Clinical Cancer Research Vol. 6, 72-77, January 2000
© 2000 American Association for Cancer Research
Cyclophosphamide and Carboplatin and Selective Consolidation in Advanced Seminoma
Robert J. Amato1,
Randall Millikan,
Dania Daliani,
Lori Wood,
Christopher Logothetis and
Alan Pollack
Departments of Genitourinary Medical Oncology [R. J. A., R. M., D. D., L. W., C. L.] and Radiation Oncology [A. P.], The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030
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ABSTRACT
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This prospective
Phase II study assesses the clinical efficacy and complications of a
treatment regimen of combination chemotherapy with cyclophosphamide and
carboplatin and selective consolidation in advanced seminoma. Of 46
patients who entered the study between December 1992 and October 1998,
46 were evaluable. Thirty-two achieved a complete remission (70%; 95%
confidence interval, 56–83%) after chemotherapy alone. Fourteen
achieved a complete remission (30%; 95% confidence interval,
18–46%) after chemotherapy plus consolidation. Forty-three of the 46
patients (93%; 95% confidence interval, 82–97%) remained in
remission after a median follow-up period of 27.4 months. No patient
experienced nephrotoxic, neurotoxic, or ototoxic effects or hemorrhagic
cystitis. No patient had neutropenic fever requiring hospitalization.
Thirteen % required platelet transfusions, and 9% required
transfusions of packed RBCs. For patients with advanced seminoma,
treatment with cyclophosphamide and carboplatin and selective
consolidation is safe and effective.
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INTRODUCTION
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At the University of Texas M. D. Anderson Cancer Center, the
treatment protocol for patients with advanced seminoma is different
from that for patients with nonseminomatous germ cell tumor. The
difference in strategy is based on the apparent greater sensitivity of
the seminoma to both chemotherapy and radiation therapy, the relative
difficulty of surgical resection, and unique clinical features.
The different sensitivities to chemotherapy of seminoma and
nonseminomatous germ cell tumors were most apparent during the initial
development of chemotherapy for germ cell tumors, before the
availability of cisplatin. The combination chemotherapy regimen of
vinblastine and bleomycin was effective in a significant proportion of
patients with nonseminomatous tumors but ineffective in patients with
seminoma (1)
. The major advance in chemotherapy of
seminoma came with the incorporation of cisplatin. In the initial
reports of the use of cisplatin as a single agent in patients with germ
cell tumors, long-term, disease-free survival was reported in patients
with seminoma but not in patients with nonseminomatous tumor
(2)
. The apparent increased sensitivity of the seminomas
to cisplatin and relative resistance to the vinblastine/bleomycin
regimen led us to study cisplatin-based chemotherapy regimens in
patients with advanced seminoma. The addition of an alkylating agent to
cisplatin for these patients was prompted by the significant antitumor
activity of these agents and their reported synergy with cisplatin
(3, 4, 5, 6)
.
Besides being more sensitive to cytotoxic chemotherapy than
nonseminomatous germ cell tumors, seminoma is known to be more
radiation sensitive (7)
. Furthermore, comparison of the
two tumor types by surgical resectability of residual masses after
chemotherapy highlights an important difference between the two.
Whereas the standard practice in nonseminomatous germ cell tumors is
elective surgery for residual disease, in seminomas the situation is
quite different. Pronounced fibrotic changes make surgery for seminomas
much more difficult and complications more frequent. Finally, the
metastatic spread of seminomas appears to be more indolent and
predictable than that of other germ cell tumors. The therapy of
seminoma at the M. D. Anderson Cancer Center has focused on
exploiting these differences.
In our initial experience of treating seminoma patients with a regimen
combining cisplatin and cyclophosphamide and selective consolidation,
we concluded that the combination was effective. Ninety-two % of the
patients had survived, free of disease, for long periods
(8)
. The major side effects were those attributed to
repeated doses of cisplatin, i.e., nephrotoxicity, neurotoxicity, and
ototoxicity. Encouraged by the therapeutic success of that initial
trial, we expanded our study to evaluate combinations of cisplatin
analogues and alkylating agents in an attempt to find a treatment with
a similar high cure rate without the relatively high complication rate.
The first alternative we evaluated was the combination of carboplatin
and ifosfamide. These two agents were selected because of their
individual antitumor activities and their relatively mild toxicity
profiles. Ninety-one % of the patients remain free of disease with a
median follow-up of 78 months (9)
. No patients experienced
deterioration of renal function, symptomatic peripheral neuropathy,
ototoxic effects, or hemorrhagic cystitis. There were no
treatment-related deaths. Ten % of the patients had neutropenic fever
requiring hospitalization. Twenty-six % required transfusion of packed
RBCs for a hemoglobin level of <8 g/dl or symptomatic anemia.
