Primary chemotherapy

In distinction to adjuvant chemotherapy given to men who have PS II disease after RPLND, primary chemotherapy refers to treatment administered to men who have CS I NSGCT after orchiectomy. The goal of primary chemotherapy is to minimize the risk for relapse and to allow men to avoid RPLND and the longer course of chemotherapy administered for patients who relapse on surveillance. The rationale underlying this approach derives from the 30% relapse rate seen during surveillance and the 20% to 25% risk for needing systemic chemotherapy after RPLND given either as adjuvant therapy for PS II disease or as treatment of relapse [8,9,12,41]. Primary chemotherapy offers patients the greatest chance of being relapse-free with any single treatment modality. Only limited long-term follow-up data are available, however, and there are lingering concerns about the potential risk for late chemotherapy-refractory relapses and late chemotherapy toxicity.

Primary chemotherapy has been investigated in at least nine case series and phase II trials, almost all of which have used two cycles of BEP chemotherapy (Table 4) [42]. Primary chemotherapy using two cycles of BEP has been associated with excellent outcomes in men who have early-

stage, high-risk NSGCT, but only limited long-term follow-up data are available [43,44]. In such patients, it is possible to reduce the recurrence rate from 30% to 60% down to about 2.5%. Many European institutions prefer BEPx2 to RPLND [45].

The largest three trials of primary chemotherapy were conducted in the United Kingdom (UK). The Medical Research Council (MRC) prospectively evaluated 114 patients who had CS I NSGCT who were estimated to have 50% or higher risk for relapse based on having at least three MRC risk factors [43]. MRC prognostic factors had been validated in a prospective surveillance trial and included vascular invasion, lymphatic invasion, absence of yolk sac elements,

Table 4

Published reports of primary chemotherapy for clinical stage I nonseminomatous germ cell testicular cancers

Table 4

Published reports of primary chemotherapy for clinical stage I nonseminomatous germ cell testicular cancers

Median

Risk

Chemotherapy

follow-up

Number

Relapse interval

Deaths from

Reference

Patients

factors

regimen

(months)

of relapses

(months)

testis cancer

Abratt

20

R2 MRC

2 cycles BEP

31

0

0

et al [51]

risk factors

(E 360)

Cullen and

114

R3 MRC

2 cycles BEP

48

2a

7, 18a

2b (1.8%)

James [42]

risk factors

(E 360)

Pont

74

LVI

2 cycles BEP

70

2

8, 27

1 (1.4%)

et al [52]

(E 500)

Ondrus

18

LVI

2 cycles BEP

36

0

0

et al [49]

(E 360)

Amato

68

LVI, AFP >80,

2 cycles CEB

38

1

21

0

et al [27]

>80% EC

(E 360)

Bohlen

58

LVI, EC,

2 cycles BEP

93

2

22, 90

0

et al [44]

2 PVB (20 pts)

Chevreau

40

LVI EC

2 cycles BEP

113

0

0

et al [50]

(E 360) 2 PVB (2 pts)

Oliver

148

R2 MRC risk

1 cycle BEP

33

6

Not reported

7 (1.4%)

et al [48]

factors

(n = 28); 2 cycles BEP (46 pts) or 2 cycles BOP (n = 74) (E 360)

Dearnaley

115

LVI

2 cycles BOP

70

3c

3, 6, 26c

1 (0.9%)

et al [53]

Pooled data

655

N/A

16 (2.4%)

7 (0.9%)

Abbreviations: AFP, a-fetoprotein; BEP, bleomycin, etoposide, cisplatin; BOP, bleomycin, vincristine, cisplatin; CEB, carboplatin, etoposide, bleomycin; E 500, etoposide dose of 500 mg/m2/cycle; E 360, etoposide dose of 360 mg/ m2/cycle; EC, embryonal carcinoma; LVI, lymphovascular invasion; MRC, Medical Research Council; N/A, not available; PVB, cisplatin, vinblastine, bleomycin.

a The original testis tumor in the patient who suffered the second relapse in this study was reclassified as adenocar-cinoma of the rete testis on central pathology review blinded to outcome.

b One death was caused by recurrent cancer and the other resulted from an ischemic stroke during chemotherapy. c It is unclear whether the third relapse in this study was a true relapse; the lesion was only biopsied after salvage chemotherapy and no neoplasm was identified. We have counted it as a relapse.

and presence of embryonal carcinoma [46,47]. With 4 years median follow-up, two men (1.7%) were reported to relapse at 7 and 18 months. The Anglian Germ Cell Tumor Group studied 382 men who had intermediate- or high-risk NSGCT who underwent either surveillance (234 men) or primary chemotherapy using either two cycles of bleomycin, vincristine, and cisplatin (BOP) or one or two cycles of BEP (n = 148). After a median follow-up of 33 months, 6 chemotherapy patients (4%) relapsed, including 6.5% after one cycle of BEP, 3.6% after two cycles of BEP, and 2.7% after BOP [48]. In contrast 30% of patients assigned to observation subsequently relapsed after a median follow-up of 83 months. The introduction of adjuvant treatment for the high-risk patients made it possible to reduce the overall relapse rate of the total cohort of patients who had CS I disease from 36% to 15.7% (P<.001). A second trial evaluating two cycles of BOP in 115 British and Norwegian men who had an elevated risk for relapse based on the presence of vascular invasion reported three relapses (2.6%) after a median follow-up of 70 months.

