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motherapy, and metabolic syndrome with or without
hypogonadism, which is associated with increased cardiovascular
morbidity and mortality, is more frequent in men who
receive GCT chemotherapy. 16,17,18
To mitigate these risks, patients should be monitored after
chemotherapy for the onset of hypertension, obesity, hyperlipidemia,
and hypogonadism, with intervention at the earliest
opportunity. 19 Smoking cessation and weight reduction
are key to cardiovascular protection. If the oncologist will not
be following the patient long-term, then a primary care physician
should oversee general health maintenance.
Second Malignant Neoplasms
Patients with GCTs have an increased risk for second non-
GCT neoplasms after both radiation therapy (RT) and chemotherapy,
20,21 but not after surgery alone. 21 RT increases
the incidence of several intra-abdominal neoplasms, including
colon, pancreas, and stomach cancer. 20,22 Although surveillance
has largely replaced RT for CS I seminoma, RT
exposure is prevalent among survivors of GCT since most
received RT for seminoma before 2005, the year of the Travis
report. 20 Early screening colonoscopy should be considered,
as is recommended for survivors of childhood malignancy. 23
The lower bound of chemotherapy dose associated with the
risk for second non-GCT malignant neoplasms is unknown.
Therefore, the use of chemotherapy in the adjuvant setting,
particularly CS I-B NSGCT, has unknown long-term risks.
However, even the lowest doses of etoposide are associated
with an increased risk for leukemia, 24 suggesting that the
long-term effects of adjuvant administration, merits consideration.
Last, men with GCT are disproportionately likely to
have multiple atypical nevi and melanoma. 20,25 Although
melanoma is not caused by treatment, dermatologic referral
of patients with GCT and pigmented nevi should also be
considered.
KEY POINTS
Late effects of cisplatin-based chemotherapy for GCT are
known and should be discussed with all patients who
require it.
In good-risk disease, new guidelines list four cycles of
etoposide/cisplatin and three cycles of
bleomycin/etoposide/cisplatin as options for clinical stage
IIA and IIB seminoma.
Treatment outcome in patients with intermediate-, poorrisk,
and relapsed disease may improve because of recent
and ongoing trials.
Most data indicate that few GCTs display driver mutations
and a better knowledge of tumor biology is needed to
identify potential therapeutic targets.
Progress will require a national and international trial
effort including participation by community oncologists to
accrue adequate patients and tumor sample for studies.
SYSTEMIC THERAPY FOR METASTATIC DISEASE
Good Risk
Since 90% to 95% of patients with good-risk disease are
cured, improvements on three cycles of BEP (BEPx3) and
four cycles of EP (EPx4) are unlikely. The lower bound of
effıcacy is known and carboplatin is inferior to cisplatin in
both relapse rate and cure rate. 1 The management of CS IIA
and IIB metastatic seminoma with chemotherapy rather than
RT is evolving. Recent studies report no relapses among 20
patients with CS IIA disease and 22 patients with CS IIB disease.
26,27 Since RT leads to an increased incidence of intraabdominal
malignancy, and RT followed by chemotherapy
leads to an even greater likelihood of both late cardiovascular
and second cancer events than either modality alone, 28 primary
chemotherapy has been added to the National Comprehensive
Cancer Network guidelines for these two groups. 29
Intermediate and Poor Risk
Four trials suggest that better outcomes can be achieved in
patients with intermediate-risk and poor-risk disease, who
have cure rates of approximately 75% and 50%, respectively.
In the fırst trial, paclitaxel added to BEP in intermediaterisk
disease led to a signifıcant 12% improvement (p 0.03)
in 3-year progression-free survival when ineligible patients
were excluded, but a nonsignifıcant improvement in the
intent-to-treat analysis. 30
A second randomized trial comparing standard-dose BEP
with a dose intense regimen with stem cell support resulted in a
16% improvement in failure-free survival, which was not significant
(p 0.057). 31 Both trials were closed early because of slow
accrual, partly because of separation of intermediate-risk and
poor-risk groups into different studies, leading to nonsignifıcant
results despite trends suggesting improved survival.
A third randomized trial of standard BEPx4 compared with
a complex BEP-based regimen with paclitaxel, oxaliplatin, and
ifosfamide in patients with poor-risk disease and an unfavorable
tumor marker decline showed an improvement in 3-year
progression-free survival from 48% to 59% (p 0.05), but with
more grade 3 to 4 toxicity. 32
Finally, a phase II trial of four cycles of paclitaxel/ifosfamide/cisplatin
(TIPx4) demonstrated a 95% 3-year overall
survival and 79% 3-year progression-free survival. 33
Together, these results suggest that the outcome of
intermediate- and poor-risk disease can be improved. Since
three of these trials incorporated paclitaxel, a direct comparison
of TIPx4 to BEPx4 is now open at several institutions
(NCT01873326). A worse outcome when the half-life of either
alpha-fetoprotein (AFP) or human chorionic gonadotropin
(HCG) is prolonged was also demonstrated in an
intergroup study in which an improvement in 1-year survival
was observed in patients with slow marker decline from 34%
for BEPx4 to 61% for BEPx2 followed by two cycles of highdose
chemotherapy. 34 Thus, a randomized trial testing a new
regimen in patients selected for unfavorable marker decline
is reasonable. In both cases, the trials should be multicenter/
multinational and include and stratify for intermediate- and
poor-risk disease.
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