Despite
the overall success of chemotherapy, approximately one third of patients
with metastatic testicular cancer will not achieve a durable remission
with first-line therapy. These failures comprise two groups of patients:
those with refractory disease (progression at 4 weeks or less following
cisplatin-based chemotherapy) and those who relapse after achieving
a first remission.
Subsequent
to the success of PVB, clinical trials established single-agent activity
for etoposide32 and thereafter for ifosfamide23
in patients with relapsed or refractory disease. Etoposide was incorporated
into first-line therapy in the BEP regimen in the early 1980s and, as
above, BEP became the established standard therapy in this country after
the results of the SECSG randomized trial demonstrated clinical equivalence
of BEP to PVB with a better toxicity profile to the former.
The
addition of ifosfamide to cisplatin plus etoposide (VIP) or to vinblastine
(VeIP) was evaluated in 1988 in a phase II trial33 at Indiana
University in a population of multiply-relapsed patients who had received
at least two prior cisplatin-containing regimens. VIP or VeIP produced
a favorable response, ie, CR or disease-free status after surgical resection,
in 20 (36%) of 56 patients treated. In the subgroup treated with VIP,
15 (47%) of 32 patients achieved disease-free status. However, only
9 patients remained continuously disease free from 15+ to 42+ months
(7 for more than two years). Using the same VIP regimen as second-line
therapy, Harstrick et al34 in 1991 reported CRs in 10 of
30 patients — 6 with the addition of surgery. Overall, 5 of the 30 patients
remained disease-free. The responses were noted almost exclusively in
the subgroup of patients who had achieved CRs to first-line therapy.
Therefore, while ifosfamide-based therapy can achieve tumor regression
in a cohort of heavily pretreated patients, the overall salvage rate
is approximately 16%.
More
recent trials have demonstrated single-agent activity for paclitaxel
and gemcitabine. Motzer et al35 reported a response rate
of 26% (3 CRs, 5 PRs) in 31 patients treated with paclitaxel at a dose
of 250 mg/m2 as a 24-hour infusion every 3 weeks. Patients
in this trial were limited to one prior cisplatin-containing regimen.
A
trial reported in 1998 demonstrated that the combination of cisplatin
and paclitaxel36 achieved an overall response rate of 25%
with 1 CR (6%) in 16 patients who had not achieved remission to first-line
therapy. The addition of ifosfamide to cisplatin and paclitaxel37
produced a CR rate of 63% in 16 patients with primary testicular neoplasms
who had relapsed from initial therapy. Eight patients had no evidence
of disease with a median follow-up of 16 months. While intriguing, the
follow-up is too short to further comment.
Bokemeyer
and colleagues38 treated 31 patients with gemcitabine, and
6 (19%) responded favorably. Although the time to disease progression
was short, this population was heavily pretreated: 71% had received
HDCT and autologous stem cell rescue (ASCR), and 61% had received prior
paclitaxel therapy. In addition, 17 (54%) were considered to be refractory
or absolutely refractory to chemotherapy. Three of the responses were
seen in patients after HDCT; one of four patients with a mediastinal
primary also responded. This level of activity warrants further investigation.
High-dose
Chemotherapy With Autologous Bone Marrow or Stem Cell Rescue
Recognizing the
exquisite chemosensitivity of germ cell tumors, investigations have
led to the use of HDCT with bone marrow or peripheral stem cell rescue
as a strategy to overcome chemotherapy resistance to standard drug doses.
Germ cell tumors would appear to be an excellent model for dose intensification
strategies because the drugs that can be escalated to multiple times
the conventional dose range have high single-agent activity in this
disease. In addition, the patient population by definition will be young,
unlikely to have comorbid medical problems, and therefore capable of
tolerating treatment toxicity.
