surveillance, 20 Gy radiation to the ipsilateral RPLN⬘s, or one to
two cycles of carboplatin. Long-term survival is nearly 100%, irrespective of the initial option chosen.9-11 For patients with low volume (⬍ 3
cm LN) stage II seminoma, 30 to 36 Gy radiation to the para-aortic
and ipsilateral iliac lymph nodes remains standard,12 whereas chemotherapy (regimen of bleomycin, etoposide, and cisplatin [BEP] ⫻ 3
or regimen of etoposide and cisplatin [EP] ⫻ 4) is preferred for
patients with bulkier disease. The management of residual masses
greater than 3 cm following chemotherapy has been aided with positron emission tomography imaging. A positive positron emission
tomography image (standard uptake value ⬎ 4) may represent active
seminoma and surgical resection is considered.13
The treatment of stage I and II NSGCT was dependent on performing a RPLND. Full bilateral suprahilar dissections with wide
templates removing all lymphatic tissues between the ureters were
performed routinely but were associated with significant morbidity.14,15 In the 1970s and 1980s, elegant lymph node mapping studies
elucidating the drainage patterns of right versus left-sided tumors were
performed in Europe and at Memorial Sloan-Kettering Cancer Center
(MSKCC) and Indiana University.15-17 Elimination of the suprarenal
component of LNs was possible based on studies by Donohue et al,15
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3085
Hanna and Einhorn
who demonstrated suprarenal LN⬘s were rarely involved in lower
stage tumors and should be removed only in some patients with
bulkier disease. Retrograde ejaculation was a common complication
for patients undergoing bilateral RPLND. Techniques to preserve the
postganglionic sympathetic nerve fibers resulted in preservation of
seminal emission and antegrade ejaculation.18-24 This modified unilateral RPLND preserves ejaculation in 90% of patients.
Subsequent research further refined the role of RPLND. Key
findings included: residual masses in the RP may contain necrosis,
teratoma, or viable germ cell tumor (GCT), the presence of teratoma
in the orchiectomy is predictive of teratoma in the RPLN, the histology
in postchemotherapy (PC) –RPLNs predict the histology of residual
masses elsewhere, particularly the lungs, and 95% 2-year progressionfree survival is now achieved with a modified, bilateral, PC-RPLND in
patients with low volume stage II disease.25-28 One area of management which remains unsettled is the role of PC-RPLND in patients
with stage II or III disease achieving a serologic and radiographic
complete response (CR). Proponents of observation at Indiana University cite the 15-year cancer-specific survival of 97% reported with
this approach,29 while investigators at MSKCC recommend PCRPLND in most patients, citing the presence of viable GCT and teratoma in some patients with normal-size RPLNs on CT.30
Three treatment options, which include active surveillance,
nerve-sparing RPLND or adjuvant chemotherapy, are standard for
stage I NSGCT, resulting in 98% to 100% long-term cure rates.31-34
Patients are characterized as high risk (relapse rates 50% with surveillance) versus low risk (15% relapse rates with surveillance) based on
the presence of vascular invasion and embryonal predominant histology.11,31 Patients with low volume stage II NSGCT (RPLN ⬍ 3 cm)
and normal postorchiectomy hCG and AFP are generally managed
with RPLND, while those with higher volume stage II disease or rising
markers receive chemotherapy (BEP ⫻ 3 or EP ⫻ 4).36,37 Cures are
achieved in approximately 95% of all patients.
