World Journal of Urology

, Volume 34, Issue 6, pp 853–857 | Cite as

Two cycles of adjuvant carboplatin in stage I seminoma: 8-year experience by the Hellenic Cooperative Oncology Group (HECOG)

  • Konstantinos Koutsoukos
  • Kimon Tzannis
  • Christos Christodoulou
  • Vasilios Karavasilis
  • Charalambos Bakoyiannis
  • Thomas Makatsoris
  • C. N. Papandreou
  • Dimitrios Pectasides
  • Meletios A. Dimopoulos
  • Aristotelis Bamias
Original Article

Abstract

Purpose

Following the establishment of adjuvant carboplatin in stage I testicular seminoma as a standard, we adopted this treatment for all stage I seminoma patients. We report our 8-year experience and compare these results with our previous adjuvant etoposide/cisplatin (EP) strategy.

Patients and methods

Patients with stage I seminoma, treated with adjuvant carboplatin and with a minimum follow-up of 1 year, were included. Two cycles of carboplatin [area under the curve (AUC) 6] were administered.

Results

A total of 138 patients with median age of 34 years, treated from September 2003 to December 2011, were selected. There were 5 relapses [5-year relapse-free rate (RFR) 96.8 % (95 % confidence interval 91.6–98.8)]: 3 relapses at retroperitoneal lymph nodes, 1 relapse at the adrenal gland, and 1 isolated brain metastasis. Four patients with relapse were cured with salvage chemotherapy. All patients with relapse had tumor diameter ≥4 cm and/or age ≤34 years. Patients with at least 1 of the above risk factors (n = 111) had a significantly higher relapse rate compared with a similar population (n = 64) treated with 2 cycles of adjuvant EP: 5-year RFR was 95 % (SE 2 %) versus 100 % (SE 0 %), (p = 0.067).

Conclusions

Age and tumor diameter were associated with relapse in stage I seminoma treated with adjuvant carboplatin. Although adjuvant carboplatin in patients with age ≤34 and/or tumor diameter ≥4 cm is associated with higher relapse rates than EP, the prognosis of these patients is excellent, and therefore, the use of less toxic treatment is justified.

Keywords

Seminoma Two cycles of carboplatin Stage I 

Introduction

Approximately 70 % of patients diagnosed with seminoma have stage I disease. Surgical treatment with inguinal orchiectomy is the standard of care. Although the overall outcome for these patients is excellent, with cure rates exceeding 95 % [1], the optimal post-surgery strategy is still debatable. Surveillance, chemotherapy, and radiotherapy are all acceptable options with different advantages and disadvantages but with the same excellent outcome.

Surveillance is a valid option since significant proportion of patients are spared unnecessary chemotherapy, but it has been associated with relapse rates of 15–20 % [2]. Moreover, active surveillance protocols require strict compliance for yearlong follow-up [3]. Most relapses following surveillance are observed at the retroperitoneum with a median time around 15 months [4] and are successfully treated by salvage chemotherapy, mostly with the BEP (bleomycin, etoposide, and cisplatin) regimen [5]. Although curative for most patients, salvage chemotherapy is associated with acute [6] and late toxicity [7] and psychological and financial burden [8].

Radiotherapy of retroperitoneal lymph nodes following orchiectomy results in relapse rates <5 % [9]. Adjuvant chemotherapy is used in stage I testicular seminoma with equal success. Updated results from a randomized trial confirmed the non-inferiority of chemotherapy with single dose carboplatin versus radiotherapy and also the reduction in metachronous contralateral germ cell tumors [10]. However, about 80 % of patients with early stage seminoma will receive unnecessary therapy [11], and all patients treated with chemotherapy will still require long-term post-treatment follow-up with computed tomography (CT) [12], although radiation exposure is expected to be lower than that for patients on surveillance protocols [13]. In order to minimize the administration of unnecessary adjuvant therapy, risk-adapted strategies, selecting for patients with high risk for relapse, have been studied [14]. The most commonly used risk factors have been tumor diameter (larger than 4 cm), rete testis invasion, and age [15].

