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A Risk-adapted Study of Cisplatin and Etoposide, with or Without Ifosfamide, in Patients with Metastatic Seminoma: Results of the GETUG S99 Multicenter Prospective Study
EUROPEAN UROLOGY 65 (2014) 381–386
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A Risk-adapted Study of Cisplatin and Etoposide, with or Without Ifosfamide, in Patients with Metastatic Seminoma: Results of the GETUG S99 Multicenter Prospective Study Karim Fizazi a,*, Re´mi Delva b, Armelle Caty c, Christine Chevreau d, Pierre Kerbrat e, Frederic Rolland f, Frank Priou g, Lionnel Geoffrois h, Olivier Rixe i, Philippe Beuzeboc j, Jean-Pierre Malhaire k, Stephane Culine l, Marie-Stephanie Aubelle m, Agnes Laplanche m a
Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France;
c
b
Radiotherapy and Oncology, Centre Galile´e, Hoˆpital Prive´ La Louvie`re, Lille, France; d Centre Claudius Regaud, Toulouse, France; e Department of Medical
Department of Medical Oncology, Centre Paul Papin, Angers, France;
Oncology, Centre Euge`ne Marquis, Rennes, France; f Department of Medical Oncology, Centre Rene´ Gauducheau, Saint-Herblain, France; g Service of Internal Medical Onco-Haematology, Hoˆpital Les Oudairies, La Roche sur Yon, France;
h
Medical Oncology, Department of Clinical Oncology, Centre Alexis Vautrin,
i
Vandoeuvre le`s Nancy, France; GRU Cancer Center, Department of Hematology Oncology, Augusta, GA, USA; j Department of Medical Oncology, Institut Curie, Paris, France; m
k
Department of Radiotherapy, Hoˆpital Morvan, Brest, France; l Department of Medical Oncology, Hoˆpital Saint-Louis, Paris, France;
Department of Biostatic and Epidemiology, Institut Gustave Roussy, Villejuif, France
Article info
Abstract
Article history: Accepted September 4, 2013 Published online ahead of print on September 13, 2013
Background: Whether patients with good prognosis and intermediate/poor prognosis advanced seminoma should be treated differently has not been defined. Objective: To assess a risk-adapted chemotherapy regimen in patients with advanced seminoma. Design, setting, and participants: A total of 132 patients were included in this prospective study. Patients with a good prognosis according to the International Germ Cell Cancer Collaboration Group (IGGCCG) were treated with four cycles of cisplatin-etoposide (EP). Patients with an intermediate prognosis according to the IGCCCG (or a poor prognosis according to the Medical Research Council classification) were treated with four cycles of VIP (EP and ifosfamide) and granulocyte colony-stimulating factor (G-CSF). Outcome measurements and statistical analysis: Survival curves were estimated using the Kaplan-Meier method. Results and limitations: The median follow-up was 4.5 yr (range: 0.4–11.6 yr). Among 108 patients (82%) with a good prognosis who received EP, grade 3–4 toxicity included neutropenia (47%) and neutropenic fever (12%). Among the 24 patients (18%) with an intermediate/poor prognosis who received VIP plus G-CSF, toxicity included grade 3–4 neutropenia (36%), neutropenic fever (23%), thrombocytopenia (23%), anemia (23%), and a toxicity-related death (n = 1; 4%). The 3-yr progression-free survival (PFS) rate was 93% (range: 85–97%) in the good prognosis group and 83% (range: 63–93%) in the intermediate/poor prognosis group ( p = 0.03 for PFS). The 3-yr overall survival (OS) rate was 99% (range: 92–100%) and 87% (range: 67–95%), respectively ( p < 0.005 for OS). Only four patients died of seminoma or its treatment. Conclusions: A risk-adapted chemotherapy policy for advanced seminoma yielded an excellent outcome with a 3-yr OS rate of 96%. # 2013 Published by Elsevier B.V. on behalf of European Association of Urology.
Keywords: Seminoma Chemotherapy Prognostic factors
* Corresponding author. Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, 39 rue Camille Desmoulins, 94800 Villejuif, France. Tel. +33 1 42 11 43 17. E-mail address: fi[email protected] (K. Fizazi). 0302-2838/$ – see back matter # 2013 Published by Elsevier B.V. on behalf of European Association of Urology. http://dx.doi.org/10.1016/j.eururo.2013.09.004
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1.
