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Controversies in the Management of Stage I Seminoma

Controversies in the Management of Stage I Seminoma

ABSTRACT: Current controversies in the treatment of stage I seminoma center on the relative roles of surveillance, adjuvant radiotherapy (RT), and adjuvant single-agent chemotherapy. Surveillance has been studied in over 800 patients, 17.1% of whom have relapsed. There is no evidence that surveillance compromises survival in properly selected, compliant patients. The economic benefit of treating only those patients who relapse is offset by the cost of screening diagnostic studies and salvage therapy, and by issues of patient anxiety and compliance. Other methods of reducing the toxicity of RT include reductions in RT dose and volume. A randomized trial has shown that omission of the pelvic field produces relapse-free survival equivalent to that achieved with pelvic plus para-aortic RT. A similar study is currently evaluating a reduction in RT dose from 30 to 20 Gy. Early results from nonrandomized studies of one or two cycles of single-agent chemotherapy demonstrate efficacy comparable to RT in the adjuvant treatment of stage I seminoma. A randomized trial is underway to determine the equivalence of adjuvant carboplatin (Paraplatin) and RT. Long-term follow-up from these studies will provide information not only on the relative efficacy of these alternative strategies but also on the late effects of therapy, including infertility and second malignancy.[ONCOLOGY 12(8):1203-1214, 1998]

Introduction

In the United States, an estimated 7,200 new cases of testicular
cancer were diagnosed in 1997, but only 340 deaths were attributable
to this cancer.[1] Seminoma represents about 50% of all germ-cell
tumors and is the most common histologic type of testicular cancer.
Seminoma has long been recognized as a radiosensitive and
chemosensitive neoplasm.

Stage I testicular cancer includes all patients without lymph node
involvement or distant metastatic spread (T1-4 N0 M0) and represents
70% of all cases of seminoma.[2] A new staging system for testicular
cancer now includes the presence of vascular lymphatic invasion and
marker elevation, as shown in Table 1.
The stage groupings have also been modified in this new system.

The management of stage I testicular cancer has followed the lead of
other successfully treated cancers, including Hodgkin’s disease
and various pediatric malignancies. The primary end point of many
ongoing studies in these tumors is not to improve efficacy, but
rather, to lessen toxicity from equally effective therapies. Several
older studies have shown that the mediastinum can be omitted from the
treatment volume of irradiated patients, even those with stage IIA
disease, thus eliminating the potential toxicity associated with
thoracic radiotherapy (RT).

The management of stage I seminoma continues to evolve. Currently,
there are significant controversies regarding the relative roles of
adjuvant RT, surveillance, and adjuvant single-agent chemotherapy.
This review focuses on the changing management of this very curable
neoplasm and addresses the results and toxicity of standard-volume
RT, reduced-volume RT, surveillance, and adjuvant single-agent
chemotherapy after orchiectomy. Potential salvage therapies for rare
primary treatment failures are also discussed.

Standard Adjuvant Therapy: Para-aortic and
Pelvic RT

Standard therapy for all patients with early-stage seminoma includes
radical inguinal orchiectomy with high ligation of the spermatic
cord. Scrotal violation has never been shown to compromise survival,
but may preclude patients from the option of postoperative
surveillance and may alter RT volumes, leading to the delivery of
unnecessary dose to normal tissues, including the remaining testicle.
Any additional therapy besides orchiectomy in stage I seminoma is
adjuvant in nature and is designed to treat subclinical nodal or
micrometastatic spread.

Radiation therapy has been a standard adjuvant treatment for
early-stage seminoma. The patterns of dissemination include
progressive spread from the retroperitoneum to the mediastinum and
supraclavicular lymph nodes. This was the rationale for
extended-field RT in early-stage seminoma, which often included
elective treatment of the mediastinum and supraclavicular lymph
nodes. Prior to the advent of cisplatin (Platinol), extensive-field
RT cured a significant number of patients, even those with lymphadenopathy.

