Annals of Oncology Advance Access originally published online on November 27, 2007
Annals of Oncology 2008 19(2):259-264; doi:10.1093/annonc/mdm472
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urogenital tumors |
Assessing prognosis and optimizing treatment in patients with postchemotherapy viable nonseminomatous germ-cell tumors (NSGCT): results of the sCR2 international study
1 Department of Medicine, Institut Gustave Roussy, Villejuif, France
2 Department of Medical Oncology, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo, Norway
3 Department of Biostatistics, Institut Gustave Roussy, Villejuif, France
4 Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
5 Department of Urology, Istituto Nazionale Tumori, Milan, Italy
6 Department of Hematology/Oncology, University of Tuebingen, Germany
7 Department of Medical Oncology, Kaiser Franz-Josef Spital and LBI-ACR, Vienna, Austria
8 Department of Medical Oncology, Copenhagen National Hospital, Copenhagen, Denmark
9 Department of Medical Oncology, Centre Léon Bérard, Lyon, France
10 Department of Oncology, Santa Maria delle Croci Hospital, Ravenna, Italy
11 Department of Medical Oncology, Russian Cancer Research Center, Moscow, Russia
12 Medizinische Fakultt, Martin-Luther-Uni Halle-Wittenberg, Halle, Germany
13 Department of Pathology, Centre Hospitalier Universitaire La Miletrie, Poitiers, France
* Correspondence to: Dr K. Fizazi, Department of Medicine, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94800 Villejuif, France. Tel: +33-1-42116264; Fax: +33-1-42115230; E-mail: fizazi{at}igr.fr
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Abstract |
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Background: The purpose of this study was to validate a prognostic index [surgical complete response 1 (sCR1)] in patients with postchemotherapy viable nonseminomatous germ-cell tumors (NSGCT).
Patients and methods: Data and specimens from 61 patients with normalized tumor markers and postchemotherapy viable nonteratomatous NSGCT treated in 13 institutions were collected.
Results: With a median follow-up of 5.4 years, the 5-year progression-free survival (PFS) rate was 65%; the 5-year overall survival (OS) rate was 72%. Favorable PFS was predicted by a complete resection, <10% of viable malignant cells, and a good International Germ Cell Consensus Classification group at presentation. Patients were assigned to one of three risk groups defined in sCR1: no risk factor (good risk), one risk factor (intermediate risk) and two to three risk factors (poor risk group). The 5-year PFS rate was 92%, 78%, and 42%, respectively (P = 0.002) (as compared with 90%, 76%, and 41% in the original sCR1 study). The 5-year OS rate was 90%, 86%, and 52%, respectively (P = 0.009) (as compared with 100%, 83%, and 51% in the original sCR1 study). Postoperative chemotherapy did not appear to improve OS compared with surveillance and treatment only at relapse.
Conclusion: In patients with postchemotherapy viable NSGCT, a complete resection of residual masses should be rigorously pursued. These data validate the sCR1 prognostic index. Given their excellent outcome, patients in the favorable group may not require postoperative chemotherapy.