EUROPEAN UROLOGY 65 (2014) 381–386
Introduction
Seminoma is the most chemosensitive solid cancer, and cisplatin-based chemotherapy cures most patients with metastatic disease [1]. Only 25% of patients with seminoma have evidence of extratesticular dissemination at diagnosis, and only 5% among them have dissemination above the retroperitoneal lymph nodes [2]. Patients with moderately enlarged metastatic lymph nodes in the retroperitoneum (stages IIA and small-volume stage IIB) are classically treated with radiotherapy, whereas cisplatin-based chemotherapy is the standard treatment for patients with larger adenopathies and for those with dissemination outside the retroperitoneum because chemotherapy is associated with a lower risk of relapse in this setting [1,3]. Treatment leads to a cure rate of up to 97% in patients with stage II seminoma [3]. Besides metastatic testicular seminoma, the rare patients with primary mediastinal seminoma are also mostly treated with cisplatin-based chemotherapy, with an excellent outcome [4], in marked contrast to those with a primary mediastinal nonseminoma [5]. Because such cases are rare, only a few randomized trials have focused on patients with advanced seminoma [6], only a few series have reported data on >100 patients, and most of them are retrospective studies [7–9]. Consequently, the optimal treatment of patients with advanced seminoma has not been clearly defined. Consensus guidelines [1,10] currently recommend (1) cisplatin-etoposide (EP) for four cycles or cisplatin-etoposide-bleomycin (BEP) for three cycles, (2) avoiding replacing cisplatin with carboplatin, and (3) the use of fludeoxyglucose positron emission tomography (FDG-PET) in patients with postchemotherapy residual masses, at least in those with masses >3 cm [11]. One important achievement was the international effort in the 1990s that led to the definition of prognostic groups in patients with metastatic germ cell tumors [12]. However, for advanced seminoma, only two prognostic groups were identified, solely based on the presence or absence of extrapulmonary visceral metastases: a good-risk group comprising 90% of patients and an intermediate-risk group, with a 5-yr overall survival (OS) probability of 86% and 72%, respectively. This effort was pursued during the following years mainly by investigators from the Medical Research Council (MRC) group who demonstrated the adverse prognostic role of elevated lactate dehydrogenase (LDH) (above twice the upper limit of normal) in patients with disseminated seminoma above the retroperitoneum, together with extrapulmonary visceral metastases [13]. This situation prompted us in 1999 to design a prospective national study whose objective was to assess a risk-adapted chemotherapy regimen in patients with advanced seminoma. Four cycles of the EP regimen were chosen as the standard treatment in patients with good-risk disease because the largest reported experience to date used this regimen [8,14]. Four cycles of cisplatin, etoposide, and ifosfamide plus granulocyte colony-stimulating factor (G-CSF) support were used in patients with intermediate/ poor-risk disease, based on the reported activity of a triple regimen containing cisplatin and ifosfamide for patients
with advanced seminoma, either in untreated patients [15] or in the salvage setting [16,17]. 2.
Patients and methods
S-99 was a French Genito-Urinary Oncology Group (GETUG) multicenter prospective study of patients with advanced seminoma requiring first-line chemotherapy. Inclusion criteria were male patients >15 yr of age; histologically proven pure seminoma of the testis, the retroperitoneum, or the mediastinum; evidence of metastatic dissemination (required if the primary was a testicular tumor); an indication for first-line chemotherapy according to available guidelines (stage IIB disease bulky disease); a normal serum a-fetoprotein (AFP) level; normal or elevated human chorionic gonadotropin (hCG; an hCG value >5000 mU/ml was an exclusion criterion because an intermediate or a poor prognosis nonseminoma component according to the International Germ Cell Cancer Collaborative Group [IGCCCG] cannot be ruled out in this case); no previous chemotherapy (except for one or two cycles of single-agent carboplatin used as adjuvant therapy for stage I testicular seminoma), with or without previous radiation, adequate hematologic, renal, and liver function permitting chemotherapy, with no previous cancer other than seminoma (except basal cell carcinoma of the skin); agreeing to receive chemotherapy after having been informed about the principle behind its use and its side effects. Written informed consent was not required of patients because this study was regarded as a prospective assessment of standard treatments and not a clinical trial. The study was approved by the Clinical Research Directorate of the Institut Gustave Roussy. The staging procedure included a computed tomography (CT) scan of the thorax, abdomen, and pelvis. Serum tumor marker levels (AFP, hCG, and LDH) were determined before chemotherapy. Follow-up was to be performed according to guidelines.