Precisplatin Chemotherapy Era
Fifty years ago, a diagnosis of metastatic testicular cancer meant a
negligible cure rate with 90% mortality within 1 year. During the
1950s and 1960s, the arsenal of chemotherapeutics now included
alkylating agents, antimetabolites such as methotrexate, antibiotics
including actinomycin-D, and plant products including the vinca
alkaloids.38 Actinomycin-D, isolated from cultures of Streptomyces
paravallus, was of particular interest in testicular cancer based on the
report of responses seen in pediatric patients with Wilms’ tumor, a
fetal tumor in the kidney, reported by Farber et al.39
The initial chemosensitivity of testicular cancer was demonstrated at MSKCC in 1960. Li et al40 reported actinomycin-D based
therapy resulted in durable remissions in 10% to 20% of patients and
a cure in approximately 5%. Li et al41 also reported the use of methotrexate to cure a patient with gestational choriocarcinoma, a landmark
event in 1956. Li et al40 studied 36 patients with advanced testicular
cancer utilizing actinomycin-D combined with an alkylating agent
(chorambucil) and antimetabolite (methotrexate) in men with advanced testicular cancer. The authors determined the best chance of
deriving benefit came with the combination of agents from different
classes. The concept of combined drug therapy given in a cyclical
manner was not new in medicine, as it had been used effectively to
treat tuberculosis, but challenged the dogma of the day in cancer
treatment. Li et al also recognized the significance of monitoring hCG
3086
© 2014 by American Society of Clinical Oncology
in the urine as a marker of persistent, microscopic disease, even when
the radiographs demonstrate a CR.
The plant Vinca rosea Linn (periwinkle) was widely cultivated as
an ornamental in gardens throughout the world and enjoyed a popular reputation as a medicinal, including as an effective oral hypoglycemic agent.42 Hertz et al demonstrated the activity of vinblastine in
patients with methotrexate-resistant choriocarcinoma.43 The activity
of vinblastine in testicular cancer was further characterized by Samuels
and Howe at MD Anderson in 1970.44 Based on this and other work
demonstrating the activity of bleomycin, Samuels and Howe studied
the combination of vinblastine plus bleomycin, each with comparable
single-agent activity to actinomycing-D, in the first-line treatment of
patients with advanced testicular cancer, resulting in a 32% CR rate in
50 patients, and remission greater than 2 years in half of patients
achieving a CR.44-46
Era of Cisplatin
The discovery of cis-diaminodichloroplatinum by Rosenberg et
al47 in 1965 is a landmark event in the history of oncology and the
single most important discovery in the treatment of metastatic testicular cancer. Platinum is a component of first-line chemotherapy in
over a dozen tumor types today. Rosenberg, a biophysicist at Michigan
State University, examined whether electrical currents played a role in
cellular division. In order to examine this, Escherichia coli cells growing
in ammonium chloride had a current applied to them through platinum electrodes. After additional investigation, it was determined that
inhibition of cellular division was not due to the electrical current, but
platinum hydrolysis products formed from the platinum electrode.
In 1971, the drug development of cisplatin began following the
observation of responses in patients with human malignancies, including testicular cancer, by Hill et al.48 Based on the observations
from Hill, Higby et al49 at Roswell Park conducted a phase I study of
cisplatin which included 11 patients with refractory testicular cancer
(previously treated with actinomycin-D– based regimens). They reported nine of 11 responded to cisplatin, including complete several
CRs, an unprecedented finding for a phase I trial even today.49 The
toxicity was substantial; however, as irreversible renal failure was observed in some patients and nausea/vomiting (sometimes lasting
weeks) was universal, necessitating hospitalization for all patients.
The addition of cisplatin to the regimen of vinblastine plus bleomycin, known as the PVB regimen, was introduced by Einhorn and
Donahue50 at Indiana University in 1974. In this phase II study,
patients with advanced testicular cancer received four cycles of PVB.
Responding patients were also treated with maintenance vinblastine
for an additional 21 months. Patients with persistent nodes in the
abdomen underwent RPLND. Thirty three of 47 patients achieved a
CR with chemotherapy alone resulting in a then astonishing 5-year
survival rate of 64%, a 1 log increase in the cure rate compared with
contemporaneous actinomycin-D based chemotherapy in metastatic
testicular cancer. Based on these stunning phase II results, the US Food
and Drug Administration granted approval for cisplatin as a commercial drug, even in the absence of a randomized trial.
