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Salvage Chemotherapy for Patients With Advanced Pure

Seminoma
By Jacqueline Vuky, Satish K. Tickoo, Joel Sheinfeld, Jennifer Bacik, Alison Amsterdam, Madhu Mazumdar, Victor Reuter,
Dean F. Bajorin, George J. Bosl, and Robert J. Motzer
Purpose: We describe the response to conventional
or high-dose salvage chemotherapy in patients with
advanced seminoma who experience disease progression after receiving first-line platinum-based treatment.
Patients and Methods: Twenty-seven patients with
progressive, advanced, pure seminoma were treated
with salvage chemotherapy. Fifteen patients were
treated with conventional-dose cisplatin-and-ifosfamide combination chemotherapy. Twelve patients
were treated with high-dose chemotherapy followed
by autologous stem-cell rescue.
Results: Fifteen patients (56%) achieved a complete
response (CR), nine achieved CR with a conventionaldose cisplatin and ifosfamide program, and six experienced CR after high-dose chemotherapy. Fourteen patients (52%) are alive and disease-free, with 13 (48%)
continuously disease-free at a median follow-up of 72
months. Twelve (57%) of 21 patients whose pretreatment tumors were studied morphologically were found

to have seminoma with atypia. Eight patients underwent resection after salvage chemotherapy; six with
histologic findings of necrotic debris/fibrosis alone are
alive and disease-free at last follow-up. Both patients
with viable seminoma found at surgery died of disease.
Conclusion: Most patients with advanced seminoma
are cured with standard first-line programs of cisplatin
and etoposide with or without bleomycin. A small minority of patients with pure seminoma have resistant
tumors and require salvage chemotherapy. In this setting, approximately 50% of patients with recurrent
pure seminoma achieve durable CR with conventional
or high-dose salvage chemotherapy. Identification of
biologic markers to predict clinical outcome and an
enhanced understanding of the basic biologic features
of seminoma may lead to improvements in the management of this disease.
J Clin Oncol 20:297-301. 2001 by American
Society of Clinical Oncology.

INCE THE INTRODUCTION of cisplatin-based combination chemotherapy, 70% to 80% of patients with
metastatic testicular germ cell cancers (GCT) are cured.1 In
this regard, pure seminoma histology is recognized as
particularly chemotherapy sensitive and is associated with a
high chance of cure, using standard chemotherapy programs
of cisplatin and etoposide with or without bleomycin.2
When patients with pure seminoma are stratified according
to internationally accepted risk criteria, 90% of patients are
classified as good risk, and more than 85% are cured with
cisplatin-based combination chemotherapy.2,3
A minority of patients with advanced pure seminoma,
however, do not achieve a complete response (CR) with
initial chemotherapy or will relapse after a CR and require
salvage therapy.3 In this setting, patients are treated on programs that have been largely used in nonseminoma, because
their histology is more likely to be refractory to standard
chemotherapy programs. Effective second-line chemotherapy
in patients with resistant GCT using ifosfamide and cisplatin
with either etoposide or vinblastine results in a CR of 50%,
with durable complete remission in approximately 25% of
patients.4,5 In patients who are not cured by ifosfamide-based
and cisplatin-based salvage chemotherapy, high-dose chemotherapy (HDCT) with autologous stem-cell rescue can cure
15% to 25% of patients.6,7 However, published series of both
regimens to date have been composed almost entirely of
patients with nonseminoma histology.

The small number of patients who require salvage chemotherapy has limited the study of optimal management of
pure seminoma in the salvage setting.8 We describe the
experience at our center in the management of 27 patients
with resistant seminoma. Treatment outcomes and surgical
resection after salvage chemotherapy are discussed.