2.1.
Chemotherapy
The choice of the chemotherapy regimen was based on the prognostic assessment of patients. The good-risk group (IGCCCG) included patients with any stage II seminoma and those with supradiaphragmatic (lymph nodes or lung) dissemination and a serum LDH level less than two times the upper limit of normal (ULN). The intermediate-risk group (IGCCCG) included only patients with extrapulmonary visceral metastases; the poor-risk group (MRC) included patients with extrapulmonary visceral metastases and also those with supradiaphragmatic (lymph nodes or lung) dissemination and serum LDH two ore more times the ULN. Patients in the good-risk group were to be treated with four cycles of the EP regimen (cisplatin 20 mg/m2 per day and etoposide 100 mg/m2 per day for 5 d, repeated every 3 wk). Patients in the intermediate/poor-risk group were to be treated with four cycles of the EP and ifosfamide (VIP) regimen plus G-CSF (cisplatin 20 mg/m2 per day, ifosfamide 1.2 g/m2 per day, and etoposide 75 mg/m2 per day for 5 d, repeated every 3 wk plus G-CSF 300 mg per day for 7 d, started on day 7). Intravenous mesna 500 mg/m2 was given at hour 0, 3, 7, and 11 of each day ifosfamide was used. Treatment was to be recycled every 3 wk provided the following conditions were met: physical condition compatible with chemotherapy, neutrophil count >1000/mm3 or >500/mm3 if they were increasing, platelet count >100 000/mm3, and absence of residual nephrotoxicity. No subsequent dose reduction was planned in case of neutropenic fever.
2.2.
Management of postchemotherapy residual masses
A CT scan was to be performed after completion of chemotherapy. Originally, the policy for the management of postchemotherapy residual masses was as follows: (1) For residual masses <3 cm, no further treatment was recommended and CT scan surveillance was to be performed (once every 3 mo for the first year and then once every
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EUROPEAN UROLOGY 65 (2014) 381–386
4 mo for the second year). (2) For residual masses 3 cm, a control CT scan was recommended approximately 2 mo later to detect a late response. In the case of a stable residual mass still 3 cm, resection was recommended. Radiation therapy was not recommended for residual masses. During the course of this study, the importance of FDG-PET for assessing postchemotherapy residual masses was progressively recognized [11,18] and implemented.
2.3.
Registration
Patients were prospectively registered by sending an inclusion form to the Biostatistics Department at the Institut Gustave Roussy, Villejuif, France.
2.4.
Statistical methods
Survival times were calculated from the date of chemotherapy initiation to the date of progression or death (progression-free survival [PFS]) and the date of death (for OS). Survival curves were estimated using the Kaplan-Meier method. Curves were compared using the log-rank test. No formal hypothesis regarding response or survival was initially put
characteristics. The median age was 37 yr (interquartile range: 33–43). Most patients had a good prognosis according to the MRC classification (n = 108) or according to the IGCCCG classification (n = 126). 3.1.
Toxicity
All 132 patients received the allocated chemotherapy regimen. Table 2 summarizes the grade 3–4 toxicity by regimen. As expected, the VIP regimen was associated with grade 3–4 hematologic toxicity more often, including neutropenic fever (23% vs 12%). One patient (0.8%) in the VIP group died of septic shock during treatment. Transfusion was more often required in patients in the VIP group (red cell transfusion: 9 [39%]; platelet transfusion: 8 [35%]) than in the EP group (10 [9%] and 1 [1%], respectively). More patients in the EP group (n = 104; 97%) were able to receive the planned four cycles than those in the VIP group (n = 21; 88%).
forward. The accrual objective was to ensure that at least 20 patients per prognostic group would be evaluable, taking into account the rarity of
3.2.
disseminated seminoma. Toxicity was assessed using National Cancer
masses
Response to chemotherapy and management of residual
Institute Common Toxicity Criteria.
3.
Results
From December 1999 to September 2008, 132 patients from 12 French centers were accrued. Table 1 lists their
Among the 128 patients assessable for response, 36 achieved a complete response to chemotherapy (defined as no detectable residual masses on CT scan): 32 of 106 (30%) in the good prognosis group and 4 of 22 (18%) in the intermediate/poor prognosis group (Fig. 1).
