Lawrence
H. Einhorn, M.D.
Indiana
University Medical Center.
President
ASCO.
PVB versus cisplatin plus VP-16 plus bleomycin (BEP)
Good-Risk (Minimal-Moderate
Disease)
Definition of poor-risk (advanced) disease
Complicated testicular cancer issues
Testicular cancer has become a model for a curable neoplasm. Our studies
with cisplatin combination chemotherapy allow us to conclude that: (1) short
duration intensive induction therapy with the most active agents in optimal
dosage is more important than maintenance therapy; (2) modest dose escalation
increases toxicity without improving therapeutic efficacy; (3) it is possible
to develop curative salvage therapy for refractory germ cell tumors; and (4) preclinical models predicting synergism, such
as vinblastine + bleomycin or cisplatin + VP-16 have clinical relevance. Finally,
testicular cancer has also become a model for new drug development. Cisplatin
was approved by the FDA for testis and ovarian cancer, and etoposide and ifosfamide
for refractory germ cell tumors. The success of these studies confirms the importance
of the continued search for new investigational drugs in all solid tumors.
Germ cell tumors are relatively uncommon, accounting for only 1% of male
malignancies in the United States. The highest worldwide incidence is in Scandinavian
countries; by contrast, testicular cancer is rare in African Americans. The
primary age group is 15-35 for nonseminomatous tumors and a decade older for
seminoma. Thus, the potential for loss of productive years of life has always
made testis cancer important both medically and economically.
In 2000, there were approximately 8,000 newly diagnosed cases in the United
States. This contrasts sharply with the 180,000 cases of prostate cancer. Most
important clinical questions have been addressed and answered in testis cancer
by randomized phase III studies, whereas many relevant issues remain unresolved
in cancer of the prostate.
Despite the paucity of cases, this tumor has become an extremely important
oncological disease. Firstly, it is the most common carcinoma in young men ages
15 to 35 and thus, has the potential to greatly shorten productive years of
life compared to most other more common carcinomas. Secondly, available serum
markers (alphafetoprotein and human chorionic gonadotropin) allow the clinician
to make important and accurate treatment-related decisions. Thirdly, it has
been demonstrated that surgical resection of radiographically persistent disease
can improve the cure rate. Fourthly, germ cell tumors have become an excellent
testing ground for active experimental drugs (e.g., cisplatin, VP-16, and ifosfamide,
all of which were approved by the FDA primarily upon data in testicular cancer).
This is an important disease because it has become a model for a curable neoplasm. The goal of chemotherapy in germ cell tumors
is never merely palliation or prolongation of survival, but cure.
Testis cancer has long been a model for a curable neoplasm.1,2 Germ cell tumors
are uniquely chemosensitive and chemocurable. Surgery also plays a major role,
both as primary treatment and for post-chemotherapy resection. Orchiectomy plus retroperitoneal lymph node
dissection has a higher cure rate than any other type of cancer surgery with
nodal metastases.
There are many published updates and reviews concerning the management
of germ cell tumors in textbooks and journals.3 This paper will review past and present accomplishments,
current chemotherapy strategies, and emphasize complicated and controversial
surgical issues.
Prior to the usage of cisplatin combination chemotherapy, standard chemotherapy
for disseminated testicular cancer consisted of dactinomycin, alone or in combination
with methotrexate and chlorambucil. Thirty years ago Dr. Li and colleagues at
Memorial Sloan Kettering recognized that testis cancer was chemosensitive, with
a 50% objective response rate including 10% to 20% complete remissions (C.R.) and a 5% to
10% cure rate.4 Samuels and colleagues at M.D. Anderson later evaluated
vinblastine + bleomycin, a synergistic regimen in preclinical studies, and achieved
a 25% long-term disease-free survival.5 However, the most
important event in chemotherapy of germ cell tumors was the discovery of cisplatin
by Dr. Barnett Rosenberg.6 In early clinical
trials, this drug was very toxic with only modest activity in various solid
tumors when used in chemorefractory and heavily pre-treated patients. Investigators
at Roswell Park evaluated cisplatin in previously treated patients with germ
cell tumors and obtained 3 complete and 3 partial remissions in 11 patients.7
With this background, in August 1974, we began our initial cisplatin +
vinblastine + bleomycin (PVB) study at Indiana University, utilizing the established
two-drug synergistic regimen of vinblastine + bleomycin, and simply adding the
then experimental promising drug cisplatin.8 The PVB regimen fulfilled
the requirements for a successful combination chemotherapy regimen: single agent
activity for each component of the PVB regimen, different and unique mechanism
of action for the three agents, separate and non-overlapping toxicity, allowing administration of
each drug in full dosage, and evidence
of pre-clinical synergism (vinblastine + bleomycin).
