1 Hospital Universitario La Fe, Valencia; 2 Institut Catalá dOncologia, Barcelona; 3 Hospital de Sant Pau, Barcelona; 4 Hospital 12 de Octubre, Madrid; 5 Hospital Clínico Universitario, Málaga; 6 Hospital Clínico, Zaragoza; 7 Hospital Son Dureta, Mallorca; 8 Hospital Germans Trias i Pujol, Badalona; 9 Hospital Doctor Peset, Valencia; 10 Hospital Gregorio Marañón, Madrid; 11 Hospital Donostia, San Sebastián; 12 Hospital General, Albacete; 13 Hospital Clínico San Carlos, Madrid; 14 Hospital del Mar, Barcelona; 15 Hospital Josep Trueta, Girona; 16 Hospital Universitari Sant Joan, Reus, Spain
Received 21 October 2002; revised 16 December 2002; accepted 23 January 2003
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Abstract |
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After decades of irradiation as standard therapy for clinical stage I testicular seminoma, alternative treatment approaches have emerged including postorchiectomy surveillance and adjuvant chemotherapy. This study was performed to assess a dual policy of surveillance and selective single-agent carboplatin (for high-risk cases) in a multicenter setting.
Patients and methods:
From 1994 to 1999, 203 patients with stage I seminoma were included. Sixty (29.6%) were considered poor-risk cases (i.e. with vascular invasion and/or pathological tumor stage pT2 or greater) and received two courses of adjuvant carboplatin, whereas 143 (70.4%) without risk criteria underwent close surveillance.
Results:
Median follow-up was 52 months (range 1492). Relapses were observed in two (3.3%) patients treated with carboplatin and in 23 patients (16.1%) on surveillance, with a median time to recurrence of 11 months (range 3.939.6). All relapsing patients were rendered disease-free, mainly with cisplatin-based chemotherapy. Four patients died from tumor-unrelated causes. Actuarial 5-year overall survival was 96.7% and cause-specific survival was 100%. Five-year disease-free survival was 83.5% for patients on surveillance, and 96.6% for those receiving carboplatin.
Conclusions:
This dual treatment policy is feasible in a multicenter setting and preserves 70% of patients from adjuvant chemotherapy. Single-agent carboplatin is effective in reducing the relapse rate in patients with high-risk stage I seminoma. A better definition of local risk features would probably improve patient selection, thus minimizing the incidence of recurrences on surveillance.
Key words: adjuvant carboplatin, prognostic factors, stage I seminoma, surveillance
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Introduction |
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Alternative treatment options have been investigated in this patient subset, including surveillance [3] and adjuvant chemotherapy [4]. Although no randomized clinical trial has been published yet, long-term patient survival does not seem to be compromised in comparison with traditional irradiation. However, surveillance is associated with relapse rates of 1520% (most of them can be salvaged with chemotherapy or irradiation), considerable psychological stress and incremental costs. On the other hand, adjuvant chemotherapy with single-agent carboplatin, although generally well tolerated, implies treating all patients with stage I seminoma, while 80% of them are thought to be cured with orchiectomy.
In 1994, the Spanish Germ Cell Cancer Cooperative Group (GG) designed a protocol to evaluate a dual treatment policy for stage I seminoma in which only high-risk patients (with an expected relapse rate >20%) were assigned to adjuvant carboplatin whereas the remainder (whose expected relapse rate is <15%) were managed with surveillance. If this strategy was feasible, most patients would be preserved from postorchiectomy treatment and the relapse rate both on surveillance and after chemotherapy would be significantly decreased. Mature results of this protocol are presented here. The objective of this study was to assess the following: (i) the percentage of patients needing adjuvant chemotherapy; (ii) the relapse rate in patients treated with either carboplatin or surveillance; and (iii) long-term overall and disease-free survival rates in both groups.
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Patients and methods |
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Potential prognostic factors for relapse were prospectively recorded, including patient age (≤30 years versus >30 years), tumor diameter (≤40 mm versus >40 mm), histological subtype (classical versus anaplastic), pT stage (pT1 versus pT24), vascular invasion, rete testis invasion and preoperative BHCG levels (negative versus positive). Histological features were reviewed locally. Overall survival (OS) and disease-free survival (DFS) were estimated from the date of orchiectomy with the KaplanMeier method [8]. Comparison of resulting curves and univariate analysis of prognostic factors were performed with the log-rank test [9]. Ninety-five per cent confidence intervals (95% CI) are given when appropriate.
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Results |
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A univariate analysis of prognostic factors for DFS was performed. In the whole series, only adjuvant therapy (favoring carboplatin versus surveillance, P = 0.0142) reached statistical significance. No predictive features could be identified in patients on surveillance, whereas positive serum preoperative BHCG levels were of adverse prognostic value (P = 0.0064) in patients treated with adjuvant carboplatin. However, in all groups, younger age was associated with a non-significant increased risk of recurrence. Table 3 depicts the distribution of relapses among prognostic categories.