Twenty-four % required platelet transfusions for a platelet count <20
cells/mm3 or for symptoms of bleeding. Ninety-eight % are
alive and disease free with a median follow-up of 84 months.
Further modification of our chemotherapy program to reduce the number
of days of administration of chemotherapy, to switch from an inpatient
to an outpatient regimen, to reduce hematological toxicity, and to
further define the role of consolidation is our present goal.
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PATIENTS AND METHODS
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Study Population.
To make this regimen less complicated, we combined cyclophosphamide and
carboplatin. To reduce hematological toxicity, we used
granulocyte-colony stimulating factor beginning on day 2 of each
chemotherapy cycle. To further modify hematological toxicity, those
patients with a predicted creatinine clearance of 
80 ml/min
(calculated by Crockcroft and Gault formulation for estimated
creatinine clearance) not related to tumor volume received a modified
dose of carboplatin. This is based on our retrospective analysis of our
previous program, ifosfamide and carboplatin. Those patients with 
3
cm residual mass after chemotherapy had a delay in deciding whether to
have consolidation radiation therapy for 3 months. Patients who
continue to have regression of their residual mass will continue to be
observed, whereas those patients who remain stable will receive
consolidation radiation therapy.
Patients were enrolled in the study between December 1992 and October
1998. Fifty patients with a diagnosis of advanced seminoma were
assessed by: a review of the histological type; serum tumor marker
assays for ß-HCG,2
AFP, and
total LDH and LDH isoenzyme-1; and computed tomographic scans of the
thorax, abdomen, and pelvis. Patients with visceral metastases were
further staged by isotope bone scan. In addition, a complete blood
count with platelet count, electrolytes, and assessment of renal and
liver function was performed.
Forty-six of the patients met the following criteria and were evaluated
in our study. Patients had histological confirmation of a pure
seminoma; advanced disease was defined as any tumor characterized by
any of the following: extragonadal origin, supradiaphragmatic
involvement, a retroperitoneal mass >10 cm in maximum transverse
diameter, visceral disease, or radiation therapy failures. Patients
were ineligible if they had an abnormal level of serum AFP (>5 ng/ml)
in two measurements 1 week apart. Four patients were excluded from this
study for the following reasons: two patients had a histological
diagnosis of nonseminomatous germ cell tumor; one patient did not
receive chemotherapy; and one patient, who after two courses with a
residual mass, died at his house of a drug overdose. The 46 patients
signed the informed consent approved by the internal review board of
the M. D. Anderson Cancer Center.
Treatment.
The induction chemotherapy consisted of i.v. cyclophosphamide at a dose
of 800 mg/m2 of body surface area given over a period of
2 h on day 1, immediately followed by i.v. carboplatin at a dose
of 400 mg/m2 of body surface area given over a period of
2 h on day 1. Dose levels are shown in Table 1
. Therapy was administered as an
outpatient in the Genitourinary Ambulatory Care Center. All patients
were scheduled to receive a minimum of four courses of induction
chemotherapy at 28-day intervals. Granulocyte-colony stimulating factor
at 5 µg/kg/day s.c. was initiated on days 2–11. Doses of
cyclophosphamide and carboplatin were modified if indicated by
granulocyte counts, platelet counts, or nonhematological toxicity
(Table 2)
. Planned radiation therapy for
those patients with a residual mass consisted of a dose of 25 Gy.
Statistical Analysis.
All evaluable patients are included in this analysis. Response duration
and survival were measured from the date of initiation of therapy.
Survival curves were generated by using the Kaplan-Meier method
(8, 9, 10)
.
Response Criteria.
The treatment of advanced seminoma with chemotherapy classically
results in a persistent residual mass (8
, 9
, 11)
. Our own
experience prompted us to adopt the following criteria. Patients were
classified as either having a complete remission in response to
chemotherapy or response to chemotherapy that required consolidation. A
complete remission to chemotherapy was defined as disappearance of all
clinical and biochemical evidence of disease with either complete
resolution on radiographic examination or a stable residual mass <3 cm
in maximum transverse diameter. A response to chemotherapy requiring
consolidation was defined as disappearance of all clinical and
biochemical evidence of disease with a persistent stable mass 3 cm or
more in maximum transverse diameter. Patients received a minimum of
four courses of induction chemotherapy, with an additional requirement
of two courses beyond complete remission or prior to consolidation.