Hanks et al found that 27% of patients with clinical stage I seminoma
treated in the US Patterns of Care Study received supradiaphragmatic
RT, and more than half received subdiaphragmatic doses > 30 Gy.[3]
In the Norwegian Radium Hospital series (1970 to 1982), radiation was
delivered to a median dose of 40 Gy prior to 1980, with only one
field treated each day.[4] Since current RT doses and volumes are
much lower, interpretation of the toxicity data from series with the
longest follow-up must take this into account.

Efficacy

Table 2 summarizes the relapse-free
survival rates of stage I seminoma patients treated with standard
ipsilateral pelvic and para-aortic RT in several studies.[3-11] Many
of these reports included some patients treated in the 1950s and
’60s. Overall, about 95% to 97% of patients were relapse-free
after standard adjuvant RT. Most of the deaths from seminoma in these
series occurred in the precisplatin era. The patterns of failure
after RT indicated that seminoma is a very radiosensitive neoplasm.

Dosmann et al found no recurrences in the treatment field in 282
patients with stage I seminoma treated with adjuvant RT.[5] Similar
results have been seen in other institutions.[7]

Toxicity

Delayed toxicity after RT, although generally occurring at a low
frequency, is important given the high likelihood of disease control.
Toxic events related to RT include infertility, cardiotoxicity,
gastrointestinal toxicity, second neoplasms, and immunosuppression.

Infertility is an important issue for many men with seminoma.
The average patient with seminoma is approximately 35 years old.
Whether infertility is the result of surgery, adjuvant therapy, a
coexisting testicular abnormality, or a combination of all of these
factors is unknown.

Southwest Oncology Group (SWOG) trial 8711 prospectively followed 53
patients treated with orchiectomy and adjuvant pelvic and para-aortic
irradiation.[12] Over half (54%) of the patients with baseline sperm
counts were subfertile. Lower testicular doses (< 0.79 Gy) were
achieved when testicular shields were used, and this protection was
associated with beneficial effects on 1-year sperm counts. Sperm
count recovered 1 year after RT in the low-testicular-dose group but
was delayed in patients who received higher doses. Similar changes
were seen in serum follicle-stimulating hormone (FSH) concentration
but not in serum testosterone level.

Cardiotoxicity--Elective mediastinal RT was associated with an
excessive number of cardiac deaths in the Patterns of Care
series.[13] The cardiac toxicity of mediastinal RT was subsequently
confirmed in Hodgkin’s disease.

Elective mediastinal therapy has no role in stage I seminoma, as
relapse-free survival is excellent without it.[6] Only about 1.9% of
patients with clinical stage I seminoma treated with standard pelvic
and para-aortic RT will develop disease recurrence in the mediastinum
or supraclavicular lymph nodes.[14] In stage II seminoma, the risk of
mediastinal recurrence depends on the size of the para-aortic
metastasis. In general, mediastinal therapy has been abandoned in
patients with retroperitoneal tumors < 5 cm in favor of
preservation of bone marrow for salvage chemotherapy, and in order to
avoid late cardiac toxicity.

Gastrointestinal Toxicity--Late gastrointestinal toxicity has
been reported after irradiation to the abdomen. In 365 stage I
seminoma patients receiving relatively high doses of adjuvant RT,
Fosså et al described 9 patients who developed gastric
ulceration and 16 who experienced dyspepsia.[4] The median mid-plane
dose in this study was 40 Gy. More conventional regimens, such as
25.5 Gy in 17 fractions, should have significantly lower rates of
gastrointestinal toxicity.

Second Neoplasms--Much of the data on second malignancy after
pelvic and para-aortic irradiation comes from large population
registries or much smaller single-institution reports. Unfortunately,
since many of the larger studies lack details on treatment, the
relative contribution of RT is difficult to determine. Data are often
combined for seminoma and other types of germ-cell tumors.

These limitations notwithstanding, the long-term toxicity data
indicate that patients who have been irradiated for seminoma have a
higher rate of second malignancy than age-matched controls. Second
testicular tumors are probably not related to treatment, but rather,
stem from a predisposition to germ-cell neoplasms. This phenomenon
has been readily observed in patients with cryptorchid testes and has
also been confirmed by large population studies.