From 1974 to 1976, we initiated and completed our first PVB study.8 As was traditional
in the mid-70’s, induction therapy was followed by maintenance chemotherapy
(vinblastine 0.3 mg/kg monthly for a total of 2 years of chemotherapy). Four
courses of PVB induction chemotherapy were utilized.
Thirty-three of 47 (70%) patients attained a C.R. and an additional 5 patients
(11%) were rendered disease-free by post-PVB surgical resection of radiographically
persistent disease.
A subsequent phase III study addressed whether we could reduce the significant
neuromuscular and myelosuppressive toxicity of vinblastine by reducing the dosage
from 0.4 to 0.3 mg/kg and still maintain therapeutic efficacy. As expected,
the lower dose of vinblastine was associated with a significant reduction in
toxicity, and the C.R. and cure rates were similar with the two arms.
Our subsequent PVB study challenged one of the basic tenets of oncology,
the utilization of maintenance therapy. Patients
achieving a disease-free status were randomized to a standard arm of 21 months
of maintenance vinblastine versus an experimental arm of just 12 weeks of PVB
with no further therapy. One hundred thirteen patients entered this study at
Indiana University or participating institutions in the Southeastern Cancer
Study Group. The relapse rate was only 5%, with or without maintenance vinblastine.9
PVB versus cisplatin plus VP-16 plus bleomycin (BEP)
Etoposide (VP-16) is an epipodophyllotoxin derivative with definite single
agent activity in refractory testicular cancer.10
In 1978, we began our initial salvage chemotherapy studies with cisplatin
plus VP-16 in patients who were not cured with PVB or similar induction therapy.
VP-16, unlike vinblastine, is essentially devoid of neuromuscular toxicity.
Schabel and colleagues demonstrated remarkable synergism with cisplatin plus
etoposide in preclinical models.11
From 1981 through 1984, the Southeastern Cancer
Study Group conducted a randomized prospective study comparing PVB and BEP as
initial induction chemotherapy.12 No maintenance therapy
was given in either arm, and if the markers were normal postchemotherapy but
there was persistent radiographic abnormalities, appropriate surgery was done.
If carcinoma was found, 2 more courses of the original induction regimen
were given, deleting bleomycin.
A total of 244 patients from 24 institutions
entered this trial. Of 121 patients
treated with PVB, 74 (61%) had a C.R., and another 15 (13%) became disease-free
after resection of teratoma (10 patients) or carcinoma (5 patients).
Among the 123 patients given BEP, 74 (60%) had a C.R., and 28 (23%) became
free of disease after resection of teratoma (22 patients) or carcinoma (6 patients). Thus, 74% became disease-free after treatment with PVB and 83% after
BEP. Nine patients on PVB and 6 receiving
BEP subsequently had recurrences. In
the subgroup of advanced disseminated disease, there was a survival advantage
for BEP (p = 0.02).
Granulocytopenic toxicity, including granulocytopenic
fever, was similar in the two arms. There was a major reduction in neuromuscular toxicity, as manifested
by paresthesia, abdominal cramps, ileus, and myalgias. This was significant
not only statistically, but also clinically. On the basis of this study, which
demonstrated a reduction in morbidity and superior survival, we have utilized
BEP since 1984 as first-line therapy for disseminated testicular cancer and
have abandoned PVB.