Table 1 – Patient population Good prognosis group (n = 108)
Intermediate/poor prognosis group (n = 24)
37 (21–67)
38 (27–63)
94 (87) 7 (6) 7 (6)
20 (83) 1 (4) 3 (13)
81 26 9 2
0 24 (100) 5 (21) 0
Age, yr, median (range) Primary tumor site, no. (%) Testis Retroperitoneum Mediastinum Staging, no. (%) Stage II Stage III Previous radiotherapy, no. (%) Previous carboplatin for stage I seminoma, no. (%) IGCCCG group, no. (%) Good risk Intermediate risk
(75) (25) (8) (2)
108 (100) 0
18 (75) 6 (25)
Overall population (n = 132) 37 (21–67) 114 (86) 8 (6) 10 (8) 81 50 14 2
(62) (38) (11) (2)
126 (95) 6 (5)
IGCCCG = International Germ Cell Cancer Collaboration Group.
Table 2 – Grade 3–4 toxicity Grade 3–4 toxicity
Neutropenia Anemia Thrombocytopenia Neutropenic fever Nausea and vomiting Renal Liver Audio Toxicity-related deaths
Good prognosis group (EP) (n = 108), no. (%) 48 5 2 13 4 0 0 1 0
(47) (5) (2) (12) (4)
(1)
Intermediate/poor prognosis group (VIP and G-CSF) (n = 24), no. (%) 8 (36) 5 (24) 5 (23) 5 (23) 1 (4) 1 (4) 1 (4) 0 1 (4) (septic shock)
EP = cisplatin-etoposide; G-CSF = granulocyte colony-stimulating factor; VIP = EP and ifosfamide.
Overall population (n = 132), no. (%) 56 10 7 18 5 1 1 1 1
(45) (8) (5) (14) (4) (0.8) (0.8) (0.8) (0.8)
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EUROPEAN UROLOGY 65 (2014) 381–386
[(Fig._1)TD$IG]
Table 3 – Reported outcome in metastatic seminoma treated with chemotherapy (95% confidence intervals)
Patients evaluable after chemotherapy (n = 128)
IGCCCG 1997 [11] Complete responses (n = 36; 28%)
Surveillance (n = 65; 71%)
Residual masses postchemotherapy (n = 92; 72%)
Surgical resection (n = 20; 21%)
Radiotherapy (n = 4; 4%)
Resection plus radiotherapy (n = 1; 1%)
PFS, % (range) 3 yr 5 yr OS, % (range) 3 yr 5 yr
MRC 1997 [12]
Present study
NA 81 (78–84)
84 (80–88) NA
91 (84–95) 85 (76–91)
NA 85 (82–88)
85 (81–89) NA
96 (91–99) 92 (83–96)
IGCCCC = International Germ Cell Cancer Collaboration Group; MRC = Medical Research Council; NA = not available; OS = overall survival; PFS = progression-free survival.
Viable seminoma (n = 1) Teratoma (n = 1)
3.3.
Progression-free survival and overall survival
Fig. 1 – Patient management after chemotherapy.
Among the 92 patients with postchemotherapy residual masses on CT scan, the median size of masses was 29 mm (range: 7–200 mm). Postchemotherapy treatment in these 92 patients was as follows: surveillance (65), resection of residual masses (20), radiotherapy (4), resection plus radiotherapy (1), and missing information (2). Overall, 76 patients underwent an 18F-FDG PET after chemotherapy (CT scan had detected residual masses in 60 of them), which was deemed normal in 58 (76%). Postchemotherapy treatment consisted of surveillance in 54 of 58 patients (93%) with a normal FDG-PET.
[(Fig._2)TD$IG] (a)
100% 80%
The median follow-up is 4.5 yr (range: 0.4–11.6 yr). Eight patients experienced progression or a relapse, three of whom subsequently died. The 3-yr PFS rate was 93% (range: 85–97%) in the good prognosis group treated with EP and 83% (range: 63–93%) in the intermediate/poor prognosis group treated with VIP ( p = 0.03 for PFS). The 5-yr PFS rate was 88% (range:77–93%) and 76% (range: 53–90%), respectively (Fig. 2). The 3-yr OS rate was 99% (range: 92–100%) in the good prognosis group treated with EP and 87% (range: 67–95%) in the intermediate/poor prognosis group treated with VIP ( p < 0.005 for OS). The 5-yr OS rate was 93% (range: 83–97%) and 87% (range: 67–95%), respectively. Table 3 shows the PFS and OS data for the overall population. The causes of the nine deaths included two seminomas, one first-line chemotherapy-related toxicity, one salvage chemotherapy–related toxicity, one second cancer (carcinoma of the larynx), two other causes, and two unknown causes.