Sequential studies from Indiana University testing PVB were
aimed at reducing the neuromuscular and myelosuppressive toxicity
of the regimen from vinblastine and challenging the tenet of maintenance therapy. The first phase III study (1976-1978) randomly assigned patients to receive PVB with vinblastine given at 0.4 mg/kg/
cycle as a control arm versus 0.3 mg/kg/cycle. No difference was
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ASCO 50th Anniversary
reported as 73% of patients remained long-term survivors with no
evidence of disease (NED).51 These results were confirmed by a more
robust study conducted by the European Organization for Research
and Treatment of Cancer (EORTC).52 The next phase III study (19781981) from Indiana University randomly assigned patients to receive
PVB with or without doxorubicin with a second random assignment
to with or without maintenance vinblastine for an additional 21
months.53 There was no improvement in survival with the addition of
doxorubicin or maintenance therapy. Therefore, PVB ⫻ four cycles
became standard therapy.
The next major advance in the treatment of testicular cancer
came with the discovery of etoposide.54 The dried roots from the
American mandrake containing podophyllotoxin were cultivated by
native North Americans and natives of Himalaya and used as an
emetic agent and to treat worm infections.55 Etoposide, a synthesized
derivative of the podophyllotoxin, entered cancer trials in 1971 and
was reported to be active as a single agent in patients with refractory
GCT.56 Based on a leukemia mouse model demonstrating the synergistic effects of etoposide with cisplatin, combination studies were
evaluated as second-line therapy in patients not cured with PVB.57 In
a trial from the Southeastern Cancer Study Group (SECSG), 43% of
patients achieved a CR, and 23% remained disease-free long term.
This was the first time in oncology that a relapsed solid tumor had
been cured with second-line chemotherapy.
While work continued at Indiana University refining the PVB
regimen, investigators at MSKCC had been refining their own chemotherapy program against testicular cancer, consisting of six successive
regimens beginning in 1972. In 1975, cisplatin was added to the regimen referred to as VAB-6, consisting of cisplatin, vinblastine, bleomycin, cyclophosphamide, and actinomycin-D with or without
maintenance therapy, and resulting in a CR rate of 67% with chemotherapy alone.58 Bosl et al59 at MSKCC conducted a randomized trial
comparing VAB-6 with EP. Based on a set of prognostic variables
(lactate dehydrogenase, hCG, number of sites of metastatic disease)
reported from MSKCC researchers, only patients with good-risk disease were eligible.60 Responses were seen in greater than 90% with
either treatment, however more patients receiving VAB-6 had residual
GCT at the time of surgery and patients treated with EP had numerically superior survival with less toxicity. Based on these results, EP
became standard treatment.
Investigators at Indiana University and the SECSG also studied
etoposide as an alternative to vinblastine, in the first-line setting. A
randomized phase III study compared PVB with BEP from 1981 to
1984.61 Two hundred and forty-four patients were randomly assigned.
Seventy-eight percent of patients receiving BEP were cured compared
with 66% receiving PVB. Based on this improved efficacy and less
toxicity, BEP became our standard of care. Attempts have been made
to improve on the efficacy, toxicity, and convenience of the BEP
regimen by testing alternative dose and schedules of BEP. The Australian and New Zealand Germ Cell trial group randomly assigned patients to receive BEP per the Indiana regimen (cisplatin 20 mg/m2 IV
day 1 through 5, etoposide 100 mg/m2 IV day 1 through 5 every 3
weeks and bleomycin 30 units intravenously [IV] weekly) versus cisplatin 100 mg/m2 day 1, etoposide 120 mg/m2 day 1 through 3 and
bleomycin 30 units IV weekly.62 The Indiana regimen resulted in
numerically superior survival and remains standard.