We have previously reported a risk-adapted study for patients with stage I seminoma and a maximal diameter of at least 4 cm and/or younger than 34 years [16]. These patients were treated with two cycles of EP after orchiectomy, resulting in no relapses over a median follow-up of 60 months. Following the establishment of adjuvant carboplatin as a standard, we adopted this treatment for all patients with stage I seminoma, regardless of risk factors. The reason for this modification in our practice was mainly based on a more favorable acute toxicity profile [17] and (non-comparative) data, suggesting lower incidence of late toxicity by carboplatin [18]. We report our 8-year experience with adjuvant carboplatin and compare these results with our previous EP strategy.

Patients and methods

Patients

Patients included in this retrospective multi-institutional study fulfilled the following criteria: histopathologically proven testicular seminoma, no elevated alpha-fetoprotein preoperatively or postoperatively, stage I disease (as shown by negative findings on computed tomography scans of the thorax, abdomen, and pelvis and no elevation of beta-chorionic gonadotropin postoperatively) and a minimum follow-up of 1 year following completion of chemotherapy. All patients provided informed consent for the administration of chemotherapy and the use of their data for analysis. All patients were advised to undergo sperm collection and cryopreservation before the initiation of chemotherapy.

Treatment and follow-up

Chemotherapy was administered on an outpatient basis. Premedication with a serotonin antagonist with or without intravenous dexamethasone was given. Two cycles of carboplatin AUC 6 were administered intravenously. The dose was calculated by the formula: 6 × (Glomerular Filtration Rate [GFR, mL/min] + 25) mg. GFR was calculated by the Cockcroft–Gault equation [19]. The second cycle was administered on day 22 if the neutrophils were >1000/μL and platelets were >100,000/μL, and no grade 3 or 4 non-hematological toxicity was present. Otherwise treatment was delayed until recovery.

After treatment completion, patients were followed up with clinical examination and tumor markers (serum AFP, beta-hCG, and LDH) every 3 months for the first 2 years, every 6 months for the next 5 years, and yearly thereafter. Chest radiography and computed tomography of the abdomen and pelvis were performed at 6, 12, and 24 months.

Results

Adjuvant carboplatin results

From September 2003 to November–December 2011, 138 patients with stage I seminoma were treated at 11 Greek oncology centers with 2 cycles of carboplatin following orchiectomy. Their baseline characteristics are shown in Table 1. All patients had undergone inguinal orchiectomy. Their median age was 34 years, with 55 % being younger than 34 years. Median maximal tumor size was 4 cm with 51 % of patients having tumors larger than 4 cm, and 24 % had rete testis invasion.
Table 1

Baseline characteristics of 138 patients treated with adjuvant carboplatin for stage I seminoma

Characteristic

Carboplatin (n = 138)

EP (n = 64)

Age

 Median (year)

34

31

 ≤34 (year)

75 (55 %)

43 (67 %)

 >34 (year)

62 (45 %)

21 (33 %)

Tumor diameter

 Median (cm)

4a

6

 ≥4 cm

65 (51 %)a

55 (86 %)

 <4 cm

63 (49 %)

9 (14 %)

Rete testis invasion

 Yes

32 (24 %)b

9 (15 %)c

 No

100 (76 %)

52 (85 %)

Risk factors

 Age ≤34 only

41 (32 %)

19 (29 %)

 Tumor size ≥4 (cm) only

36 (28 %)

15 (24 %)

 Rete testis invasion only

7 (6 %)

Not available

 Age ≤34 or tumor ≥4 cm

111 (84 %)

64 (100 %)

 Tumor ≥4 cm or rete testis invasion

86 (67 %)

Not available

 Tumor ≥4 cm and rete testis invasion

11 (8 %)

Not available

aData available for 128 patients

bData available for 132 patients

cData available for 61 patients

All patients received 2 cycles of carboplatin with minor toxicities. Nausea/vomiting, anemia, and neutropenia of all grades were 14.5, 11.6, and 11.6 %, respectively. Only grade 3 toxicities reported were: neutropenia (n = 3) AST/ALT elevation (n = 1) and constipation (n = 1). No grade 4 toxicity or neutropenic infection was reported. All toxicities are listed in Table 2.
Table 2

Toxicities reported for 138 patients treated with 2 cycles carboplatin AUC 6 for stage I seminoma

Toxicity

Grade 1

Grade 2

Grade 3

Grade 4

Anemia

16 (12 %)

Neutropenia

7 (5 %)

6 (4.3 %)

3 (2.1 %)

Thrombocytopenia

6 (4.3 %)

3 (2.1 %)