60%
4.
40% p = 0.0334 20% 0% 0 95 23
At risk
(b)
1 86 21
2 71 16
3 60 14
4 49 9
5 34 6
6 23 4
Years
100% 80% 60% 40%
p = 0.0044
20% 0% At risk
0 107 23
1 95 22
2 80 17
3 66 15
4 55 11
5 37 8
6 Years 25 5
Fig. 2 – (a) Progression-free survival and (b) overall survival by risk group (red curve: good-risk; blue curve: intermediate/poor risk).
Discussion
Advanced seminoma requiring chemotherapy is a rare situation. There are only a few reported prospective studies comprising >100 patients [6,19]. We report here the results of a national treatment policy applied prospectively in 132 patients over a decade, with the treatment burden adapted to the prognosis. This strategy led to an OS of 96%, with ultimately only two patients dying of progressive seminoma. According to published evidence and guidelines [1,10], patients requiring first-line cisplatin-based chemotherapy are those with a bulky clinical stage II seminoma (with an ongoing debate over what the lymph node diameter cut-off should be for the choice between radiotherapy and chemotherapy), extraretroperitoneal lymph node dissemination, or a primary mediastinal seminoma [4]. These patients with advanced seminoma represented only 9% (29 patients) of the 339 patients included in a recently reported European Organization for Research and Treatment of Cancer phase 3 trial focusing on IGCCCG intermediate-risk advanced GCT [20]. In the large (n = 1384) Swedish and Norwegian testicular cancer group (SWENOTECA) program collecting virtually all patients with seminoma treated in these two countries from 2000 to 2006, only 73 patients (5%)
EUROPEAN UROLOGY 65 (2014) 381–386
and 42 patients (3%) with stage IIA–B and stage IIC–D seminoma, respectively, were treated with EP-based chemotherapy [21]. This rarity makes it unlikely that a randomized phase 3 trial will be conducted specifically in these patients. The two regimens currently recommended for patients with good-risk advanced seminoma are four cycles of the EP regimen or three cycles of the BEP regimen [1,10]. Four cycles of EP were administered in most of the published studies [7–9,14,21], and this regimen was chosen in the current trial. With a 3-yr OS rate of 99% (range: 92–100%) in the good prognosis group, our data indicate that this treatment is appropriate for most patients, and they also raise the question as to whether a decrease in the chemotherapy burden could be attempted. To test this hypothesis, a GETUG trial exploring the role of FDG-PET for the early assessment of response after two cycles of EP is ongoing, specifically to limit the number of chemotherapy cycles and thus the risk of long-term ototoxicity and peripheral neurotoxicity [22]. Although numerous studies indicate that bleomycin should be used in good-risk nonseminoma and that three cycles of the BEP regimen should be preferred over four cycles of EP (with 5 vs 12 deaths reported in a randomized trial comparing the two regimens [23]), such evidence has not been conclusively provided in metastatic seminoma. However, there is a clear demonstration that single-agent carboplatin therapy is not as efficient as cisplatin-based combination regimens for patients with advanced seminoma [6]. The 3-yr OS rate of 99% (range: 92–100%) achieved in the good prognosis advanced seminoma group in this study indicates that almost universal cure can be obtained when these patients are adequately treated with four cycles of EP. Only very limited published data are available for patients with intermediate prognosis seminoma according to the IGCCCG [12] classification or poor prognosis seminoma according to the MRC [13] classification. For example, in the SWENOTECA experience of 1384 patients with seminoma, only 6 (0.4%) had intermediate prognosis disease according to the IGCCCG [21]. Guidelines recommend four cycles of the BEP regimen for these patients [1], although this is based on an analogy with intermediate prognosis nonseminoma and not on a randomized trial focusing on seminoma or even on large prospective noncomparative data. In this study, 24 patients with intermediate/poor prognosis seminoma (according to IGCCCG or MRC classifications) were prospectively treated with four cycles of the VIP regimen plus G-CSF. The rationale for replacing bleomycin with ifosfamide in the triplet was based on the well-recognized activity of ifosfamide in seminoma [15]. Four cycles of VIP is a recognized alternative to four cycles of BEP for intermediate or poor prognosis metastatic germ cell tumors [1,24,25]. The 3-yr PFS rate of 83% (range: 63–3%) achieved in the present study with four cycles of VIP compares favorably with the 56% rate reported in poor prognosis seminoma by the MRC [13]. This possible increased efficacy of four cycles of VIP is to be balanced with the wellrecognized toxicity of this regimen, including one death due to septic shock in this study. Whether standard
385