Each successive cycle of BEP resulted in cumulative chemotherapyinduced nephrotoxicity, neurotoxicity, ototoxicity, and bleomycinwww.jco.org
induced pulmonary toxicity. Therefore, from 1984 to 1987, the
SECSG randomly assigned patients with good risk disease to receive
three versus four cycles of BEP. This was done in an attempt to
eliminate the most toxic cycle of therapy, due to cumulative toxicity.63
One hundred and eighty-four patients were enrolled and 92% cure
rates were reported on each arm. Remarkably, 98% of metastatic
patients with an hCG of less than 1,000 were cured with only three
cycles of BEP. In a larger study, the EORTC randomly assigned patients with good risk disease to either BEP ⫻ 3 versus BEP ⫻ 3 then
EP ⫻ 1; they reported a 90% progression-free survival in both arms
and no difference in efficacy between a 3- and 5-day regimen of EP,
although the 3-day regimen had more hematologic toxicity, ototoxicity, and nausea.64 For patients with good risk metastatic disease, standard therapy remains BEP ⫻ 3 or EP ⫻ 4. An attempt to define the
superiority of one regimen over the other was undertaken by the
French Federation of Cancer Centers who randomly assigned patients
with good risk disease to either of these regimens, reporting 91% and
86% durable responses with BEP ⫻ 3 and EP ⫻ 4, respectively.65 Thus
from 1974 to 1987 randomized studies substituted etoposide for vinblastine with decreased toxicity and increased efficacy and shortened
duration of therapy from 2 years to 9 weeks for most patients with
metastatic disease.
Two achievements in the 1990s laid the groundwork for additional success in the management of patients with testicular cancer,
namely, identification of universally agreed on prognostic groups and
the discovery of the first selective serotonin type 3 (5HT3) receptor
antagonists. In 1997, following a multinational analysis, a consensus
statement for metastatic GCT was published by the International
Germ Cell Cancer Collaborative Group (IGCCCG).66 The IGCCCG
risk stratification system takes into account the primary tumor site,
metastatic sites, and amplitude of serum tumor marker levels. Patients
with advanced GCT are now subdivided into 3 risk groups: good
(⬎ 90% rate of cure), intermediate (75% rate of cure) and poor (50%
rate of cure). The second major achievement came in 1991. Before the
advent of effective antiemetics, cisplatin-based chemotherapy was extremely difficult for most patients, as frequent and prolonged nausea/
vomiting was universal. In one phase III study, the median number of
emetic episodes on day 1 of chemotherapy was 10.67 Before the US
Food and Drug Administration approval of ondansetron in 1991,
antiemetic prophylaxis for cisplatin consisted of dexamethasone,
lorazepam and high-doses of metoclopramide, which frequently resulted in troubling extrapyramidal adverse effects in young patients.
Today the median number of emetic episodes on day 1 with modern
antiemetic therapy is zero.68
Bleomycin causes severe pulmonary toxicity in a dose-related
fashion in some patients.69 Investigators from the EORTC randomly
assigned patients to BEP ⫻ 4 versus EP ⫻ 4, demonstrating inferior
results with the deletion of bleomycin (95% v 87% cure rates).70 These
results confirmed the importance of bleomycin reported from an
earlier study from the Australasian Germ Cell Trial Group comparing
PVB with PV71 and another trial from the Eastern Cooperative Oncology Group (ECOG) comparing BEP versus EP (95% v 86% cure
rates).72 Therefore, bleomycin remains a valuable contributor to the
overall efficacy of treatment in good-risk patients and can be safely
given to most patients when limiting therapy to three cycles.
Additional attempts to reduce toxicity and preserve efficacy in
good risk patients included substitution of carboplatin for cisplatin.