Nausea/vomiting

18 (13 %)

2 (1.4 %)

AST/ALT elevation

10 (7.2 %)

2 (1.4 %)

1 (0.7 %)

Fatigue

6 (4.3 %)

1 (0.7 %)

Bilirubin increase

2 (1.4 %)

1 (0.7 %)

Constipation

2 (1.4 %)

1 (0.7 %)

1 (0.7 %)

Renal

1 (0.7 %)

Minimum follow-up was 12.3 months, while a minimum follow-up of 2, 3, 4, and 5 years had been completed in 81, 65, 49, and 38 %, respectively. There were 5 relapses (5-year RFR: 96.8 % [95 % CI 91.6–98.8]) (Fig. 1). Five-year RFR for patients with tumor ≥4 cm and/or rete testis invasion was 96.2 % (95 % CI 88.9–98.8), and it did not differ from that of patients without these factors (p = 0.628). Relapses were localized at: retroperitoneal lymph nodes (n = 3), left adrenal gland (n = 1), and isolated brain metastasis (n = 1). All patients with relapse had tumor diameter ≥4 cm and/or age ≤34 years. Two metachronous testicular seminomas were also reported, 9 and 11 years after the diagnosis of the first testicular cancer. They were both stage I and were managed with orchiectomy.
Fig. 1

Kaplan–Meier curve for relapse-free survival for 138 patients with stage I seminoma treated with 2 cycles of adjuvant carboplatin

The four of five relapsed patients were successfully treated with salvage chemotherapy; 2 patients received BEP (bleomycin, etoposide, and cisplatin) and 2 patients I-BEP (ifosfamide–BEP). They remain disease-free for 8 months, 2, 5, and 7 years, respectively, following relapse. The other patient was treated by radiotherapy to the brain metastasis and was subsequently lost to follow-up (Fig. 2).
Fig. 2

Kaplan–Meier curves for relapse-free survival for patients with stage I seminoma and tumor >4 cm and/or age <34 treated with carboplatin or etoposide/cisplatin

Comparison with EP-treated patients

Since all patients who experienced a relapse were either younger than 34 years or had a tumor larger than 4 cm, we compared the outcome of this subgroup (n = 111) with that of a similar population treated with 2 cycles of EP (n = 64) and had no relapses reported [16]. Baseline characteristics of the EP-treated patients are also shown in Table 1. Patients treated with carboplatin had a trend for higher relapse rate compared with those treated with 2 cycles of adjuvant EP (Fig. 1): 5-year RFR was 95 % (SE 2 %) versus 100 % (SE 0 %), (p = 0.067).

Discussion

Our study confirms that adjuvant carboplatin protects most stage I seminoma patients from relapse. The 96.8 % 5-year RFR mirrors that reported in large series of adjuvant carboplatin or radiotherapy [20, 21, 22]. Although late relapses are well established in seminoma patients, they are rare [4] and over 90 % occur within the first 3 years from diagnosis [23]. Since 49 % of our patients had at least a 3-year follow-up, any possible underestimation of the RR in this series would be minimal. We also confirmed the excellent prognosis of relapsed patients with salvage BEP chemotherapy, since 4 of 5 relapsed patients have been effectively cured with this strategy. We utilized 2 cycles of carboplatin. This number is in concert with other studies using the same number of cycles [24, 25]. Nevertheless, results from recent studies suggest that 1 cycle of carboplatin AUC 7 is probably adequate [22, 26], and in agreement with the current guidelines [27], we have adopted 1 cycle of carboplatin AUC 7 as our standard adjuvant therapy in stage I seminoma.

In an effort to increase the benefit from adjuvant therapies, risk factors for relapse after orchiectomy for stage I seminoma have been sought. Tumor size >4 cm and rete testis invasion have been long recognized as independent risk factors in surveillance studies and are currently used in several risk-adapted protocols [22, 25]. The value of these factors has been reinforced by a recently reported study involving 389 patients with stage I seminoma and none of the above risk factors who were followed on surveillance programs: after a median follow up of 3.6 years, RR was only 2.9 % [22]. As a consequence, active surveillance is currently the preferred option in international guidelines [28, 29], especially for patients without risk factors, able to comply with strict surveillance protocols [30]. Patients with tumors >4 cm and/or rete testis invasion have a 20 % chance of relapse after orchiectomy [22]. Apart from surveillance, adjuvant chemotherapy can be offered to these patients. We showed a relapse rate of 3.8 %, which is numerically lower than the 9 % reported in SWENOTECA study [22]. This difference may be due to the fact that in SWENOTECA, adjuvant chemotherapy was recommended to patients with both risk factors present.