Initial
investigations of HDCT with autologous bone marrow transplantation were
carried out in populations of patients who were heavily pretreated,
the majority of whom were defined as cisplatin-refractory. Of 40 patients
treated at Indiana University39 between 1986 and 1989 with
1 or 2 cycles of high-dose carboplatin and etoposide, 12 (30%) achieved
a CR. Six patients (15%) had no evidence of disease 24 months after
therapy. While only 11% of patients with refractory disease (defined
as disease progression within 4 weeks of cisplatin therapy) achieved
NED status, the possibility of “cure” in even this small percentage
was unexpected with any other therapeutic maneuver. A similar outcome
was obtained by Motzer et al.40 Of 58 patients, 23 (40%)
achieved a CR, five with resection of residual disease. Of these 23
patients, 20 had received 2 cycles or tandem high-dose therapies. Twelve
(21%) remained disease-free at a median follow-up of 28 months. As in
the Indiana trial, nearly two thirds of the patients had never achieved
a CR to cisplatin-based chemotherapy. Combining the results of several
single-institution trials in patients with multiply-relapsed disease
treated with HDCT and autologous stem cell support using combinations
of carboplatin and etoposide yields an overall durable remission rate
of 16%.41 In the subgroup of patients defined as cisplatin-refractory,
15% achieved durable CRs. These trials support the concept that resistance
to cisplatin can be overcome in a small number of patients with massive
doses of carboplatin. While the number of cycles of high-dose therapy
was variable among the trials, of note in the Indiana trial is that
a second cycle of therapy converted 8 of 12 patients from a PR to a
CR. The MSKCC trial also suggested that a single HDCT had limited benefit
since less than 10% of patients who received 1 cycle of therapy remained
continuously disease-free. In these trials, no induction therapy was
given.
Subsequent
to the demonstration of some limited degree of salvageability of refractory
patients with HDCT alone, patients were treated “earlier” in their disease
course, ie, in first relapse or when failing to achieve a CR to primary
therapy. The results of two trials using conventional salvage chemotherapy,
generally ifosfamide-based, followed by one course of HDCT with carboplatin
plus etoposide with42 or without43 ifosfamide,
resulted in approximately one third of patients achieving a durable
remission with a median follow-up of 55 and 26 months, respectively.
The single-institution trial from Europe reported by Rick et al42
included a sample size of more than 150 patients.
The
use of tandem HDCT with autologous stem cell rescue after conventional-dose
“induction” appears to increase the percentage of long-term disease-free
patients. In an Indiana trial,44 15 of 25 patients were rendered
disease-free initially, with 52% alive without disease at a median of
26 months (range: 14 to 36 months) posttherapy. In a similar study design
at the City of Hope45 that included only those patients who
were not refractory to cisplatin, 9 (45%) were disease-free at a median
of 45 months posttherapy.
Whether
the 45% to 52% disease-free survival at a median of greater than 2 years
with tandem therapy is really different from the 34% to 39% disease-free
survival reported with a single high-dose therapy course remains questionable.
Except for the single-institution European trial with 150 patients,
the other studies all reported on fewer than 50 patients, and outcomes
may have been related to patient selection.
The
use of high-dose therapy integrated into the primary treatment of poor-risk
patients with germ cell malignancies was reported in 1992 by Droz and
colleagues46 from the Institut Gustave Roussy. Twenty-eight
patients with poor-risk disease with a calculated probability of CR
of 0.05 using a prognostic mathematical model based on pretreatment
levels of HCG and AFP were treated with a double-dose regimen of cisplatin,
vinblastine, cyclophosphamide, and etoposide (modified PVeBV), followed
by HDCT with cisplatin, etoposide, cyclophosphamide and ABMT. Seventeen
patients achieved a CR, 12 of whom were alive and in continuous CR after
a median follow-up of 66 months. These data suggested that the outcome
of patients with predicted poor outcome to conventional therapy might
be improved with the addition of high-dose therapy.
Similarly,
Motzer et al47 reported on a phase II trial of high-dose
therapy for patients selected for treatment failure to conventional
dose therapy on the basis of reduced clearance of tumor markers (prolonged
half-life of AFP >7 days, HCG >3 days). Twenty-two of 28 poor-risk
patients in the trial received conventional-dose VAB-6 followed by high-dose
carboplatin and ABMT. Twelve achieved a CR. The study suggested a trend
toward improved survival for the patients treated with HDCT compared
to a historical population of poor-risk patients.
