Testicular cancer is one of the therapeutic triumphs of the 20th
century. Long before cisplatin (Platinol) was first used in patients
with testicular cancer, radiation therapy was the standard treatment
for patients with seminoma. The noted sensitivity of seminoma to
radiation led to its routine use, even in advanced disease. Most
patients with stage II disease (and, as mentioned by Fiveash and
Sandler, even some patients with stage I disease) received
prophylactic mediastinal radiotherapy.
With the advent of cisplatin-based combinations for nonseminomatous
germ cell tumors, chemotherapy also proved successful in treating
metastatic seminoma. Numerous studies have suggested that seminoma
may be even more chemosensitive than is nonseminoma when compared
stage for stage. Consequently, the newer international staging system
does not consider any patient with seminoma to have advanced (or
Despite these successes, several unresolved issues remain in the
treatment of seminoma, particularly in early-stage disease. This
article does a fine job of outlining these issues and presenting a
balanced discussion of the treatment alternatives.
Radiation Therapy: Balancing the Risks vs Benefits
In large part, this article balances the sins of omission with the
sins of commission. Phrased more specifically, it seeks to answer the
question, does radiation therapy potentially cause as many problems
as it solves? To clarify this issue, it is useful to delineate the
natural history of clinical stage I seminoma.
Several published series of surveillance conducted in patients with
stage I seminoma report relapse rates of approximately 17% (as shown
in the authors Table 2), with
a range of 8.7% to 33%. Thus, if all patients with clinical stage I
were given prophylactic adjuvant chemotherapy, over 80% would receive
such therapy needlessly.
The same argument can be made against the need for primary
retroperitoneal lymph node dissection in patients with stage I
nonseminomatous germ cell tumors. A principal difference between
these two local treatment approaches is that long-term toxicity is
not commonplace in patients undergoing retroperitoneal lymph node dissection.
Both retroperitoneal lymph node dissection and radiation therapy are
associated with morbidity in patients with early (stage I) testicular
cancer. In large part, the side effects of retroperitoneal lymph node
dissection are apparent shortly after the procedure. One of the
principal toxicities, retrograde ejaculation, has been largely
abrogated by the use of nerve-sparing dissections. This approach
still entails the potential risk (albeit small) of complications from
anesthesia and necessitates recovery from surgery. Other long-term
complications are infrequent.
In contrast, radiation therapy to the peri-aortic lymph nodes has
relatively few short-term complications but a certain risk for
long-term complications, such as secondary malignancies, infertility,
and cardiovascular events.
Treatment Alternatives for Early-Stage Disease
In both seminoma and nonseminoma, the success of cisplatin-based
combination chemotherapy has provided a "safety net" that
has enabled researchers to explore treatment alternatives for
early-stage disease. Modifications in systemic therapy have been a
product of numerous prospective, randomized trials, which have
extended our understanding of the optimal and minimal therapy needed
to achieve high cure rates in patients with disseminated disease. In
the last few years, several trials have shown that there is a minimal
threshold that must be crossed in order to achieve therapeutic success.
For example, prospective, randomized trials have demonstrated that
lowering the dose of cisplatin is associated with a worse outcome.
Also, when three cycles of cisplatin and etoposide are given rather
than the three-drug combination of bleomycin, etoposide, and Platinol
(BEP), the omission of bleomycin is associated with a decrease in
relapse-free survival. Finally, the substitution of carboplatin
(Paraplatin) for cisplatin in combination regimens also has been
shown to worsen therapeutic outcome.
In summary, these trials have suggested that the minimal therapy for
patients with favorable-prognosis disseminated germ cell tumors is
three cycles of BEP or four cycles of cisplatin plus etoposide.
Some of the same questions about modifying therapy surround the
management of stage I seminoma. As Fiveash and Sandler point out,
these issues relate to radiation doses and fields, surveillance, and
adjuvant chemotherapy for stage I disease.
Radiation Doses and Fields
With respect to radiation dose and schedule, the authors do an
excellent job of summarizing the many single- and multi-institution
studies that have been performed. Particularly pertinent are the side
effects associated with radiation therapy, which can potentially be
avoided by minimizing field size and decreasing radiation doses.
Problems associated with infertility, cardiovascular toxicity,
gastrointestinal toxicity (including peptic ulcer disease), and
second malignancies (including solid tumors and leukemia) are all
seen with much higher frequency in patients who receive radiation therapy.