Subsequent
Studies
Good-Risk (Minimal-Moderate
Disease)
Several groups have designed staging systems that attempt to discriminate
good-risk from poor-risk disease.13,14 We began a phase
III study in 1984 evaluating the standard 4 courses of BEP versus 3 courses
(9 weeks) of BEP in good-risk (minimal or moderate extent) disease. One hundred
eighty-four patients entered this study, and 97% achieved an NED status confirming
the accuracy of minimal and moderate extent disease as “good-risk”. An identical
92% of patients on each arm are continuously NED.15 We have updated this
study for the 118 patients entered at Indiana University (median follow-up 9
years). There remains no differences between the two arms, with only 4 deaths
in each arm. Furthermore, for patients with serum HCG less than 1,000 mIU/ml,
there were only 2 deaths out of 104 patients.16
The Eastern Cooperative Oncology Group (ECOG) completed a phase III study
in good-risk disease randomizing patients to a standard arm consisting of BEP
for 3 courses versus the identical therapy, but with the deletion of bleomycin.
One hundred seventy-one patients were evaluable, and 94% attained an
NED status with the three drug regimen compared to 88% for cisplatin + VP-16
(p = 0.20). The failure-free survival favored the bleomycin arm, 86% versus
69% (p = 0.004). Overall survival was also superior for the three drug regimen,
95% versus 86% (p = 0.011).17
A large European study randomized 419 good prognosis nonseminomatous patients
to four cycles of cisplatin + etoposide with or without 30 units of bleomycin
weekly for 12 weeks. The European version of BEP (and EP) in this study utilized
a dosage of 120 mg/m2 days 1, 3, and 5
(360 mg/m2) compared to an etoposide dosage of 100 mg/m2 for 5 days (500 mg/m2) in the United States. Eighty-seven percent on EP achieved
a disease-free status, compared to 95% with BEP (p = 0.0075). Due to the low
number of unfavorable events, there was no statistically significant difference
in overall survival (p = 0.262).18
Investigators at Memorial Sloan Kettering Cancer Center (MSKCC) randomized
164 patients with good prognosis germ cell tumors to 4 courses of cisplatin
+ etoposide (100 mg/m2 x 5) versus the five drug VAB-6
regimen. Therapeutic results were equivalent, but there was a statistically
and clinically significant reduction in toxicity favoring EP.19 Based upon this phase
III study, 4 courses of EP became the standard therapy for good prognosis disease
at MSKCC. Subsequent updates have confirmed the high cure rate with this regimen.20,21
Another approach to reduce toxicity in good
prognosis disease was to substitute the less toxic carboplatin for cisplatin.
A large European study randomized 598 patients with good prognosis nonseminomatous
disease to 4 cycles of BEP with the etoposide dosage 120 mg/m2 days 1-3 versus CEB
with substitution of carboplatin using AUC (area under curve) of 5. There were 10 deaths on the BEP arm versus
27 with CEB (p = 0.003).22
Investigators at MSKCC and Southwest Oncology
Group (SWOG) evaluated 4 courses of etoposide + either cisplatin or carboplatin
(500 mg/m2 every 4 weeks). The VP-16 dosage
was 100 mg/m2 for 5 consecutive days on both
arms. Two hundred sixty-five evaluable patients were analyzed. Although the
initial NED rate was similar for both arms (90% versus 88%), the relapse rate
was 3% versus 12% and the continuous NED rate was 87% versus 76% favoring the
cisplatin arm (p = 0.005).23
An European EORTC study randomized 812 good-risk patients to BEP x 3 versus
BEP x 3 with a fourth course of EP. This large study was done to try to detect
a 5% difference. However, once again,
the results were identical, with 90.4% (3 courses) versus 89.4% progression-free
survival. A second randomization evaluated
the traditional five day courses versus 2 to 3 days (same total dosage).
The therapeutic results were identical, but there was increased nausea
and ototoxicity with the compressed regimen.24 At Indiana University, we continue to recommend the
5 day course of BEP, which I do not personally feel is that much more inconvenient
compared to the 3 day course. However,
this data is reassuring for some individual situations such as holiday weekends,
which allows us to give the 3 day course with the confidence that it will not
compromise the cure rate.