PATIENTS AND METHODS

Patients
Twenty-seven patients with metastatic pure seminoma who required
salvage chemotherapy were identified from July 1987 to December
1999 on a clinical trial approved by the institutional review board at

From the Genitourinary Oncology Service, Divisions of Solid Tumor


Oncology and Biostatistics, Departments of Medicine, Biostatistics and
Epidemiology, and Surgery, and Urology Service, Memorial SloanKettering Cancer Center, and Departments of Medicine and Pathology,
Joan and Sanford I. Weill Medical College of Cornell University, New
York, NY.
Submitted May 21, 2001; accepted August 13, 2001.
Supported in part by a grant from the Brian Piccolo Cancer
Research Fund and grant nos. NIH CA-09207-23 and NIH K24
CA-82431 from the National Institutes of Health, Bethesda, MD.
Address reprint requests to Robert J. Motzer, MD, Memorial
Hospital, Memorial Sloan-Kettering Cancer Center, 1275 York Ave,
New York, NY 10021; email: motzerr@mskcc.org.
2001 by American Society of Clinical Oncology.
0732-183X/01/2001-297/$20.00

Journal of Clinical Oncology, Vol 20, No 1 (January 1), 2002: pp 297-301


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297

298

VUKY ET AL
Table 1.

Salvage Chemotherapy Regimens


Salvage Regimen

Standard-dose cisplatin and ifosfamide-containing chemotherapy


Etoposide or vinblastine/ifosfamide/cisplatin5
Paclitaxel/ifosfamide/cisplatin10
High-dose chemotherapy with autologous stem-cell support
Paclitaxel/ifosfamide followed by high-dose carboplatin and
etoposide9
High-dose carboplatin/etoposide/cyclophosphamide7

No. of
Patients

15
13
2
12
9
3

Memorial Sloan-Kettering Cancer Center (MSKCC). For all patients,


salvage chemotherapy consisted of conventional-dose cisplatin and
ifosfamide or high-dose chemotherapy with autologous stem-cell
rescue.5,7,9,10 All patients met criteria for prechemotherapy histologic
diagnosis of pure seminoma, including (1) normal alpha fetoprotein at
initial diagnosis, (2) histologic diagnosis confirmed at MSKCC, and (3)
clinical evidence of chemotherapy resistance by demonstration of
progressive disease after treatment with platinum-based combination
chemotherapy. Progression of disease was evident by increasing human
chorionic gonadotropin (HCG), viable unresected seminoma, and/or
increasing mass on radiologic studies.
The salvage chemotherapy programs, toxicities, and treatment results of the trials have previously been reported.5,7,9,10 Fifteen patients
(56%) were treated on conventional-dose cisplatin and ifosfamide
regimens with vinblastine, etoposide, or paclitaxel.5,10 Twelve patients
(44%) were treated on high-dose chemotherapy with autologous
stem-cell rescue programs that consisted of etoposide and carboplatin
with or without cyclophosphamide (Table 1).7,9 Since 1993, patients
were prospectively identified by clinical features and risk-stratified to
conventional or high-dose second-line chemotherapy.9,10 Patients with
a gonadal primary site who experience relapse after CR with first-line
therapy have a chance for cure with conventional-dose cisplatin and
ifosfamide salvage therapy. These patients were entered onto a trial of
combined paclitaxel with ifosfamide and cisplatin in a first-line salvage
program.10 In contrast, patients with an incomplete response (IR) to
first-line therapy rarely achieve a durable CR to conventional-dose
cisplatin plus ifosfamide salvage therapy.5 These patients were treated
on a clinical trial of repetitive cycles of dose-intense therapy that
consisted of paclitaxel and ifosfamide followed by high-dose carboplatin and etoposide with autologous stem-cell rescue.9
After chemotherapy, clinical restaging, including serum tumor markers (HCG, lactate dehydrogenase [LDH], alpha fetoprotein) and radiographic studies, were performed to evaluate initial sites of disease.
Patients with normalization of serum tumor markers and radiographic
evidence of residual disease after salvage chemotherapy were referred
for surgical resection at the discretion of the treating physician.
Responses were categorized as either CR or IR. A CR to chemotherapy was defined as the disappearance of all clinical, radiographic,
and biochemical evidence of disease for a minimum of 4 weeks after
chemotherapy; this included patients for whom surgical resection of
residuum yielded only necrotic debris or fibrosis. A CR to chemotherapy plus surgery was defined as the complete excision of all masses that
contained seminoma.5 An IR was, therefore, observed in patients who
did not achieve a CR with chemotherapy with or without surgery. This
included patients who experienced disease progression on therapy, had
unresectable seminoma at surgery, or had a partial response with
negative markers. The latter consisted of patients who had a residual
radiographic abnormality after chemotherapy but were not evaluated by

surgery and who remained progression-free at the time of analysis, with


normal values of LDH and HCG.5

Surgical Resection After Salvage Chemotherapy


Operative reports were reviewed with a urologic surgeon (J.S.), and
surgical resections were characterized as complete or incomplete.
Pathologic reports of each resected specimen were reviewed and
categorized as fibrosis/necrosis-only or viable seminoma.