These problems have led investigators to evaluate lower doses of
radiation therapy and decreased field size. The obvious benefits of
this strategy are a decrease in the extent of irradiation of bone
marrow, a favorable impact on spermatogenesis, and, perhaps, a
decrease in the risk of secondary tumors. Obviously, however, there
is a minimal threshold of radiation that is necessary to achieve
tumoricidal effects. Clinical trials evaluating radiation fields and
doses, which are currently underway in Europe, are to be commended.
Pros and Cons of Surveillance
As mentioned above, with chemotherapy functioning as a successful
safety net for patients with early-stage germ cell tumors,
surveillance would appear to have a potential role in the management
of clinical stage I seminoma. As the authors discuss, cumulative data
suggest that patients who are managed with observation rather than
primary radiotherapy have about a 17% risk of developing a recurrence
and a long-term survival rate of approximately 97%.
These data can be looked at in two different ways. First, only 3 out
of 100 patients with clinical stage I disease would be expected to
die from the disease. However, for patients who develop a recurrence,
the chances of dying are approximately 18% (3 ÷ 17%). Although
infrequent, some patients may develop recurrent disease that is more
advanced and, as a consequence, less likely to be cured by
chemotherapy. The potential disadvantage of surveillance for
seminomas is that, unlike nonseminomatous germ cell tumors, serum
markers are not reliably elevated. Thus, there is a need for greater
dependence on noninvasive radiographic studies, such as CT scans, for screening.
A potential benefit of surveillance is that only those patients who
are destined to develop a recurrence receive radiation therapy. Thus,
one can spare patients who do not need therapy additional long-term
morbidity. It should be emphasized that the best results of
surveillance have been achieved in patients who are quite meticulous
about complying with follow-up evaluations. Surveillance is not meant
to be a substitute for radiation therapy in patients who are not
willing or able to undergo routine follow-up CT scans.
Role of Adjuvant Chemotherapy
The final issue in early-stage seminoma is the role of adjuvant
chemotherapy in clinical stage I disease. Potential advantages of
chemotherapy are that it avoids the potential long-term side effects
of radiation therapy and that it may decrease the incidence of
car-cinoma in situ (although the latter advantage has been hotly
debated). The therapeutic outcome of patients treated with adjuvant
chemotherapy appears to be comparable to that achieved with radiation
therapy or with surveillance.
Major objections to the use of single-agent carboplatin or cisplatin
stem from observations made in the systemic treatment of
nonseminomatous germ cell tumors (highlighted above). Does the choice
of drugs, dose, and number of cycles of therapy make a difference? I
believe so, as has been proven in other prospective trials conducted
in large numbers of patients.
By definition, of 100 patients with clinical stage I disease treated
with totally ineffective therapy, 83% will achieve long-term survival
because they are true pathologic stage I patients. Thus, the
denominator of treated patients who could possible be affected by
therapy is only 17. A drug that is 90% effective will cure 15 out of
17 patients, an 80% effective drug will cure roughly 13.6 patients,
and a 70% effective drug will cure 12 patients. Thus, the difference
between 90% efficacy and 70% efficacy amounts to 3 patients (15
patients 12 patients).
Thus, one is unlikely to find a statistically significant difference
between therapies unless large numbers of patients are entered into
clinical trials. Nonetheless, virtually 99% to 100% of patients with
clinical stage I disease should be cured, either by primary radiation
therapy or salvage chemotherapy. One should be cautious in
recommending "minimal therapy" for patients unless
prospective, randomized trials have proved therapeutic equivalents.
No such trial has been conducted to date, and until one is done, it
is my strong belief that primary chemotherapy should not be
considered a therapeutic option, except in very rare circumstances.
When chemotherapy is used, it is logical to prescribe the drug
combinations and schedules that have proven most effective in
advanced disease, rather than single-agent therapy.
As we survey the therapeutic options for patients with clinical stage
I seminoma, we can feel comfortable that the vast majority of
patients will have a normal life expectancy. Nonetheless, as these
authors have thoughtfully done, we must also be cognizant of the
long-term sequelae of our therapies. The success and failure of our
therapeutic approaches can no longer be measured in the time frame
surrounding therapy, but rather, in the lifetime of the patient.