Unfortunately, carboplatin substitution (a platinum agent with less
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3087
Hanna and Einhorn
Table 1. Standard Treatment of Seminoma
Stage
Treatment Options
I
Surveillance or 20 Gy radiation
or carboplatin ⫻ 1-2
30-36 Gy radiation preferred
for nonbulky disease (⬍ 3
cm) BEP ⫻ 3 or EP ⫻ 4
preferred for bulky disease
(⬎ 3 cm)
EP ⫻ 4 or BEP ⫻ 3
II
III
Table 3. Landmark Achievements in Testicular Cancer
5-Year
OS (%)
Reference(s)
⬎ 99
9-11
⬎ 95
12
⬎ 90
Year
59, 63
Event
Significance
Ref
1937
hCG first reported in the
urine of patients with
testicular cancer
3
1940s
Seminomas are
radiation-sensitive
1960
Actinomycin-D based
chemotherapy tested
in advanced testicular
cancer
1965
Discovery of cisplatin
1974
PVB regimen first tested
1980s
Nerve-sparing RPLND
1981
1985
PVB with or without
maintenance
vinblastine
EP regimen
Improved ability to diagnose,
stage, assess response,
detect relapse, estimate
prognosis
95% cure rate for stage I or
II seminoma prior to era
of cisplatin-based
chemotherapy
Durable complete responses
and some cures reported
for the first time in
patients with metastatic
testicular cancer
Revolutionized the treatment
of testicular cancer,
achieving cures in ⬎ 80%
of patients with
metastatic disease
Increased cure rate by 1 log
compared with
contemporaneous
chemotherapy
Preserves ejaculatory
function in ⬎ 90% of
patients undergoing this
procedure
Eliminated need for
maintenance therapy
1987
PVB versus BEP
1989
BEP ⫻ 3 versus 4 cycles
in good risk
IGCCC prognostic
groups
Abbreviations: BEP, bleomycin, etoposide, and cisplatin; EP, etoposide and
cisplatin; OS, overall survival.
nephrotoxicity and emetogenic potential) for cisplatin also results in
inferior outcomes.73,74 In one study, Bajorin et al73 randomly assigned
patients to receive four cycles of EP versus etoposide plus carboplatin
(EC), reporting a 10% inferior relapse free survival with EC. In another study comparing bleomycin plus etoposide with either cisplatin
or carboplatin, relapse rates more than doubled with carboplatin
(32% v 13%) resulting in more deaths.74
While greater than 90% of patients with good risk metastatic
disease are cured with chemotherapy, patients with intermediate- or
poor-risk disease face of much less certain future. The worldwide
standard for poor-risk disease is four cycles of triple-drug therapy, but
nearly half of these patients are not cured. Therefore, intensification of
therapy beyond BEP ⫻ 4 has been investigated. The SECSG evaluated
BEP comparing double dose (40 mg/m2 day 1 through 5) cisplatin
versus standard dose (20 mg/m2 day 1 through 5) cisplatin for four
cycles each in 151 randomly assigned patients.75 Two thirds of patients
in each arm were cured. de Witt et al from the EORTC randomly
assigned patients to BEP with or without paclitaxel (T) in patients with
intermediate risk disease demonstrating no survival difference in 337
randomly assigned patients, although 3-year progression-free survival
favored the T-BEP arm (79 v 71%).76 Investigators from ECOG randomly assigned 304 men with advanced disseminated GCT to BEP ⫻
4 or cisplatin, ifosfamide, and etoposide (VIP) ⫻ 4. Overall complete
remission rate and 2-year overall survival (VIP, 74%; BEP, 71%) were
Table 2. Standard Treatment of Nonseminomatous Germ Cell Tumors
Stage
Treatment Options
I
II
III: Good risk
III: Intermediateⴱ/
poor risk
Surveillance or RPLND or
BEP ⫻ 1
RPLND preferred for
nonbulky disease (⬍ 3
cm) BEP ⫻ 3 or EP ⫻ 4
preferred for bulky
disease (⬎ 3 cm)
BEP ⫻ 3 or EP ⫻ 4
four cycles of 3-drug therapy
5-Year
OS (%)
Reference(s)
⬎ 99
31, 34
98
32, 36
⬎ 90
50-80
59, 61, 63, 65
77, 78
Abbreviations: BEP, bleomycin, etoposide, and cisplatin; EP, etoposide and
cisplatin; OS, overall survival; PFS, progression-free survival; RPLND, retroperitoneal lymph-node dissection.