Pathology Review
Twenty-one (78%) of 27 patients had histopathologic material
available for adequate review for presence of seminoma with atypia
versus usual seminoma by a pathologist (S.K.T.).11 All samples
reviewed were obtained before the initiation of salvage chemotherapy.
Fine needle-aspiration (cytologic) specimens were not included in the
analysis as a result of the difficulty with specimen interpretation in
regard to this distinction. Patients were defined as having atypia when
moderate to marked nuclear pleomorphism, nuclear overlapping, lack
or paucity of tumor lymphocytic infiltration, and/or absence of cytoplasmic clarity were observed.11 Tumors found to contain more than
50% of such features were considered seminomas with atypia, and all
others were categorized as classical seminomas.
Twelve (57%) of 21 patients with tumors studied morphologically
were found to have the presence of seminoma with atypia. Seven of
these patients had pathologic material reviewed from testis, and five,
from retroperitoneal lymph node. Eleven were obtained before the
patient received any chemotherapy, and one was obtained after chemotherapy but before entry onto this study.

Statistical Methods and Prognostic Analysis


Survival time for the 27 patients was measured from the first date of
salvage treatment at MSKCC to the date of death or last follow-up.
Survival distributions were estimated using the Kaplan-Meier method.12
Factors considered in univariate analysis included site of metastatic
disease (presence or absence of nonpulmonary visceral metastases) and
histology before salvage chemotherapy (classical seminoma v seminoma with atypia11). The relationship between survival and each of the
variables was analyzed using a permutation test on the basis of the
log-rank statistic.13

RESULTS

Patient Characteristics
Patient characteristics are shown in Table 2. Primary site
was testis in 26 (96%) and extragonadal (retroperitoneum)
in one patient. Initial response to first-line therapy was CR
in eight patients (30%) and IR in 19 (70%). Six patients
(22%) had prior radiation therapy. Twenty-three patients
(85%) had been treated with one prior cisplatin-based or
carboplatin-based regimen, and four patients (15%) had
received two prior regimens. Twelve (44%) and 17 (65%)
had abnormally elevated serum concentrations of HCG and
LDH, respectively, before salvage chemotherapy.
Response and Survival Analysis
CR to salvage chemotherapy was achieved in 15 (56%) of
27 patients; none of these patients required resection of

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299

SALVAGE CHEMOTHERAPY FOR ADVANCED SEMINOMA


Table 2.

Patient Characteristics

Characteristic

No.

Patients
Age, years
Median
Range
Site of metastatic disease before salvage
treatment
Retroperitoneum
Lung
Mediastinum
Bone
Liver
Other
Sites of metastatic disease
1
2
3
Abnormal value prechemotherapy markers
HCG (normal, 2.2 mIU/mL), mIU/mL
Median
Range
LDH (normal, 200 U/L), U/L
Median
Range
Prior cisplatin or carboplatin chemotherapy
1 regimen
2 regimens
First-line chemotherapy regimen
Etoposide and cisplatin
Bleomycin, etoposide, and cisplatin
Etoposide and carboplatin
Other cisplatin-based
Prior response to first-line chemotherapy regimen
CR
IR

27

35
23-62

19
7
6
4
2
6

70
26
22
15
7
22

12
12
3

44
44
11

18.7
2.6-7,736
494
212-2,180
23
4

85
15

14
7
2
4

52
26
7
15

8
19

30
70

residual viable seminoma (Table 3). Twelve patients (44%)


achieved an IR. This included nine patients who experienced failure of normalization or increased serum tumor
marker values and/or increased radiographic masses and

Table 3.