Patients achieving a complete remission were simply observed. Patients
with a persistent stable mass of 3 cm or more in maximum transverse
diameter were evaluated for consolidation consisting of definitive
radiation therapy. Reevaluation in 3 months occurred. If regression in
size of the residual mass occurred, those patients were observed,
whereas those patients with stability in the size of the residual mass
received radiation therapy. We planned surgical resection of the
residual mass only for those patients with clinical features that led
us to suspect the existence of nonseminomatous tumor. Patients were
defined in our protocol to be at risk if they had a poor response to
chemotherapy or a biomarker response that is not characteristic of a
pure seminoma, i.e., a late rise in the serum AFP level.
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RESULTS
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Patient Characteristics.
Clinical features were recorded for the evaluable 46 patients (Table 3)
. Seventeen % of the patients were
radiation therapy failures. Eighty-five % of the patients presented
with a primary testicular tumor, whereas 15% presented with a tumor of
extragonadal origin. The extragonadal primary site was the mediastinum
for three patients, retroperitoneum for three patients, and pineal body
for one patient. Eighty-five % of the patients presented with an
elevated ß-HCG level, with a median value of 5.7 mIU/ml (normal, <1;
range, 1.2–313.3). Sixty-five % of the patients presented with an
elevated LDH with a median value of 1028 IU/l (normal, 313–618; range,
629–7501). Serum AFP was not elevated in any patient, as defined by
the eligibility criteria.
Seminoma is commonly characterized by its advanced local complications,
as was the case with our patients (Table 4)
.
Response and Survival.
The responses to therapy are outlined in Table 5
. Between four and six (median, four)
courses of cyclophosphamide and carboplatin were delivered to each
patient. Of the 46 patients evaluable for response, 32 (70%) achieved
a complete remission in response to chemotherapy alone, whereas another
14 (30%) achieved a complete remission in response to chemotherapy
plus consolidation, for an overall 100% complete remission rate.
Postchemotherapy consolidation consisted of radiation therapy or
surgery. Thirteen patients, each with a persistent residual mass of 3
or more cm in maximum transverse diameter, were followed 3 months after
the completion of chemotherapy to decide whether the need of definitive
radiation therapy was necessary (12 retroperitoneal and 1 in the
mediastinum). All patients received definitive radiation therapy. One
patient with pineal primary tumor received involved field radiation
therapy, despite achieving a complete remission with chemotherapy. Two
patients, who underwent planned postchemotherapy surgery for removal of
undescended testes in the pelvis, were found to have no evidence of
viable seminoma or nonseminomatous elements. These patients were
evaluated in the complete remission in response to chemotherapy alone
group.
All patients responded to the combination of cyclophosphamide and
carboplatin. Three patients who completed four courses of chemotherapy
had early relapses at <6 months (two patients had consolidation
radiation therapy). One patient, who presented with a new
supraclavicular node, biopsy-proven seminoma without secreting AFP, was
salvaged with cisplatin-based therapy and remained free of disease for
9 months. The remaining two patients recurred with elevated AFP with
visceral disease. One patient died on salvage chemotherapy with
progressive tumor. The other patient was salvaged with cisplatin-based
therapy and remains free of disease for 7 months.
The complete remission rate was durable (Fig. 1)
. Forty-three of the 46 patients (93%)
remained free of disease with a median follow-up period of 27.4 months.
Three patients relapsed. One with seminoma achieved a second complete
remission with cisplatin-based salvage chemotherapy. Of the two
patients who relapsed with an elevated AFP and visceral disease, one
died of progressive tumor and one achieved a second complete remission
with cisplatin-based chemotherapy. The overall survival is shown in
Fig. 2
. Forty-five patients (98%) are
alive and disease-free with a median follow up period of 27.8 months.
Toxic Effects.
Toxic effects are summarized in Table 6
.
There were no treatment-related deaths. Nadir blood counts are
summarized in Table 7
. No patient
experienced deterioration of renal function, symptomatic peripheral
neuropathy, ototoxic effects, or hemorrhagic cystitis. No patient had
neutropenic fever. No hospital time was required. Nine % required
transfusions of packed RBCs because of a hemoglobin level <8 g/dl or
symptomatic anemia. Thirteen % required platelet transfusion for a
platelet count <20 cells/mm3 or symptoms of bleeding. Four
of the patients (9%) had their chemotherapy dose reduced to dose level
minus 1 because of hematological effects. No patient required an
additional dose reduction.
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DISCUSSION
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Chemotherapy with the combination of cyclophophamide and
carboplatin and consolidated therapy as needed is a highly effective
approach for patients with advanced pure seminoma. Ninety-three % of
the patients treated with this strategy remained in complete remission
after a median follow-up period of 27.4 months. This follow-up is
beyond the risk of failure for the majority of patients with seminoma.