ⴱ
The addition of paclitaxel to BEP improves PFS but not OS in intermediate
risk patients76; some patients can be treated with BEP ⫻ 3 or BEP ⫻ 3
followed by EP ⫻ 1.105
3088
© 2014 by American Society of Clinical Oncology
1997
2007
Largest series to date
reported on HDCT in
relapsed disease
Cures possible in the
second-line setting
BEP supplants PVB as
standard therapy
Eliminates fourth cycle of
BEP in good risk patients
Allows for more accurate
study of treatment
outcomes by risk groups
Cures achieved in ⬎ thirdline, poor-risk groups,
including platinumrefractory patients
6
40
47
50
18-24
53
57
61
63
66
89
Abbreviations: BEP, bleomycin, etoposide, and cisplatin; EP, etoposide and
cisplatin; hCG, human chorionic gonadotropin ; HDCT, high-dose chemotherapy;
IGCCC, International Germ Cell Cancer Collaborative Group; PVB, cisplatin,
vinblastine, and bleomycin; RPLND, retroperitoneal lymph-node dissection.
not significantly different between the two treatments, despite more
toxicity in the VIP arm.77 Two randomized clinical trial compared
BEP ⫻ 4 with BEP ⫻ 2 followed by high-dose chemotherapy as
first-line treatment in patients with poor-risk GCT78,79 and one trial
compared BEP ⫻ 4 with VIP ⫻ 1 followed by high-dose VIP ⫻ 3.80 All
of these studies failed to demonstrate any advantage over BEP ⫻ 4
with durable CR’s seen in approximately 50% of patients, and toxicity
was more severe with the investigational regimens. Furthermore,
some have advocated intensification of therapy based on the rate of
tumor marker decline, an independent prognostic variable in patients
with poor risk disease, following the first or second cycle of BEP.81 This
strategy may result in fewer relapses requiring salvage therapy, but has
failed to prove a survival advantage to date.
Salvage Therapy for Relapsed GCT
Patients who relapse after initial chemotherapy can still be cured
with second-line and even third-line regimens. VIP, vinblastine
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(VeIP), or paclitaxel (TIP) are commonly used.82-86 These studies
showed durable response rates in patients with recurrent GCT.
Bone marrow transplantation (BMT) entered patient care in the
1950s and was increasingly successful by the end of the 1960s with the
use of platelet transfusion support, improved antibiotics, growth factor support, and more effective cancer drugs. In 1986, investigators
at Indiana University began work with high-dose chemotherapy
(HDCT) in patients with relapsed testicular cancer. Significant escalation of cisplatin dose is limited by extramedullary toxicities; therefore,
high-dose carboplatin and etoposide were evaluated since myelosuppression, which can be managed with bone marrow rescue, is their
dose-limiting toxicity. In a phase I/II trial, 33 patients with recurrent
disease were treated from 1986 to 1988. Enough bone marrow for two
courses of therapy was harvested a few days before chemotherapy. The
median time to hematopoietic recovery was about 25 days and 25%
achieved a CR. Cures were observed even in the third- and fourth-line
setting, which was unprecedented at the time.87
In 1995, it was reported that peripheral blood stem cells (PBSC)
resulted in sustained trilineage reconstitution after HDCT more rapidly than bone marrow.88 Therefore, in 1996, PBSC transplantation
could replace BMT for the treatment of recurrent GCT at Indiana
University.89 Einhorn et al reported the experience from Indiana University with HDCT (using carboplatin and etoposide) followed by
PBSC rescue in 184 patients with metastatic GCT that had progressed
after first-line cisplatin-based chemotherapy. Of the 184 patients, 63%
achieved a CR without relapse during a median follow-up of 48
months; 70% of patients who received the treatment as second-line
therapy were cured, as were 45% treated in greater than or equal to the
third-line setting.
Investigators from MSKCC have also evaluated HDCT, the
TI–CE protocol, incorporating paclitaxel and ifosfamide (TI) as induction chemotherapy and stem cell mobilization, followed by three
cycles of high-dose carboplatin and etoposide (HD-CE) and autologous stem-cell transplantation. In their experience, 54 (50%) patients
achieved a CR, including 42% with chemotherapy alone and 8% with
chemotherapy and surgery. The 5-year disease-free survival was 47%
and overall survival was 52%.90
Refinements in the use of HDCT continue today. Patients
with recurrent disease have been classified into very low, low,
intermediate, high, and very high risk categories.91 In a large 1,500patient multi-institutional retrospective study, HDCT cured 27%
of patients with very high–risk disease compared with only 3% with
standard-dose salvage therapy.91 In addition, two other series report that patients with recurrent disease and unfavorable prognostic features including primary mediastinal NSGCT are curable with
HDCT, a result rarely seen with standard-dose therapy.90,91 Based
on this data, some have argued using HDCT for most patients in
the second-line setting, while others have proposed HDCT only in
high- or very high–risk groups unlikely to be cured with standarddose salvage therapy. There are current attempts to address this
with a proposed phase III study comparing TIP with TI-CE as
initial salvage chemotherapy.