Combining data from these three trials and six other published studies, a total of 655 men received primary chemotherapy (see Table 4) [27,44,49-52]. Sixteen relapses (2.4%) were documented. Six men (0.9%) died of testis cancer. Four reports including 287 subjects had a median follow-up of at least 70 months and reported 7 (2.4%) relapses and 2 (0.7%) deaths from testis cancer [44,50,53]. In these four studies, the median time to relapse was 22 months. A lingering question is whether long-term follow-up will reveal an increased rate of late relapses after primary chemotherapy because of unresected retroperito-neal teratoma, but insufficient data exist to address that question at this time. The available data suggest that primary chemotherapy is associated with much lower relapse than RPLND (2.5% compared with 6% to 30% depending on the presence of high-risk features) with no significant difference in disease-specific survival.

Adverse effects of primary chemotherapy

Almost all men who have CS I NSGCT become long-term survivors and therefore the toxicities associated with treatment represent a prominent issue. Short- and long-term side effects from BEP and other cisplatin-based germ cell tumor regimens are well documented but the vast majority of the data comes from patients who have received a minimum of three cycles of treatment. Data from men receiving two cycles of chemotherapy are sparse. Among men receiving three or more cycles of BEP or cisplatin, vinblastine, and bleomycin (PVB), Raynaud phenomenon (30%), sensory peripheral neuropathy (20%), ototoxicity (20%), long-term renal toxicity (20% reduction in creatinine clearance, persisting hypomagnesemia or hypophosphatemia) are the most commonly reported side effects [54]. Among men receiving two cycles of BEP or BOP, 8% to 19% report long-term grade I/II neurotoxicity or ototoxicity [31,48,53]. Organ function testing after two cycles of cis-platin-based chemotherapy has documented a median 5dB hearing loss at 8 kHz (P = .008), a 5% reduction in DLCO (P = .03), and a 9% decline in glomerular filtration rate (P = .014) [53]. The clinical significance of these changes has not been established. The impact of two cycles of BEP or BOP chemotherapy on fertility seems to be small to nonexistent, but few data are available [53].

Long-term survivors of testicular cancer who have received three or more cycles of cisplatin-based chemotherapy are at risk for cardiac events and an unfavorable cardiovascular risk profile. The major cardiovascular issues that have been studied in connection with treatment of testicular cancer include metabolic syndrome [55-57], early atherosclerosis and coronary artery disease [58-60], Ray-naud phenomenon [61,62], and thromboembolic events [63]. A large British study with a median follow-up of 10.2 years reported a relative risk of 2.59 for cardiac events with cisplatin-based chemotherapy, independent of cardiac risk factors [59]. Moreover, a recently published Dutch large series in 2512 5-year survivors of testis cancer reported a 1.9-fold and 1.5-fold increased cardiovascular disease risk with PVB and BEP regimens, respectively, after a prolonged follow-up of 18.4 years [60]. Whether such complications ensue from only two cycles of chemotherapy is unknown. We have found no reports of clinically significant pulmonary toxicity following two cycles of BEP or BOP.

Germ cell tumor chemotherapy also poses a risk for secondary malignancy. An international cancer registry study of 40,576 testis cancer patients reported that 10-year survivors who had been treated with chemotherapy had an 80% increased risk for developing non-germ cell solid tumors compared with the general population. Because this study compared chemotherapy recipients to the general population rather than to testis cancer patients who did not receive chemotherapy, however, the study was unable to distinguish the extent to which the excess cancers resulted from treatment as opposed to an inherited or acquired predisposition to cancer [64]. Cisplatin and etoposide are leukemogenic and the risk is dose related. Following a typical three- or four-cycle course of BEP, the incidence of secondary leukemia is less than 0.5% [65]. The risk associated with two cycles of chemotherapy is unknown.

Long-term side effects from chemotherapy underlie much of the opposition to primary chemotherapy in the United States. Studies of men who have received three or more cycles of germ cell tumor chemotherapy have clearly demonstrated a risk for severe late complications but future studies will need to define whether two cycles of chemotherapy poses similar dangers.

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