Because none of the patients with a residual mass had further
regression at 3 months, radiation therapy consolidation was necessary.
The response rate we report compares favorably with that of our
previous trial with cyclophosphamide and cisplatin, ifosfamide and
carboplatin, and also with those reported by other investigators,
despite the advanced stage of disease in patients we treated (8
, 7
, 11, 12, 13, 14, 15, 16, 17, 18)
. Our ability to assure that this modification is
indeed superior to the regimen used previously is limited, however, by
the number of patients that we treated.
The overall rate of long-term, tumor-free survival of the patients
treated in this study was 98%, with a median follow up of 27.8 months.
Of the three patients who relapsed and were treated with
cisplatin-based salvage therapy, the patient with a seminoma remains
free of disease after 9 months, and of the other two patients who
relapsed with elevated AFP associated with visceral disease, one died
of tumor progression and one remains free of disease after 7 months.
These results mirror those achieved in our other patients with advanced
pure seminoma who have been treated under this strategy (8
, 9)
. Although recent reports document that carboplatin is
inferior to cisplatin in germ cell tumors (12)
,
carboplatin does not appear to adversely effect the outcome of patients
we treated. This could be attributed to either the unique sensitivity
of seminoma to platinum analogues or to the strategy in which we used
the drugs.
In contrast to other chemotherapy regimens reported
(12, 13, 14, 15, 16, 17)
, this combination caused no deaths in the series.
The most severe complications of the cyclophosphamide and carboplatin
combination were hematological effects. Some patients required
transfusions (Table 6)
. No hospitalization time was required. No
neutropenic fever was observed. There were no infectious complications,
perhaps because there was no mucositis and because of the use of
granulocyte-colony stimulating factor. There were no significant acute
nonhematological toxic effects, and no long-term complications have yet
been observed. This is in contrast to the moderate toxic effects
suffered by patients treated with our initial regimen that incorporated
the sequential delivery of cisplatin (8)
. Total avoidance
of the neurotoxic, ototoxic, and nephrotoxic effects that accompany
cisplatin is a major advantage of the combination of cyclophosphamide
and carboplatin. Moreover, the frequency of nonhematological and
hematological toxic effects was lower than that reported with other
regimens (11, 12, 13, 14, 15, 16, 17, 18)
.
Bleomycin-induced pulmonary toxic effects are reported at a higher rate
in patients with seminoma than in those with nonseminomatous tumors.
The difference in frequency of the occasionally fatal bleomycin effects
may be a function of the older age of the patients with seminoma
compared with those with nonseminomatous tumors. We believe the data we
have reported here confirm the published suggestion that bleomycin is
not required for therapy of seminoma (19)
. In
nonseminomatous tumors, bleomycin appears to be essential, even in the
patients with a favorable prognosis (19)
.
The contribution of each of the therapy components to the result
we achieved cannot be determined. Two factors that may have contributed
to the results were the selection of patients for consolidation and the
selection of patients for entry into the trial. The selection of
patients for consolidation was based on the radiographic appearance of
the residual mass after chemotherapy. Radiographic reevaluation was
performed after completion of every two courses of cyclophosphamide and
carboplatin. When patients achieved maximum improvement, complete
remission to chemotherapy, or response to chemotherapy requiring
consolidation, an additional requirement of two courses were
administered. The residual mass appeared frequently as a poorly defined
desmoplastic response (<3 cm; Refs. 8
, 9
, and 11
). Because patients in
our earlier study who had this characteristic response to chemotherapy
have not experienced relapse, we have since considered this response a
complete remission requiring no further therapy (8
, 9)
.
The data of this trial confirmed the validity of that conclusion.
Patients with a residual discreet mass (3 cm) in contrast were
considered at risk of relapse (8
, 9
, 11)
. Such patients
had fine-needle aspiration biopsy of the residual mass, followed by
radiation therapy to the involved field (8
, 9)
. No biopsy
revealed viable disease, indicating either that the majority have no
remaining disease or that the fine-needle aspiration has limited
ability to detect residual viable cancer in seminoma patients after
chemotherapy (8
, 9)
. In our study, the 13 patients who had
a residual mass 3 cm in maximum transverse diameter were delayed in
receiving definitive radiation therapy. Although we realize that
regression continues after the completion of chemotherapy, this is a
delayed event, and as per our design, by obtaining radiographic
evaluation after every two courses, we were able to determine a stable
maximum improvement and thus complete chemotherapy without recognizing
further regression during that short time frame. In our previous
protocols, consolidative radiation therapy was planned immediately
after the completion and recovery from chemotherapy (8
, 9)
. To reduce the number of patients receiving radiation
therapy, a delay of 3 months was planned. No patient had further
regression; thus, all 13 received radiation therapy. A delay in 3
months from the completion and recovery of chemotherapy did not affect
the number of patients receiving radiation therapy. A minority of
patients (30%) received radiotherapy for consolidation. The dose of
radiation therapy was a median of 25 Gy, ranging from 25 to 30 Gy.