treatment should be four cycles of VIP or four cycles of BEP in intermediate prognosis seminoma will likely be impossible to sort out with a phase 3 trial given the rarity of this situation. Both regimens should be considered possible options based on the available evidence. The management of postchemotherapy residual masses has evolved during the last 2 decades: FDG-PET avoids a high number of unnecessary resections and is now a recognized standard. Extensive experiences reported a high negative predictive value [11], although false-positive results have recently been reported to occur more often than originally thought [26]. The timing of FDG-PET is critical to avoid false positives; it should not be performed before 6 wk after day 21 of the last chemotherapy cycle [11]. In a rare disease like metastatic seminoma, which is almost universally curable with inexpensive cheap and widely available drugs, cumulative data indicate that guidelines are not properly followed in many countries, thus potentially reducing the chances of curing patients [27,28]. Although no progress in germ cell tumors has been directly demonstrated by randomized trials during the last 25 yr [29], an indirect and unrecognized benefit of performing national or international multicenter prospective studies may well be the improvement of the quality of care for patients with these rare tumors, probably because physicians may be more inclined to follow protocol rules than to refer to guidelines. 5.
Conclusions
The 96% OS rate achieved in the present study shows that excellent results can be obtained in a multicenter setting when treating metastatic seminoma in regional cancer centers or university hospitals if a rigorous protocol is followed. Author contributions: Karim Fizazi had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Fizazi, Culine, Laplanche. Acquisition of data: Fizazi, Delva, Caty, Chevreau, Kerbrat, Rolland, Priou, Geoffrois, Rixe, Beuzeboc, Malhaire, Culine, Aubelle, Laplanche. Analysis and interpretation of data: Fizazi, Laplanche, Aubelle. Drafting of the manuscript: Fizazi. Critical revision of the manuscript for important intellectual content: Fizazi, Delva, Caty, Chevreau, Kerbrat, Rolland, Priou, Geoffrois, Rixe, Beuzeboc, Malhaire, Culine, Aubelle, Laplanche. Statistical analysis: Aubelle, Laplanche. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Fizazi. Other (specify): None. Financial disclosures: Karim Fizazi certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
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available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Testis Cancer Editorial by Tim Oliver on pp. 387–388 of this issue
A Risk-adapted Study of Cisplatin and Etoposide, with or Without Ifosfamide, in Patients with Metastatic Seminoma: Results of the GETUG S99 Multicenter Prospective Study Karim Fizazi a,*, Re´mi Delva b, Armelle Caty c, Christine Chevreau d, Pierre Kerbrat e, Frederic Rolland f, Frank Priou g, Lionnel Geoffrois h, Olivier Rixe i, Philippe Beuzeboc j, Jean-Pierre Malhaire k, Stephane Culine l, Marie-Stephanie Aubelle m, Agnes Laplanche m a
Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France;
c
b
Radiotherapy and Oncology, Centre Galile´e, Hoˆpital Prive´ La Louvie`re, Lille, France; d Centre Claudius Regaud, Toulouse, France; e Department of Medical
Department of Medical Oncology, Centre Paul Papin, Angers, France;
Oncology, Centre Euge`ne Marquis, Rennes, France; f Department of Medical Oncology, Centre Rene´ Gauducheau, Saint-Herblain, France; g Service of Internal Medical Onco-Haematology, Hoˆpital Les Oudairies, La Roche sur Yon, France;
h
Medical Oncology, Department of Clinical Oncology, Centre Alexis Vautrin,
i
Vandoeuvre le`s Nancy, France; GRU Cancer Center, Department of Hematology Oncology, Augusta, GA, USA; j Department of Medical Oncology, Institut Curie, Paris, France; m
k
Department of Radiotherapy, Hoˆpital Morvan, Brest, France; l Department of Medical Oncology, Hoˆpital Saint-Louis, Paris, France;
Department of Biostatic and Epidemiology, Institut Gustave Roussy, Villejuif, France
Article info
Abstract
Article history: Accepted September 4, 2013 Published online ahead of print on September 13, 2013