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Discussion |
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To our knowledge, this is the first report evaluating a dual policy of postorchiectomy surveillance and selective adjuvant chemotherapy for stage I seminoma. Our results suggest that this schedule is feasible in a nationwide multicenter setting, and long-term results are equivalent to those achieved with other modalities (i.e. no seminoma-related mortality was seen). Considering patients treated with adjuvant chemotherapy and after tumor relapse, 120 of 203 cases (59.1%) were safely preserved from any form of therapy. With only two of 60 relapses (3.3%), we confirm two courses of carboplatin as an effective adjuvant treatment even for patients with high-risk criteria. Moreover, it seems evident that starting chemotherapy within 10 days after orchiectomy is not mandatory [1820]. The main limitation of this study was the absence of universally accepted prognostic factors for relapse in patients managed by surveillance at the time of its design. In a single center experience, tumor diameter, microvascular invasion and age reached statistical significance [21]. In the Royal Marsden Hospital series of 103 patients managed by surveillance, the only significant prognostic factor for relapse was the presence of lymphatic and/or vascular invasion (9% versus 17% relapse rate) [15]. More recently, in a joint study with 638 patients from three large series of surveillance, only tumor size and rete testis invasion entered the multivariate prognostic model [22]. We chose pTNM and vascular invasion because of its widespread use and general acceptance [23]. However, a 16.1% relapse rate on surveillance (similar to that expected in unselected stage I patients) makes us question the predictive value of our criteria. None of the prognostic factors studied in this report achieved statistical significance; a fact that could be related to the small number of events (relapses) and/or the impact of selective adjuvant chemotherapy. Thus, in 1999 the Spanish GG started a second dual policy study using the new selection criteria (tumor size >40 mm and rete testis invasion) [22], employing carboplatin with the more adequate area-under-the-curve (AUC 7) dosing, and using a 21-day interval between cycles.
We have not specifically addressed other important issues such as long-term carboplatin toxicity, fertility, quality of life aspects and economic costs both on surveillance and after carboplatin because all of them were investigated in previous studies [3, 4, 1419]. However, it is noteworthy that we observed in this series six second malignancies (four of them germ-cell tumors), but none of them occurred in the group treated with carboplatin. Then, a protective effect of chemotherapy against a second contralateral testicular tumor (in comparison with surgery alone) can not be ruled out, as suggested by Oliver et al. [4]. The simplification of treatment according to our multicenter protocol means that there would be reduced referral of early stage testis cancer to specialist centers to discriminate between high- and low-risk patients. Although our simplified surveillance policy seems adequate, it should be possible to minimize costs by further increasing the intervals for follow-up investigations.
In conclusion, although there is need for improvement, this dual treatment policy for patients with stage I seminoma is feasible, preserves 70% of cases from adjuvant treatment (and 59% from any form of postorchiectomy therapy) without compromising long-term results, and it could be used as a risk-adapted alternative to irradiation, surveillance and carboplatin.
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Acknowledgements |
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Participant members of the Spanish Germ Cell Cancer Cooperative Group are as follows: Jorge Aparicio, Ana L. Yuste (Hospital Universitario La Fe, Valencia); Xavier García del Muro, José R. Germà (Institut Catalá dOncologia, Barcelona); Pablo Maroto (Hospital de Sant Pau, Barcelona); Luis Paz-Ares (Hospital 12 de Octubre, Madrid); Emilio Alba (Hospital Clínico Universitario, Málaga); Alberto Sáenz (Hospital Clínico, Zaragoza); Josefa Terrasa (Hospital Son Dureta, Mallorca); Agustí Barnadas (Hospital Germans Trias i Pujol, Badalona); Daniel Almenar (Hospital Doctor Peset, Valencia); José A. Arranz (Hospital Gregorio Marañón, Madrid); Miguel Sánchez (Hospital Donostia, San Sebastián); Antonio Fernández Aramburu (Hospital General, Albacete); Javier Sastre (Hospital Clínico San Carlos, Madrid); Joan Carles (Hospital del Mar, Barcelona); Joan Dorca (Hospital Josep Trueta, Girona); Josep Gumà (Hospital Universitari Sant Joan, Reus); Sonia Del Barco (Hospital Clínico San Cecilio, Granada); Alberto Rodríguez (Hospital J.R. Jiménez, Huelva); Enrique Barrajón (Hospital General, Elche); Romà Bastús (Mutua de Terrassa); Severina Domínguez (Hospital Txagorritxu, Vitoria); Carmen Crespo (Hospital Ramón y Cajal, Madrid); Marta López-Brea (Hospital Marqués de Valdecilla, Santander); Adolfo Murias (Hospital Insular de Gran Canaria); Enrique Gallardo (Hospital de Terrassa); Purificación Martínez (Hospital de Basurto, Bilbao); Francisco J. Dorta (Hospital Nª Sª de la Candelaria, Tenerife); María Lomas (Hospital Infanta Cristina, Badajoz); Antonio Colmenarejo (Hospital del Aire, Madrid).
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Footnotes |
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Members of the Spanish Germ Cell Cancer Cooperative Group are listed in the Acknowledgements.
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References |
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