Long-Term Issues in Survivors
Given the high cure rates in patients with testicular cancer,
this young population has been evaluated for the long-term toxicity of diagnostic studies, therapy, and other long-term issues affecting survivors. There has been an emerging concern about the risks
www.jco.org
of second cancers due to the frequent exposure to diagnostic radiation to the abdomen and pelvis in young patients undergoing
active surveillance. van Walraven et al92 explored this issue in 2,569
men, observed for a median of 11 years, reporting no increased risk
of second cancers. However, follow-up may not have been long
enough to observe secondary malignancies. Similarly, the risk of
treatment-related second cancers from surgery, chemotherapy,
and therapeutic radiation has been reported.93,94 Fung et al95 evaluated 12,691 patients treated with chemotherapy or surgery and
reported a 40% increased risk for cancers for those receiving chemotherapy. Secondary leukemia is also recognized to result from the
cumulative exposure to etoposide, particularly beyond 2000 mg/
m2.96 Testicular cancer survivors are also at risk for metabolic
syndrome, cardiovascular disease, infertility, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, psychosocial disorders, and behavioral issues including problem drinking.97-103 A
multi-institutional effort is underway to understand the genetic
underpinnings of long-term cisplatin toxicities, identify single nucleotide polymorphisms associated with these toxicities, and to
systematically collect data regarding various cardiovascular risk
factors in testicular cancer survivors.
Vexing Issues in Testicular Cancer Remain
The last 50 years of testicular cancer research have produced
stunning results, but multiple challenges remain. Ninety-five percent of patients with testicular cancer, including 80% with metastatic disease, can be assured they will be cured. The primary focus
today is to develop more effective treatments for those with poorrisk disease, especially those with multiple poor-risk features at
diagnosis, and those whose disease has relapsed following first-line
chemotherapy. Secondly, patients with late relapse (⬎ 2 years from
diagnosis) and those with malignant transformation of teratoma
are less chemotherapy sensitive.104 They are managed primarily
with surgery and fewer than half will remain continuously free of
disease following treatment. Thirdly, common clinical scenarios
can still be vexing for clinicians less experienced at managing
patients with testicular cancer.
Final Thoughts
The success in the treatment of testicular cancer is not the
result of a single individual or institution, but rather the collective
work of an international community of cancer researchers (Tables
1 and 2). Each major discovery is dependent on the discoveries that
precede them (Table 3). Refinements in surgical mapping of disease, discovery of radiation and its application to cancer care,
isolation of tumor markers initially in the urine and subsequently
in the serum, development of preclinical tumor models to test the
potential of cancer drugs, development of chemotherapy principles, and the discovery of cisplatin each predated the landmark trial
of PVB in 1974. The refinement of chemotherapy at each institution built off the experiences reported from other institutions. This
collaborative spirit continues today as an international group of
researchers work with a common spirit to ensure no person will die
of testicular cancer in the future.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
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AUTHOR CONTRIBUTIONS
Manuscript writing: All authors
Final approval of manuscript: All authors
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ASCO Community Research Forum Annual Meeting
As part of ASCO’s efforts to support community-based researchers, this meeting provides a unique opportunity to discuss
barriers and develop solutions to common challenges that are faced in the community research setting, and provides a
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Space is limited, so register early! For more information, visit asco.org/communityresearchforum.
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Acknowledgment
L.H.E. was supported in part by the National Cancer Institute Grant No. R01 CA157823-01A1.
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