Simultaneously,
the group at MSKCC treated 13 patients in first relapse or with refractory
disease with a similar treatment protocol including HDCT.48
Those patients who received the upfront HDCT had less hematologic toxicity.
The number of days to granulocyte recovery to 500 was 16 in the upfront
group vs 22 in the refractory/relapse group. Likewise, platelet recovery
to >50,000 was shortened to 15 days compared with 23, respectively.
In addition, there were fewer episodes of culture positive sepsis (12%
vs 26%, respectively). The only death occurred in the relapse group.
These data suggested that early use of HDCT in a poor-risk population
had a better toxicity profile and might result in a better outcome.
While
some patients with resistant testis cancer respond to HDCT, the exact
algorithm for use of this modality is not definitively established.
Two trials that are underway may help to resolve the issue. In Europe,
the use of HDCT with ASCR as consolidation therapy to conventional salvage
chemotherapy is being evaluated. Patients in first relapse or with incomplete
response to initial therapy will receive 2 cycles of “standard” ifosfamide-based
therapy with either VIP or VeIP. Those patients with chemosensitive
tumor will then be randomized to two additional courses of conventional-dose
chemotherapy (arm A) or an additional cycle of conventional-dose therapy
followed by a single course of HDCT with carboplatin, etoposide, and
cyclophosphamide (Fig 2). In the United States, an Intergroup trial
is assessing the value of HDCT as first-line therapy in patients with
poor- or intermediate-risk disease. Patients will be randomized upfront
to receive 2 cycles of standard BEP followed by tandem HDCT with ASCR
or 2 additional cycles of conventional-dose BEP therapy (Fig 1). Since
there is a definite salvage of patients with second or subsequent relapse,
high-dose therapy would appear at present to be the most optimal salvage
therapy for such patients, although the durable remission rate is small.
 |
| Fig
2.— Kaplan-Meier disease-specific survival plots by 1997 TNM
staging classification for patients who had a partial vs radical
nephrectomy from 1987 to 1997 (operative deaths excluded in each
group). |
The various studies of HDCT have defined a number of prognostic factors.
Patients with progression of disease entering HDCT fair poorly.49
Likewise, patients with primary mediastinal nonseminomatous disease
are rarely salvaged with HDCT stategies.39,50 Incomplete
response to first-line therapy predicts for a poorer outcome. In some
trials, the degree of elevation of the serum tumor markers AFP (>1,000
ng/mL) or HCG (>10,000 mIU/mL) as well as the presence of lung metastases
were poor prognosis predictors.51,52
Primary
Chemotherapy for Stage II Disease
In
the era before the advent of effective chemotherapy, the standard of
care for patients with stage I or II disease was immediate retroperitoneal
lymph node dissection (RPLND). Perhaps the largest series of patients
undergoing RPLND has been reported by investigators at Indiana University.53
Between 1965 and 1989, the procedure was performed on 1,180 patients;
174 patients were considered to have clinical stage II disease. However,
at surgery, 41 (23%) had no evidence of disease in the lymph nodes examined.
Reviewing the data of 140 patients with clinical stage II disease treated
between 1979 and 1989 in the cisplatin chemotherapy era, 108 patients
had documented retroperitoneal disease. Forty-nine patients received
no adjuvant therapy, of which 18 (37%) relapsed and thereafter required
chemotherapy. The remaining 59 patients received immediate cisplatin-based
chemotherapy. While the overall survival of this patient population
was 98%, only 31 patients received monotherapy, ie, surgery alone.
These
results may be compared to reports from a number of centers54-56
using primary chemotherapy for stage II disease. The survival in these
studies ranged from 96% to 97%, which is comparable to the primary surgery
series. The incidence of surgery was 22%, 25%, and 29.5% from the M.D.