Key words: chemotherapy, germ cell tumor, non seminoma, residual masses, surgery
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Germ-cell tumors (GCT) have become a paradigm for a chemosensitive and curable neoplasm [1]. With multimodality therapy comprising cisplatin-based combination chemotherapy and subsequent resection of residual metastatic deposits, an overall long-term disease-free status can be achieved in
80% of patients with advanced disease. Prognostic factors predictive of survival have been identified and subsequently validated [2–4]. In nonseminomatous germ-cell tumors (NSGCT), surgical resection of postchemotherapy residual masses is universally recommended. These masses may harbor complete necrosis, teratoma, or viable malignant GCT in 34%–67%, 25%–44%, and 5%–22%, respectively [5, 6]. Teratoma may lead to complications such as the growing teratoma syndrome [7] and therefore all efforts should be made to radically resect teratoma-containing lesions. Besides viable GCT, postchemotherapy residual masses can also harbor non-GCT cancer, especially in primary mediastinal NSGCT [8], and this so-called ‘teratoma with malignant transformation’ is associated with a dismal prognosis [9, 10]. In patients with postchemotherapy retroperitoneal and pulmonary lesions, discordant histologies between the two sites have been reported in 30% of cases, thus justifying the removal of lesions from both sides of the diaphragm [11, 12]. However, the high pathological concordance rate (95%) between residual lesions from both lungs argues in favor of avoiding a contralateral thoracotomy when complete necrosis is identified in operative specimens from the one lung [12]. The presence of viable cells in completely resected residual masses has been designated a ‘surgical complete response’ (sCR). In some cases, this may indicate resistance to cisplatin and a worse prognosis compared with specimens with residual teratoma or necrosis/fibrosis alone. Until recently, the rarity of this situation has made it difficult to power studies with sufficient number of patients to reliably identify relevant risk factors [13]. In 2001, our multi-institutional study group reported on 238 patients with postchemotherapy viable NSGCT [5]. In this ‘sCR1 study’, the 5-year progression-free survival (PFS) rate was 64% and the 5-year overall survival (OS) rate was 73%. Three independent factors were predictive of both favorable PFS and OS: a complete resection of residual masses (P < 0.001), <10% of viable malignant cells (P = 0.001), and a good International Germ Cell Consensus Classification (IGCCC) group at presentation (P = 0.01). Patients were assigned to one of three risk groups of a prognostic index: those with no risk factors (good risk group), those with one risk factor (intermediate group), and those with two or three risk factors (poor risk group). These risk groups represented 22%, 40%, and 38% of the patient population, respectively. The 5-year OS rates for the good-, intermediate-, and poor risk groups were 100%, 83%, and 51%, respectively. After adjustment on the three aforementioned prognostic factors, postoperative chemotherapy was associated with a significantly better PFS (P < 0.001) but not with a better OS. According to this prognostic index, patients in the favorable risk group had a 100% 5-year survival rate, with or without postoperative chemotherapy.
Since the sCR1 study was based on a single series of patients without a validation set and the assessment of viable NSGCT was carried out locally at the individual sites, we validated these prognostic factors using a separate set of patients with a central review of pathological tumor specimens.
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patients and methods |
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European and US-American institutions dedicated to the treatment of NSGCT were asked to participate in the present multicentre international study called ‘sCR2’. Resection of residual postchemotherapy masses had to have taken place between October 1996 and February 2001 for institutions that had participated in the sCR1 study and between May 1980 and May 2001 for institutions that had not participated in the sCR1 study.
Male patients were eligible for the study if: (i) they had residual masses after first-line platin-based (cisplatin or carboplatin) chemotherapy for disseminated NSGCT, (ii) serum tumor markers (alfa-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase) had normalized before resection, (iii) the resection status, i.e. complete or incomplete, was known (iv) the pathological specimen contained viable nonpure teratoma GCT (with or without necrosis), (v) follow-up data were available. Patients with residual viable NSGCT containing malignant non-GCT neoplasms such as sarcoma and adenocarcinoma (teratoma with malignant transformation) were included in the study.
Patient characteristics, treatment data, and follow-up data of eligible patients were recorded at the respective institution and analyzed centrally by a biostatistician (AD). All pathological specimens were reviewed centrally by an expert pathologist in urological malignancies (GF). The review pathologist scored the percentage of viable cells based on the entire material that was sent to her.
patients and sample selection
Of 105 initially submitted cases, 61 fully fulfilled eligibility criteria. The reasons for exclusion of 44 cases were as follows: tumor specimen unavailable for central pathological review (n = 20), no evidence of viable nonteratomatous GCT on the submitted material (n = 17), unavailable IGCCC prognostic group (n = 4), tumor markers had not normalized before resection (n = 2), unknown completeness of surgery (n = 1).