Response to Salvage Treatment and Current Status

Total
No. of Patients

Alive at Last
Follow-Up
No.

27
Response to salvage therapy
CR
Combination cisplatin ifosfamide
High-dose chemotherapy
IR
Combination cisplatin IR
ifosfamide
High-dose chemotherapy

15
9
6
12
6
6

14

93
8
6

8
0
1

Fig 1.

Survival of 27 patients who underwent salvage chemotherapy

three who had a partial response with normal serum tumor


markers but did not have surgery to evaluate residual
radiographic abnormalities. Of the 15 patients treated with
cisplatin-containing and ifosfamide-containing chemotherapy, nine (60%) achieved a CR, with eight (53%) alive and
without evidence of disease at last follow-up. None of the
six patients with an IR to cisplatin-containing and ifosfamide-containing chemotherapy are alive at last follow-up.
Of the 12 patients treated with high-dose chemotherapy, six
(50%) of the 12 patients achieved a CR, and all six patients
remain alive and disease-free at last follow-up. One patient
treated with high-dose chemotherapy achieved a partial
response with normalization of markers and is progressionfree at 33 months but is considered alive with disease.
Therefore, seven (58%) of 12 patients treated with highdose chemotherapy are alive at last follow-up (Table 3).
Two patients experienced relapse from a CR to conventional-dose cisplatin and ifosfamide combination chemotherapy. One patient achieved a CR to subsequent high-dose
chemotherapy with autologous stem-cell transplant and
remains disease-free at 85 months.
The median survival time for the 27 patients has not been
reached, with a median follow-up of survivors of 72 months
(range, 9 to 157 months) (Fig 1). The 2-year survival rate is
57% (95% confidence interval, 38 to 77). Overall, 14
patients (52%) are alive without evidence of disease, 13
(48%) of whom are alive and continuously disease-free after
CR with salvage chemotherapy at last follow-up (Table 4).
Seven patients are alive and continuously disease-free after
conventional-dose cisplatin and ifosfamide chemotherapy,
and six patients are alive and continuously disease-free after
high-dose chemotherapy at last follow-up.
Six (22%) of 27 patients had nonpulmonary visceral
(bone and liver) metastases before treatment with salvage
chemotherapy. Twelve (57%) of 21 patients with tumors

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300

VUKY ET AL
Table 4.

Survival Status
No. (N 27)

14
1
12
13

52
4
44
48

Overall status
Alive, disease-free
Alive with disease
Dead
Continuously disease-free

studied morphologically were found to have the presence of


seminoma with atypia. No statistically significant difference
in survival was found when comparing those patients with
and without nonpulmonary visceral metastases or when
comparing classical versus seminoma with atypia. However, it must be noted that prior response was used to stratify
patients to conventional-dose or high-dose chemotherapy.
Surgery After Salvage Chemotherapy
Surgical exploration after salvage chemotherapy was
undertaken in eight patients (Table 5). Histologic findings
of necrosis/fibrosis were found in six; all are alive at 9 to
87 months. Both patients with viable seminoma in resected residua at surgery died of disease.
DISCUSSION

A minority of patients with pure seminoma have an IR to


initial cisplatin-based chemotherapy or relapse from a CR
and require salvage chemotherapy. One prior report also
addressed treatment results of salvage cisplatin and ifosfamide therapy in patients with pure seminoma.8 The CR
proportion in patients treated with cisplatin and ifosfamide
chemotherapy in the present series was lower than that
reported by Miller et al,8 but the durable response rate was
identical. The difference in CR between the two series may

Table 5.
Patient No.