Anderson Cancer Center, the Mayo Clinic, and the Royal Marsden Hospital,
respectively. While 36 of 122 (29.5%) patients in the series by Horwich
et al56 required postchemotherapy surgery, only 1 specimen
contained viable tumor, 29 teratoma. The incidence of surgery postchemotherapy
is related to the size of the initial tumor — 39% of patients with stage
IIB disease (tumor that was more than 2 cm but less than 5 cm) were
taken to surgery, whereas only 17% patients with stage IIA disease (less
than 2 cm) had a residual mass. In addition, the presence of teratoma
in the primary tumor more likely predicted for teratoma in the retroperitoneum.
Thus, in the M.D. Anderson experience, 34% of patients with initial
teratoma were ultimately taken to surgery, while only 8% of patients
with embryonal cell carcinoma without teratoma in the primary specimen
required surgical intervention. Therefore, monotherapy is possible in
at least 70% of patients with stage II disease who are initially treated
with chemotherapy with an equivalent outcome to primary surgery.
In
a report from the Brigham and Women’s Hospital and the Dana-Farber Cancer
Institute,57 all patients with marker-positive disease only
who were subjected to primary RPLND ultimately required chemotherapy
thereafter.
These
reports confirm that the survival for patients with stage II testicular
cancer is high and essentially equivalent with either primary chemotherapy
or initial surgery. Those patients with marker-positive disease should
always be treated with chemotherapy as this subgroup is rarely cured
by surgical techniques alone. Patients with pure embryonal cell carcinoma
have a low incidence of surgery postchemotherapy and also are likely
to require only one modality for successful outcome. Those patients
with initial large volume disease or teratoma in the primary are most
likely to undergo surgery but even in these groups the overall incidence
of surgery is approximately 34% to 39%. This number represents an upper
limit since continued study has suggested that not all patients with
residual masses must be subjected to surgery. The size of the residual
mass as a percentage of the original size is predictive of the presence
of residual viable tumor. As such, some patients without complete radiological
response may be followed since the likelihood of teratoma or viable
tumor is low.58
The
approach at our institute favors primary chemotherapy for stage II metastatic
disease. Since all of those patients considered appropriate for surgical
intervention will by definition have good-risk disease, treatment consists
of 3 cycles of BEP.
Primary
Chemotherapy for Stage I Nonseminomatous Disease
Therapy
after orchiectomy for clinical stage I patients (those with normal markers
and negative tomographic studies) classically has been retroperitoneal
node dissection. Numerous reports of surveillance programs59-62
have established the risk of relapse in stage I patients of approximately
30%. Thus a policy of immediate surgery is of no value for the 70% who
will never have metastatic disease. The nearly universal salvage of
patients who relapse on surveillance63 has resulted in a
shift in this country to the option of surveillance for stage I disease.
However, to maintain excellent outcome, surveillance requires meticulous
follow-up and should not be advocated in situations were compliance
is questionable.
Studies
of patients who relapse on surveillance identify factors that increase
the risk of relapse: the presence of lymphatic or vascular invasion,
the lack of yolk sac elements, the presence of embryonal cell carcinoma,
the stage of the primary tumor, or the elevation of markers prior to
orchiectomy.63-66 In the review by Freedman et al65
of 259 surveillance patients, the presence of any three of the first
four factors resulted in a risk of relapse of 58%. Two factors were
associated with a risk of relapse of 24%, and one factor was associated
with a risk of relapse of 10%. Vascular invasion of any type was associated
with a risk of relapse of 45%.
Using
the four criteria above to identify high-risk patients, the Medical
Research Council of the United Kingdom treated patients with any three
of the four factors with 2 cycles of adjuvant chemotherapy with BE360P.67
Only 2 of 114 patents developed recurrent disease at a median follow-up
of four years, one of whom did not have a germ cell tumor on review
of the primary pathology. Ninety three (82%) have been followed for
more than two years. Similarly, Bohlen and colleagues68 reported
on the outcome of 58 high-risk clinical stage I patients treated with
adjuvant chemotherapy consisting of 2 cycles of PVB or BEP. All patients
have been followed for more than 32 months. Of the 58 patients, 56 have
survived without relapse, 1 relapsed with teratoma only at 22 months,
and 1 patient represents a case of late relapse 7.5 years after chemotherapy.