Background: Whether patients with good prognosis and intermediate/poor prognosis advanced seminoma should be treated differently has not been defined. Objective: To assess a risk-adapted chemotherapy regimen in patients with advanced seminoma. Design, setting, and participants: A total of 132 patients were included in this prospective study. Patients with a good prognosis according to the International Germ Cell Cancer Collaboration Group (IGGCCG) were treated with four cycles of cisplatin-etoposide (EP). Patients with an intermediate prognosis according to the IGCCCG (or a poor prognosis according to the Medical Research Council classification) were treated with four cycles of VIP (EP and ifosfamide) and granulocyte colony-stimulating factor (G-CSF). Outcome measurements and statistical analysis: Survival curves were estimated using the Kaplan-Meier method. Results and limitations: The median follow-up was 4.5 yr (range: 0.4–11.6 yr). Among 108 patients (82%) with a good prognosis who received EP, grade 3–4 toxicity included neutropenia (47%) and neutropenic fever (12%). Among the 24 patients (18%) with an intermediate/poor prognosis who received VIP plus G-CSF, toxicity included grade 3–4 neutropenia (36%), neutropenic fever (23%), thrombocytopenia (23%), anemia (23%), and a toxicity-related death (n = 1; 4%). The 3-yr progression-free survival (PFS) rate was 93% (range: 85–97%) in the good prognosis group and 83% (range: 63–93%) in the intermediate/poor prognosis group ( p = 0.03 for PFS). The 3-yr overall survival (OS) rate was 99% (range: 92–100%) and 87% (range: 67–95%), respectively ( p < 0.005 for OS). Only four patients died of seminoma or its treatment. Conclusions: A risk-adapted chemotherapy policy for advanced seminoma yielded an excellent outcome with a 3-yr OS rate of 96%. # 2013 Published by Elsevier B.V. on behalf of European Association of Urology.
Keywords: Seminoma Chemotherapy Prognostic factors
* Corresponding author. Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, 39 rue Camille Desmoulins, 94800 Villejuif, France. Tel. +33 1 42 11 43 17. E-mail address: fi[email protected] (K. Fizazi). 0302-2838/$ – see back matter # 2013 Published by Elsevier B.V. on behalf of European Association of Urology. http://dx.doi.org/10.1016/j.eururo.2013.09.004
382
1.
EUROPEAN UROLOGY 65 (2014) 381–386
Introduction
Seminoma is the most chemosensitive solid cancer, and cisplatin-based chemotherapy cures most patients with metastatic disease [1]. Only 25% of patients with seminoma have evidence of extratesticular dissemination at diagnosis, and only 5% among them have dissemination above the retroperitoneal lymph nodes [2]. Patients with moderately enlarged metastatic lymph nodes in the retroperitoneum (stages IIA and small-volume stage IIB) are classically treated with radiotherapy, whereas cisplatin-based chemotherapy is the standard treatment for patients with larger adenopathies and for those with dissemination outside the retroperitoneum because chemotherapy is associated with a lower risk of relapse in this setting [1,3]. Treatment leads to a cure rate of up to 97% in patients with stage II seminoma [3]. Besides metastatic testicular seminoma, the rare patients with primary mediastinal seminoma are also mostly treated with cisplatin-based chemotherapy, with an excellent outcome [4], in marked contrast to those with a primary mediastinal nonseminoma [5]. Because such cases are rare, only a few randomized trials have focused on patients with advanced seminoma [6], only a few series have reported data on >100 patients, and most of them are retrospective studies [7–9]. Consequently, the optimal treatment of patients with advanced seminoma has not been clearly defined. Consensus guidelines [1,10] currently recommend (1) cisplatin-etoposide (EP) for four cycles or cisplatin-etoposide-bleomycin (BEP) for three cycles, (2) avoiding replacing cisplatin with carboplatin, and (3) the use of fludeoxyglucose positron emission tomography (FDG-PET) in patients with postchemotherapy residual masses, at least in those with masses >3 cm [11]. One important achievement was the international effort in the 1990s that led to the definition of prognostic groups in patients with metastatic germ cell tumors [12]. However, for advanced seminoma, only two prognostic groups were identified, solely based on the presence or absence of extrapulmonary visceral metastases: a good-risk group comprising 90% of patients and an intermediate-risk group, with a 5-yr overall survival (OS) probability of 86% and 72%, respectively. This effort was pursued during the following years mainly by investigators from the Medical Research Council (MRC) group who demonstrated the adverse prognostic role of elevated lactate dehydrogenase (LDH) (above twice the upper limit of normal) in patients with disseminated seminoma above the retroperitoneum, together with extrapulmonary visceral metastases [13]. This situation prompted us in 1999 to design a prospective national study whose objective was to assess a risk-adapted chemotherapy regimen in patients with advanced seminoma. Four cycles of the EP regimen were chosen as the standard treatment in patients with good-risk disease because the largest reported experience to date used this regimen [8,14]. Four cycles of cisplatin, etoposide, and ifosfamide plus granulocyte colony-stimulating factor (G-CSF) support were used in patients with intermediate/ poor-risk disease, based on the reported activity of a triple regimen containing cisplatin and ifosfamide for patients
with advanced seminoma, either in untreated patients [15] or in the salvage setting [16,17]. 2.