Twelve of the 14 patients remain free of disease with no additional
complications; two of the patients relapsed, and both are in complete
remission for 7 and 9 months, respectively.
Patients selected for consolidation therapy at other institutions were
similar, but the method of consolidation differed. Surgical excision is
used with postoperative radiation therapy or additional chemotherapy if
viable seminoma was encountered, whereas we used primary radiation
therapy to the involved field. We planned resection only for those
patients with clinical features that lead us to suspect the existence
of nonseminomatous tumor. Two patients in this clinical trial did
undergo surgical exploration to remove undescended testes in the pelvis
to exclude the possibility of viable tumor. Neither patient had a
viable carcinoma or teratomatous elements.
The combination of cyclophosphamide and carboplatin is probably
inferior to existing regimens for the treatment of patients with
nonseminomatous germ cell tumors. This specificity of treatment by
histological type requires that precautions be taken to assure the
correct histological classification of germ cell tumors. Of the
patients we treated, 80% had their tumor classified by
histopathological study of the primary testicular cancer. An additional
9% were diagnosed by a biopsy of the metastatic site, and 11% were
diagnosed by a fine-needle aspiration. The study protocol required that
all patients have two measurements of serum levels of AFP assayed 1
week apart and that both levels be within normal range. In two of the
46 patients we treated, the tumor converted to a mixed histological
type. Because of our ability to correctly classify the germ cell
cancer, we believe review of the tumor specimen by an experienced
pathologist and normal serum AFP concentrations together give a safe
distinction between seminoma and nonseminomatous tumors for treatment
purposes.
The strict pathological entry criteria did not adversely affect
our ability to accrue representative patients with truly advanced
seminoma. The clinical criteria excluded all patients except those with
a retroperitoneal mass of >10 cm in maximum transverse diameter,
metastatic sites above the diaphram, primary extragonadal origin, or
radiation therapy failures (Table 3)
. Our patients were characteristic
of those with advanced seminoma. A total of seven patients (15%)
presented with an extragonadal tumor; three of those were mediastinal,
three were retroperitoneal masses >10 cm, and one was pineal. The 39
patients (85%) whose tumors were of testicular origin included 31
retroperitoneal masses >10 cm, 8 with supradiaphramatic involvement,
and 8 radiation therapy failures. The advanced stage of the disease in
these patients was further reflected by their local complications
(Table 4)
, by the performance status of some of the patients with
neglected cancers, and by the frequency of evaluation of both the
ß-HCG and LDH levels (Table 3)
.
Some investigators have reported an adverse treatment outcome in
patients whose seminomas are of extragonadal origin have visceral
disease, express serum tumor makers, who have poor initial performance
status, or who have already been treated by radiation therapy. Because
of the high overall complete remission rates in this and our other
report (8
, 9)
, we conclude that no single clinical feature
of seminoma predicts an adverse outcome, and that patients with
seminomas should be considered to have a favorable prognosis. Patients
in this study with visceral or bone involvement remain in complete
response to induction therapy.
A total of 124 patients with seminoma have now been treated at the
M. D. Anderson Cancer Center with the combination of an alkylating
agent and a cisplatin analogue and selective consolidation therapy
(Table 8)
. There were no late relapses or
second primary malignancies. These results support the concept of
seminoma as a unique clinical entity and justify treating seminomas
differently from nonseminomatous tumors. They also indicate that
seminoma has an excellent prognosis with carboplatin-based therapy. If
future studies should confirm these findings, the therapeutic strategy
we used should become the treatment of choice for advanced seminoma.
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FOOTNOTES
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom requests for reprints should be
addressed, at Department of Genitourinary Medical Oncology, The
University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe
Boulevard, Box 013, Houston, TX 77030. Phone: (713) 792-2830; Fax:
(713) 745-0827. 
2 The abbreviations used are: ß-HCG, ß-human
chorionic gonadotropin; AFP, 
-fetoprotein; LDH, lactate
dehydrogenase.
Received 6/ 9/99;
revised 9/15/99;
accepted 9/16/99.
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ABSTRACT
INTRODUCTION