A 5 year French study randomized 250 good-risk patients to BEP x 3 versus
EP x 4. 95.6% versus 95.5% achieved
an NED status. Adverse events (failure
to achieve C.R., relapse, or carcinoma in resected specimen) occurred in 13.5%
(BEP x 3) versus 19.5% (EP x 4) (p = NS).25
Dr. Toner and colleagues completed a phase III study in good prognosis
patients as defined by the modified Memorial-Sloan Kettering criteria. The first
regimen was the standard Indiana University BEP for 3 courses. The second regimen
was based upon a previous UK regimen and was comprised of 4 cycles of 100 mg/m2 of cisplatin on day 1 and 120 mg/m2 of etoposide on days
1-3, and 30 units of bleomycin on day 1 only repeated every 21 days for 4 courses.
One hundred-sixty six patients were randomized with 83 on each arm. This
study was stopped early when a survival difference appeared. The overall survival
was substantially better with the 3 courses of BEP with only 3 deaths compared
to 13 deaths with the UK version (p = 0.008).26
There are two appropriate and standard approaches for good-risk disease,
namely BEP x 3 or EP x 4. Our personal preference is for the abbreviated 3 courses
of cisplatin combination chemotherapy. Nine weeks (270 units) of bleomycin in
good-risk disease is essentially devoid of any clinically significant pulmonary
toxicity.15-17 Neither 3 courses
of EP nor substitution of carboplatin for cisplatin is appropriate. Since 98% of patients with minimal or moderate
extent disease and serum HCG less than 1,000 mIU/ml are alive and disease-free
following 3 courses of BEP, 4 courses of BEP represents overtreatment in this
patient population.16
Definition of poor-risk (advanced) disease
Several investigators have proposed classifications
to stratify patients with disseminated germ cell tumors into good and poor risk
categories. The strategy for good risk disease was to maintain the approximately
90% cure rate and reduce cost and toxicity. As mentioned previously, 3 courses of BEP or
4 courses of EP constitutes standard therapy. It would be very difficult to
document that an alternative regimen could improve these results.
Poor-risk disease is a more heterogeneous
patient population, and has been defined based upon tumor markers, volume of
metastatic disease, and multiplicity of anatomic sites.13,14 These patients will have a 40-60% cure rate
with standard therapy. In this group,
the impetus has been to evaluate more aggressive chemotherapy in phase II and
phase III studies to try to improve the therapeutic outcome. Unfortunately, thus far, no chemotherapy regimen
has been documented to be superior to the standard 4 courses of BEP.
An international group was convened to develop a consensus classification
for poor risk (and good risk) germ cell tumors. Data were available on 5,862 patients, with
median follow-up time 5 years. Only
14% of these patients comprised the poor risk category, with a 41% 5 year disease-free
survival and overall 48% 5 year survival.27
The cure rate with
standard BEP is probably 10% higher, since the intergroup consensus included
older regimens (e.g., PVB and VAB regimens) that did not include etoposide.
This new definition (Table 1) is now incorporated in the current American intergroup
trial for poor risk disease.
TABLE
1
POOR RISK DISEASE (ALL NONSEMINOMATOUS PATIENTS)
1. LDH > 10 times upper limit of normal, HCG
> 50,000 IU/ml, or AFP > 10,000 Ng/ml
2. Any primary mediastinal nonseminomatous germ
cell tumor
3. Non-pulmonary visceral metastases (bone, liver,
brain, etc.)