A short course of adjuvant chemotherapy appears to be highly effective
in reducing the risk of recurrence in a high-risk population.
While
the short-term toxicities are manageable, the long-term risks are unclear.
The effects on fertility, risk of hypertension, and lung toxicity need
to be assessed. Primary chemotherapy for clinical stage I disease may
be considered in patients who are at high risk for failure on surveillance
and who are judged to be either poorly compliant with follow-up or psychologically
incapable of handling a no-treatment strategy.
Long-term
Treatment Toxicity
The
high cure rate achievable for the majority of patients with testicular
cancer treated with chemo therapy has led to a large number of patients
who have survived years after therapy, allowing for the assessment of
long-term treatment complications or toxicity. These predominantly fall
into five categories: neurologic, pulmonary, vascular, reproductive,
and hematologic.
Boyer
et al69 reported an incidence of high-frequency hearing loss
in 77% of patients tested at least four years after therapy; 50% had
evidence of peripheral nerve damage by electrophysiologic testing. Symptomatic
findings were uncommon. Decreased single breath diffusing capacity for
carbon monoxide was noted in 20%, all of whom were smokers. No apparent
increased risk of ischemic heart disease was noted. Stoter et al70
reported an incidence of hypertension in 16%, Raynaud’s phenomenon in
23%, and ototoxicity in 25%. These results were derived from a questionnaire
and retrospective review of patient charts and are a reasonable estimate
of symptomatic toxicity.
While
reduced spermatogenesis has been reported by various investigators even
prior to the initiation of chemotherapy, recovery occurs in at least
half of the patients. In a study of 54 patients treated with chemotherapy
and surgery, 72% were either azoospermic or oligospermic prior to therapy.
Interestingly, only 48% had azoospermia or oligospermia after therapy;
however, the percentage of patients who were azoospermic had increased
to 28% from a pretreatment incidence of 4%.71 With modern
fertility techniques, it is estimated that that nearly three quarters
of the survivors could potentially father children. The incidence of
congenital malformations is not apparently increased.
Recent
reports72 suggest a risk of leukemogenesis associated with
etoposide therapy. These data derive primarily from the HDCT treatment
groups with a cumulative drug dose of greater than 2 g/m2.
This increased risk affects only 1.3% of all patients who receive drug
dose in this range. The risk of leukemia with conventional doses of
etoposide chemotherapy is 0.4% to 0.6%, which is small compared to the
curative potential of the treatment.73 Secondary solid tumors
are not associated with treatment with chemotherapy alone, but they
appear to be attributed to exposure to radiation therapy.74
Overall,
the long-term toxicities associated with curative therapy for testicular
cancer are modest and manageable, and most patients are able to return
to normal functional status.75
Conclusions
With
the present state of the art, a high percentage of patients with metastatic
testicular cancer can be cured with acceptable long-term toxicity. Those
patients with good-risk parameters require only 9 weeks of multiagent
(BEP) chemotherapy to achieve disease-free status in greater than 90%
of cases. At present, the best treatment for patients with poor-risk
disease remains 12 weeks of BEP. However, with this therapy, at least
one third of patients will not achieve a remission. Studies of newer
agents in combination with standard drug therapy and/or the integration
of high-dose therapy into first-line treatment represent present strategies
to increase the survival of patients in this subgroup.
Salvage
therapy with conventional-dose ifosfamide-based chemotherapy or HDCT
without induction therapy yields durable remissions in a minority of
patients. Ongoing studies may help to identify those patients who will
benefit by intensive-dose strategies. Newer agents such as gemcitabine
and paclitaxel hold promise of future treatment success.
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From
the Division of Hematology/Oncology at the William J. Harrington Center
for Blood Diseases, University of Miami Sylvester Cancer Center, Miami,
Fla.
Address
reprint requests to Pasquale Benedetto, MD, Division of Hematology/Oncology,
William J. Harrington Center for Blood Diseases, 1475 NW 12th Ave (D8-4),
Miami, FL 33136.
No
significant relationship exists between the author and the companies/organizations
whose products or services may be referenced in this article.