The following institutions had participated in the sCR1 study: Istituto Nazionale Tumori, Milan, Italy (n = 7), Institut Gustave Roussy, Villejuif, France (n = 6), University of Tübingen, Germany (n = 4), KFJ Spital and LBI-ACR VIEnna, Vienna, Austria (n = 3), Centre Léon Bérard, Lyon, France (n = 3), Santa Maria delle Croci Hospital, Ravenna, Italy (n = 2), Russian Cancer Research Center, Moscow, Russia (n = 2), Martin Luther University, Halle, Germany (n = 1). Three additional institutions had not participated in the sCR1 study: the Cancer Clinic, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway (n = 21), the UT MD Anderson Cancer Center, Houston, USA (n = 9), and Copenhagen National Hospital, Copenhagen, Denmark (n = 3).
statistical analysis
Median follow-up was estimated using the inverse Kaplan–Meier method [14]. PFS and OS were determined using the Kaplan–Meier method and differences were tested by the log-rank test. The 95% confidence interval (95% CI) was calculated whenever appropriate. The association between the characteristics of the patients and survival was evaluated with a Cox model. All tests were two-tailed and P < 0.05 was considered significant. The data were analyzed with SAS software® (version 8.2; SAS Software, Cary, NC).
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patient characteristics and initial treatment
Among the 61 patients, the prognosis according to the IGCCC was as follows: favorable in 23 (38%), intermediate in 18 (30%), and poor in 20 (33%). Patient characteristics are summarized in Table 1. First-line chemotherapy was cisplatin based in 55 patients (90%) and is summarized in Table 2.
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Sites of postchemotherapy residual masses included the retroperitoneum in 53 (87%) patients, the lungs in 11 (18%), the mediastinum in 5 (8%), and the liver in 5 (8%). Four patients had an orchiectomy at the time of surgery for their residual masses. In most patients (n = 45; 74%), only one site of residual masses was resected, whereas 13 (21%) and three (5%) patients were operated on at two or three sites, respectively. Surgery led to a complete resection in 44 patients (72%) and to incomplete resection in 17 patients (28%).
survival and prognostic factors
With a median follow-up of 65 months, the 5-year PFS was 65% (95% CI 53–76) and the 5-year OS was 72% (95% CI 60–82).
The three favorable prognostic factors identified in the sCR1 study [5], i.e. a complete resection of residual masses, <10% viable malignant cells, and a favorable IGCCC group at presentation, were tested in the multivariate analysis (Table 3). A complete resection of residual masses was the most powerful prognostic factor and strongly predictive of both PFS (P = 0.0007) and OS (P = 0.004). The proportion of viable malignant cells in the residual specimen was of borderline statistical significance (P = 0.06) for PFS and was clearly associated with OS (P = 0.01). PFS was also significantly associated with a good IGCCC status (P = 0.02) in this multivariate analysis.
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The prognostic index developed in the previous sCR1 study [5] was also highly predictive of both PFS (P = 0.0008) and OS (P = 0.003) therefore validating its value (Table 4 and Figure 1).
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postoperative chemotherapy
Among the 61 patients in this study, 36 (59%) had received postsurgery chemotherapy and 25 (41%) patients had not. Among these 36 patients, postoperative chemotherapy consisted in the induction regimen (with or without bleomycin) in only four patients (11%), while 29 patients (81%) had received a different regimen because their oncologist considered the presence of viable malignant cells to be an indicator of at least partial chemoresistance to the induction regimen. Three additional patients (8%) had received a regimen containing high-dose chemotherapy with stem-cell rescue. No death related to postoperative chemotherapy had occurred. Three patients (5%) had also received postoperative radiotherapy.
As in our previous study [5], patients who relapsed within a month following surgery were excluded from the analysis of the effect of postoperative chemotherapy on relapse and survival. Neither PFS nor OS were apparently improved in patients who had received postoperative chemotherapy when compared with those who had not (log-rank test, P = 0.18 and P = 0.46, respectively) (Figure 2), although the small number of patients and the nonrandomized design of this study preclude definitive conclusions regarding the role of postoperative chemotherapy.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The results of this study on patients with postchemotherapy viable NSGCT are very similar to those previously reported in the sCR1 study [5], which can thus be considered validated. The 5-year PFS rates were 64% and 65%, while the OS rates were 73% and 72% in the sCR1 and in the present sCR2 study, respectively. The prognostic index based on three previously identified prognostic factors (a complete resection of residual masses, <10% viable malignant cells, and a favorable IGCCC group at presentation) confirmed its value in this study, as it was strongly predictive of both PFS (P = 0.0008) and OS (P = 0.003). The excellent outcome of patients with viable malignant cells classified in the good prognosis group according to this index (no adverse factors) was also confirmed in this study with an estimated 5-year PFS of 92% (versus 90% in the previous sCR1 study).