In poor risk (advanced) disease, utilizing the Indiana classification,13 an intergroup study
addressed the therapeutic question to test whether double dose (40 mg/m2 x 5) cisplatin could
improve the cure rate. One hundred fifty-three patients were evaluable. As expected, patients receiving double dose
cisplatin experienced considerably more toxicity than standard BEP. Unfortunately, there was no evidence of therapeutic
superiority for the high dose cisplatin arm, with 62.2% continuously NED with
high dose and 63.6% with standard BEP.28
A successor intergroup study in advanced disease
was completed in 1992. The standard arm of BEP was compared to an experimental
arm of VP-16 + ifosfamide + cisplatin (VIP). The VIP regimen was chosen because of its success
as salvage therapy after PVB and/or BEP. This represented a similar philosophy
for ifosfamide compared to VP-16; namely single agent activity, incorporation
as a curative salvage regimen, and then evaluation as first-line therapy. Three
hundred four patients entered this intergroup study. With a minimal follow-up
of 2 years, there was no difference, as 56% are continuously NED with VIP and
57% with BEP.29 An update of
this data using the international classification for advanced disease also demonstrated
similar results for BEP compared to VIP.30
The current intergroup study for poor risk
disease utilizes the new international staging system.27
The control arm consists
of 4 courses of standard BEP versus the experimental arm of BEP x 2 followed
by 2 courses of very high dose carboplatin, etoposide and cyclophosphamide with
peripheral stem cell rescue. Since only 14% of patients fulfill the category
of poor risk it is very important that as many eligible patients as possible
enter this important study. Participants include Indiana University, MSKCC,
and the American co-operative groups.
Our concept for salvage therapy has always been to use cisplatin plus other
active agents not previously utilized, as long as there was not progression
during cisplatin combination chemotherapy. Cisplatin + etoposide was initiated
in 1978 as salvage therapy after PVB. Our initial salvage therapy after BEP
had been vinblastine 0.11 mg/kg day 1 and 2 + ifosfamide 1.2 grams/m2
x 5 + cisplatin 20
mg/m2 x 5 (VeIP) every 3 weeks for 4 courses. Between 1984 and 1989, 135 patients received
this regimen as second-line therapy. Sixty-seven patients (49.6%) achieved NED
status (no evidence of disease), including 15 (11%) who were NED after postchemotherapy
resection of teratoma and 10 (7.4%) NED after postchemotherapy resection of
carcinoma. Thirty-two (23.7%) are continuously NED with minimal follow-up of
5 years. Thirty of 100 testicular primaries are continuously NED, compared to
2 of 3 extragonadal seminoma and 0 of 32 nonseminomatous extragonadal patients.31
High dose therapy with carboplatin and VP-16 and autologous bone marrow
transplant (ABMT) was first started at Indiana University in 1986. Initially,
this was used as a last attempt at curative therapy (third-line or later or
following progression during cisplatin therapy). Six of these first 40 patients
are 5+ years continuously NED.32 We now utilize peripheral
stem cells and G-CSF, and we are able to safely administer carboplatin 700 mg/m2 x 3 + etoposide 750 mg/m2 x 3. We currently
utilize this therapy as initial salvage chemotherapy. Thirty-seven of 65 (57%)
are continuously disease-free for a minimal of 16 months with this approach.33
However, we continue
to use VeIP as initial salvage for seminoma, as 19 of 23 (83%) achieved an NED
status and 13 of 23 (56%) are continuously NED with this regimen as second-line
chemotherapy.34
Another approach for salvage therapy was done
by Motzer and colleagues at Memorial-Sloan Kettering Cancer Center. Thirty patients
with previously treated germ cell tumors who had prior complete remission to
first-line chemotherapy and then relapsed were treated with 4 courses of paclitaxel
with escalation among patient cohorts with dose levels of 175, 215, and 250
mg/m2 + ifosfamide 5 grams/m2
+ cisplatin 100 mg/m2 every 3 weeks with
G-CSF. The 250 mg/m2 dosage of paclitaxel
was selected for the phase II part of the study. Twenty-three (77%) of 30 patients achieved
a complete remission to chemotherapy. Twenty-two
(73%) of the patients remain progression-free with a median follow-up of 33
months.35
Despite the success with the above mentioned
types of salvage chemotherapy, there continues to be a group of patients that
are not curable with platinum combination chemotherapy. One approach for palliation in these patients
is daily oral VP-16.44 Another approach is to take newer agents that
have activity in platinum refractory disease. Both paclitaxel and gemcitabine have modest single agent activity.
ECOG completed a phase II study of paclitaxel 110 mg/m2 over 1 hour followed by gemcitabine
1,000 mg/m2 over 30 minutes on days 1, 8,
and 15 every 4 weeks for a maximum of 6 cycles. Twenty-eight patients were treated
and there were 7 responses including 2 complete remissions of 15+ and 25+ months.