Wanderås et al updated the Norwegian Radium Hospital experience
with second germ-cell tumors, including 2,201 patients with primary
germ-cell tumors.[15] In 1,135 patients with seminoma, the cumulative
risk of a second germ-cell tumor was 3.4% at 15 years (relative risk
[RR], 27.7). Age may be an important risk factor for posttherapeutic
neoplasia. Patients diagnosed with a germ-cell tumor when they were
under 30 years of age had a cumulative risk of 7.8% at 15 years.

Hanks et al found 14 second tumors among 387 patients treated with RT
for stage I and II seminoma.[13] This corresponded to an 8% risk at
15 years (RR, 3.4). Of the 14 second malignancies, 2 were leukemias,
1 was an in-field melanoma, and 1 was a second testicular tumor. All
of the remaining malignancies were marginal or out-of-field tumors.

A large, population-based study from Denmark included 3,256 patients
with seminoma treated from 1943 to 1987 with various modalities.[16]
For all second malignancy sites, the overall relative risk was 1.5
compared to the expected incidence in the overall population. A
statistically significant increased risk was seen for cancers of the
stomach (RR, 1.9), colon (RR, 1.7), pancreas (RR, 2.1), kidney (RR,
2.2), and bladder (RR, 2.1); nonmelanoma skin cancer (RR, 1.8); and
leukemia (RR, 2.3). Only 1 of the 13 patients who developed leukemia
had received chemotherapy.

What cannot be ascertained from these studies is whether RT causes a
higher rate of second tumors, or whether seminoma patients are
predisposed to developing second tumors even without RT. Three
studies have compared the rate of second malignancy in patients who
did and did not receive RT.

In a large, population-based study of second non-germ-cell tumors in
patients from Norway, Wanderås et al found a relative risk of
1.58 (95% confidence interval [CI], 1.3 to 1.9) in patients who
received RT without chemotherapy, 3.54 (95% CI, 2.0 to 5.8) in
patients who received RT and chemotherapy, and 1.31 (95% CI, 0.4 to
3.4) in patients who received neither RT nor chemotherapy.[17] Even
when second germ-cell tumors were excluded in this study, the
relative risk of secondary malignancy was still greater than 1 in
patients treated with surgery alone, possibly indicating that these
patients are at an increased risk of second tumors even without
cytotoxic therapy, (although the 95% CI included 1).

The Connecticut Tumor Registry data combined with the Surveillance,
Epidemiology, and End Results (SEER) data of the National Cancer
Institute (NCI) included 9,739 patients with testicular tumors (all
histologies).[18] Ten-year survivors of seminoma were at increased
risk for cancers of the pancreas (RR, 3.23), kidney (RR, 3.22), and
bladder (RR, 2.94), as well as acute nonlymphocytic leukemia (RR,
5.77). This study confirmed the findings of the Norwegian population
study that excess second tumors occur at a higher rate in patients
treated with surgery alone (RR, 1.40).

Testicular cancer patients undergoing RT in the Netherlands had a
relative risk of 4.4 for a second gastric cancer.[19] No increased
risk was seen in patients who were treated with surgery alone, but
since there were so few cases of gastric cancer, the 95% confidence
intervals overlapped significantly. The relative risk of gastric
cancer did increase with follow-up interval, suggesting that RT had
some role in causation.

Unfortunately, follow-up from the more recent prospective
surveillance studies is not long enough for an accurate assessment of
second malignancies to be made. It is interesting to note that some
of the tumors ascribed to RT, such as gastric cancer, have been seen
in surveillance patients as well.[20]

Immunosuppression--Total lymphoid irradiation, as used in
Hodgkin’s disease, is chronically immunosuppressive.[21]
Alterations in CD4+ lymphocyte counts have been described in this
setting. Similar changes may occur after para-aortic and pelvic RT
for seminoma. Any role this potential immunosuppression may play in
the pathogenesis of second malignancies is unknown.

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