A complete resection was the strongest predictive factor for both OS and PFS with an hazard ratio (HR) of 4.4 and 4.5, respectively. These figures are consistent with those reported in sCR1, 3.8 and 2.7, indicating the high reliability of this parameter. For clinical practice, this finding underlines the importance of ensuring that initial resection is complete when postchemotherapy viable malignant cells are identified. Repeat resections are technically more difficult and should only be carried out by very experienced surgeons [15]. Some incomplete resections might be avoided by referring patients to high-volume centers, at least those bearing large and/or poorly accessible lesions. If viable malignant cells are identified on the dissected retroperitoneal lymph node specimen, all efforts should be made to completely remove all residual lesions at other sites (lung, liver, etc.). This recommendation is also applicable to patients with residual masses after salvage chemotherapy for NSGCT [16].
The percentage of viable nonteratomatous GCT in the residual mass likely reflects resistance to cisplatin-based chemotherapy but indicates a better prognosis when the magnitude is <10% as opposed to higher proportions. The fact that it is difficult to resect viable GCT could be a confounding factor in the case of this parameter. Nevertheless, cisplatin-resistant residual NSGCT portend a dismal prognosis. This parameter has a greater impact on OS (HR: 4.4) than on PFS (HR: 2.1) and may reflect limited treatment options when faced with resistance to cisplatin. A smaller report on 28 patients with postchemotherapy viable NSGCT indicated that those with >25% viable embryonal carcinoma in the resected specimen or those with a highly proliferative residual tumor had a risk of relapse exceeding 70% after surgery [17]. The factors influencing resistance to cisplatin in GCT are not fully understood, although recent findings indicate that defects in the DNA mismatch repair pathway may be involved [18]. Recent evidence that the excision repair cross-complementation group 1 protein is involved in cisplatin resistance in non-small-cell lung cancer [19] makes it a potential candidate for further studies in NSGCT.
As in the sCR1 study, there was no evidence of a survival benefit associated with immediate postoperative chemotherapy in this sCR2 study, when patients who had received postsurgery chemotherapy were compared with those who had not. However, this result should be cautiously considered since both studies were not randomized and we cannot ascertain whether the two groups were well balanced in terms of known and unknown prognostic variables. Given the overall excellent outcome, regardless of whether they had received postoperative chemotherapy or not, in both sCR1 and sCR2 studies, we consider that patients in the favorable group according to our prognostic index need not receive postoperative chemotherapy. In patients with one or more adverse factors (those from the intermediate or poor risk groups according to our index), the practical and important message is that a complete resection of residual masses is likely to improve outcome more than postsurgery chemotherapy. Therefore, all efforts should be undertaken to achieve this objective. Regarding the usefulness of postsurgery chemotherapy in patients with intermediate- and poor risk disease according to our index, evidence is limited in the absence of data from a randomized trial. In the sCR1 study, a significant benefit was indicated for recipients of immediate postoperative chemotherapy in the intermediate risk group in terms of both PFS (84% versus 42%, P < 0.001) and OS (88% versus 56%, P = 0.02) compared with patients managed by surveillance alone with treatment in case of a relapse [5]. However, we cannot ascertain whether this result was not biased due to unbalanced groups. The very small number of patients (n = 22 patients allocated to the intermediate risk group) prohibited a survival analysis with risk stratification in this study. Moreover, in the sCR1 study, there was no evidence that a ‘salvage’ regimen used adjuvantly after surgery could improve outcomes over recycling of the induction regimen [5]. Consequently, in the absence of strong evidence-based data, oncologists may consider either immediate postoperative chemotherapy or surveillance with treatment in case of a relapse in patients with postchemotherapy viable malignant cells allocated to the intermediate or poor risk groups, according to our index. The concept of using postoperative chemotherapy in this setting should be revisited in the future when more active agents/regimens are hopefully identified in cisplatin-resistant NSGCT.
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The authors thank L. Saint Ange for editing.
Received for publication June 13, 2007. Revision received August 27, 2007. Accepted for publication September 3, 2007.
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