Therapy was well-tolerated. There appears to be a modest chance for long-term
survival with this 2 drug regimen in patients who were otherwise felt to be
incurable with platinum-based chemotherapy.45
Finally, a third generation platinum compound, oxaliplatin, also has demonstrated
modest activity in this patient population.46
Complicated testicular cancer issues
I. Management of NSGCT clinical stage I, but with elevated
HCG and/or AFP: this is a rare clinical situation; namely, normal radiographic
studies, but elevated HCG or AFP (after accounting for proper time to normalize
postorchiectomy). In the past, standard therapy was RPLND. However, investigators
from both Indiana University36 and MSKCC37
have concluded that
chemotherapy (alone) is optimal treatment (4 courses of EP or 3 courses of BEP).
In reality, these patients have a high probability of having disease
outside, rather than inside the RPLND field as the cause of their elevated marker,
thus making chemotherapy a logical choice.
II. Management of residual mass postchemotherapy in a patient with seminoma:
At MSKCC, if the persistent mass is 3 cm. or larger, RPLND is recommended.38 At Indiana University,
we would simply follow such patients with repeat abdominal C.T. every 3 months
the first year, every 4 months the second year, and once or twice a year for
the next 3 years.39
A recent series from Royal Marsden also supported the policy of observation
in these patients, and documented that postchemotherapy irradiation was not
beneficial.40
III. Should patients presenting with large (> 3 cm) retroperitoneal
masses undergo a postchemotherapy RPLND if they achieve a C.R. with chemotherapy? At MSKCC, 22 patients in this category underwent
postchemotherapy RPLND and 2 had persistent carcinoma and 3 teratoma.41
It is unknown how many received a non-etoposide containing regimen. At Indiana, we have retrospectively reviewed
36 such patients treated with chemotherapy alone. Thirty-four of 36 (94%) are
continuously NED with median follow-up 5 years. There was only one relapse,
as the other patient not continuously NED developed a second primary.42 Thus, we do not feel that surgery should ever be performed postchemotherapy
if a C.R. is achieved; regardless of the size of the initial mass.
IV. Should the presence or absence of teratoma in the
orchiectomy specimen influence the decision about postchemotherapy RPLND for
residual mass? Obviously, the presence of teratoma in the orchiectomy specimen,
especially if the dominant cell type, strongly suggests a postchemotherapy residual
mass will also contain teratoma. We retrospectively evaluated this issue at
Indiana University. Seventy-nine patients with teratoma in the orchiectomy and
a residual postchemotherapy mass underwent RPLND. As expected, most
had teratoma (65 of 79; 82%); 10 (13%) had necrosis and 4 (5%) had carcinoma. Forty-four patients had no teratoma in the orchiectomy specimen
and less than a 90% volumetric regression with chemotherapy, and underwent subsequent
RPLND. In this category, despite no
teratoma in the orchiectomy specimen, 18 of 44 (41%) had teratoma in the RPLND
specimen, 4 had residual cancer, and the remaining 50% necrosis.42
V. Do patients with testis cancer experience
late relapse? Testicular cancer is a
rapidly proliferating and uniquely chemo-sensitive tumor. We now recognize the fact that approximately
2-3% of patients who are disease-free at 2 years will experience a late relapse
and about half of those relapses will be beyond 5 years. This is often manifested
by a rising alphafetoprotein on a routine evaluation. Unfortunately, with very
rare exceptions, these patients are not curable with chemotherapy. Proper management
for these patients is to find where their disease is radiographically and attempt
to surgically resect their disease.43
It is important to
recognize that testicular cancer patients require lifelong follow-up. Our current
policy postchemotherapy is routine history and physical exam including palpation
of contralateral testis, serum HCG and AFP, and posteroanterior and lateral
chest x-ray every 2 months the first year, every 4 months the second year, every
6 months years 3-5 and then annually. If a postchemotherapy resection contained
bulky (> 5 cm) teratoma, abdominal C.T.’s are done at least every 3 months
the first year, every 6 months the second year, and annually years 3-5.
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Correspondence
to:
leinhorn@iupui.edu