Surgical Procedure

Retroperitoneal lymph node dissection

2
3

Retroperitoneal lymph node dissection


Resection of residual retroperitoneal mass

Resection of residual retroperitoneal mass

Resection of retroperitoneal mass and


pulmonary parenchymal disease
Resection of residual retroperitoneal mass
Inguinal lymph node dissection
Resection of pulmonary nodules

6
7
8

reflect patient selection because our series included some


patients who were more heavily pretreated.
Until specific prognostic features are identified for pure
seminoma, our approach to using high-dose chemotherapy
for these patients follows the same paradigm used in the
management of patients with resistant nonseminoma.9,10
Nine patients with seminoma in this series were selected to
receive dose-intensive chemotherapy, with paclitaxel, ifosfamide, carboplatin, and etoposide as second-line therapy
on the basis of unfavorable prognostic features; all nine
patients had achieved a prior IR to initial cisplatin-combination chemotherapy.9 Six (67%) of the nine patients are
alive, and all are progression-free. In this regard, seminoma
patients with an IR to initial chemotherapy, characterized by
progressive disease or residual radiographic disease and
normal markers of less than 6 months, are offered treatment
with a high-dose program.
The role for postchemotherapy surgery in seminoma after
first-line chemotherapy is controversial.14 We are not aware
of any series that addresses the issue following salvage
chemotherapy. None of the patients with findings of viable
seminoma after salvage chemotherapy surgery are alive.
However, all six patients with necrosis found at surgery
remain alive without evidence of disease at 9 to 87
months after salvage chemotherapy. Because both patients
with histologic findings of viable seminoma at surgery died,
a therapeutic benefit for surgery was not evident in this
small series. However, distinguishing seminoma from necrosis is useful in the assessment of response and prognosis
and could be used to direct high-dose chemotherapy to
patients with unresectable viable seminoma after treatment
with cisplatin and ifosfamide salvage chemotherapy.
Seminoma with atypia is distinguished by atypical morphologic features and a distinct immunohistochemical stain-

Resection After Salvage Chemotherapy


Comment

Complete resection; difficult resection


with dense, desmoplastic reaction
Complete
Large mass, incomplete resection with
dense desmoplastic reaction
Complete resection; second resection of
retroperitoneum
No operative report available
No operative report available
Right inguinal lymph node dissection
Bilateral thoracotomies and wedge
resection of residual pulmonary lesions

Pathology Resected
Residual

Status

Follow-Up
(months)

Fibrosis

Alive

52

Necrosis
Necrosis

Alive
Alive

21
72

Fibrosis

Alive

87

Seminoma

Dead

Seminoma
Necrosis
Necrosis

Dead
Alive
Alive

13
9
12

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301

SALVAGE CHEMOTHERAPY FOR ADVANCED SEMINOMA

ing pattern (c-kit negativity or decreased positivity, rare


single-cell positivity of CD30, increased expression of
blood group antigens, and greater nuclear positivity of
Ki-67)11,15 The clinical course has been suggested to be
more aggressive in some cases than classic seminoma.15,16
Seminoma with atypia has been proposed to represent early
transformation to nonseminomatous histology.3,15-17 Given
the small sample size in this study, we were unable to
identify an unfavorable prognosis for seminoma with atypia
to treatment with salvage chemotherapy. However, the
number of patients with seminoma with atypia in this series
(selected by chemotherapy resistance) was substantial. It is
possible that atypia may result from chemotherapy-induced
changes in this setting. However, our prior observations on
such changes in untreated cases11 raise the possibility that
seminoma with atypia may be a poor prognostic feature for
patients with advanced seminoma that warrants prospective
study in untreated patients.
In conclusion, seminoma is highly chemosensitive, and
most patients are cured with standard first-line programs of
cisplatin and etoposide with or without bleomycin. A

minority of patients with pure seminoma have resistant


tumors and require salvage chemotherapy. In this setting,
approximately 50% of patients with recurrent pure seminoma achieve durable CR to conventional or high-dose
salvage chemotherapy. Until specific prognostic features are
identified for pure seminoma in directing salvage chemotherapy, our approach has been to follow the same paradigm
used in the management of patients with resistant
nonseminoma.
A high number of patients with seminoma with atypia
were identified in this series, which was selected by chemotherapy resistance, and this histology warrants study as a
prognostic feature in untreated patients. Identification of
biologic markers to predict clinical outcome and an enhanced understanding of the basic biologic features of
seminoma may lead to improvements in the management of
this disease.
ACKNOWLEDGMENT
We thank Carol Pearce for her review of the manuscript and Jessica
Zwaska for data collection.

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