In concert to risk-adapted strategies, it would be reasonable to attempt to identify risk factors for relapse after adjuvant carboplatin in order to select patients who might benefit from more intense chemotherapy. These factors might not be necessarily identical to those found for orchiectomy. Indeed, we found no relapses among patients with rete testis invasion. The importance of this factor has been recently challenged by an analysis of 685 stage I seminoma patients managed with surveillance [31]. In our series, age below 34 years was a feature of relapsed patients (along with tumor diameter). Young age has been previously recognized as an adverse prognostic factor by other investigators [32], but it has not been confirmed in recent reports [23, 30]. In our previous study, 2 EP courses resulted in no relapse in a population of 64 patients who had at least one of these risk factors [16]. The 5-year RFR of 5 % for patients with similar risk features treated with adjuvant carboplatin was found inferior to the outcome after EP. On the other hand, EP was associated with more frequent neutropenia (37.5 vs. 11.6 %), nausea and vomiting (66 vs. 14.4 %), and diarrhea (10 vs. 0.7 %). Furthermore, concern has been raised regarding long-term toxicity by cisplatin-based chemotherapy in testicular cancer survivors [33]. Although late toxicity cannot be determined in this analysis due to the relatively short follow-up, recent data support the notion that single-agent carboplatin does not increase overall mortality and cardiovascular disease or secondary cancer incidence compared to combination chemotherapy [34]. Arguably, further long-term follow-up of patients treated with adjuvant carboplatin is required in order to draw final conclusions. Taking into consideration that due to the efficacy of BEP in relapsed patients, cure rates still approach 100 % with adjuvant carboplatin, 1 cycle of carboplatin should be the preferable adjuvant chemotherapy in stage I seminoma.

In conclusion, we confirm that adjuvant carboplatin is an effective adjuvant therapy in stage I seminoma and is a valid option for patients with tumor diameter >4 cm and/or rete testis invasion. Nevertheless, relapse rate in this population is fairly low and identification of more potent risk factors might further refine the selection of patients who would derive a more significant benefit by adjuvant chemotherapy. Tumor size seems to be the most consistent prognostic factor either in surveillance or in adjuvant therapy settings. In the molecular era, new translational data and gene expression signatures that will more accurately predict relapses are needed.

Notes

Authors’ contribution

K. Koutsoukos collected and managed the data, and wrote and edited the manuscript; K. Tzannis analyzed the data; C. Christodoulou, V. Karavasilis, C. Bakoyiannis, T. Makatsoris, and C. N Papandreou collected the data; D. Pectasides developed the protocol; M. A. Dimopoulos developed the protocol and collected the data; A. Bamias developed the protocol, analyzed the data and was the Protocol Coordinator.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Konstantinos Koutsoukos
    • 1
  • Kimon Tzannis
    • 1
  • Christos Christodoulou
    • 2
  • Vasilios Karavasilis
    • 3
  • Charalambos Bakoyiannis
    • 4
  • Thomas Makatsoris
    • 5
  • C. N. Papandreou
    • 6
  • Dimitrios Pectasides
    • 7
  • Meletios A. Dimopoulos
    • 1
  • Aristotelis Bamias
    • 1
  1. 1.Oncology Unit, Department of Clinical TherapeuticsUniversity of Athens, School of Medicine, Alexandra HospitalAthensGreece
  2. 2.Second Department of Medical Oncology“Metropolitan” HospitalPiraeusGreece
  3. 3.Department of Medical Oncology, “Papageorgiou” HospitalAristotle University of Thessaloniki School of MedicineThessalonikiGreece
  4. 4.Second Department of Medical OncologyHygeia HospitalAthensGreece
  5. 5.Division of Oncology, Department of Medicine, University HospitalUniversity of Patras Medical SchoolPatrasGreece
  6. 6.Department of Medical Oncology, University Hospital of LarissaUniversity of Thessaly School of MedicineLarissaGreece
  7. 7.Oncology Section, Second Department of Internal Medicine“Hippokration” HospitalAthensGreece

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