Patients and methods
S-99 was a French Genito-Urinary Oncology Group (GETUG) multicenter prospective study of patients with advanced seminoma requiring first-line chemotherapy. Inclusion criteria were male patients >15 yr of age; histologically proven pure seminoma of the testis, the retroperitoneum, or the mediastinum; evidence of metastatic dissemination (required if the primary was a testicular tumor); an indication for first-line chemotherapy according to available guidelines (stage IIB disease bulky disease); a normal serum a-fetoprotein (AFP) level; normal or elevated human chorionic gonadotropin (hCG; an hCG value >5000 mU/ml was an exclusion criterion because an intermediate or a poor prognosis nonseminoma component according to the International Germ Cell Cancer Collaborative Group [IGCCCG] cannot be ruled out in this case); no previous chemotherapy (except for one or two cycles of single-agent carboplatin used as adjuvant therapy for stage I testicular seminoma), with or without previous radiation, adequate hematologic, renal, and liver function permitting chemotherapy, with no previous cancer other than seminoma (except basal cell carcinoma of the skin); agreeing to receive chemotherapy after having been informed about the principle behind its use and its side effects. Written informed consent was not required of patients because this study was regarded as a prospective assessment of standard treatments and not a clinical trial. The study was approved by the Clinical Research Directorate of the Institut Gustave Roussy. The staging procedure included a computed tomography (CT) scan of the thorax, abdomen, and pelvis. Serum tumor marker levels (AFP, hCG, and LDH) were determined before chemotherapy. Follow-up was to be performed according to guidelines.
2.1.
Chemotherapy
The choice of the chemotherapy regimen was based on the prognostic assessment of patients. The good-risk group (IGCCCG) included patients with any stage II seminoma and those with supradiaphragmatic (lymph nodes or lung) dissemination and a serum LDH level less than two times the upper limit of normal (ULN). The intermediate-risk group (IGCCCG) included only patients with extrapulmonary visceral metastases; the poor-risk group (MRC) included patients with extrapulmonary visceral metastases and also those with supradiaphragmatic (lymph nodes or lung) dissemination and serum LDH two ore more times the ULN. Patients in the good-risk group were to be treated with four cycles of the EP regimen (cisplatin 20 mg/m2 per day and etoposide 100 mg/m2 per day for 5 d, repeated every 3 wk). Patients in the intermediate/poor-risk group were to be treated with four cycles of the EP and ifosfamide (VIP) regimen plus G-CSF (cisplatin 20 mg/m2 per day, ifosfamide 1.2 g/m2 per day, and etoposide 75 mg/m2 per day for 5 d, repeated every 3 wk plus G-CSF 300 mg per day for 7 d, started on day 7). Intravenous mesna 500 mg/m2 was given at hour 0, 3, 7, and 11 of each day ifosfamide was used. Treatment was to be recycled every 3 wk provided the following conditions were met: physical condition compatible with chemotherapy, neutrophil count >1000/mm3 or >500/mm3 if they were increasing, platelet count >100 000/mm3, and absence of residual nephrotoxicity. No subsequent dose reduction was planned in case of neutropenic fever.
2.2.
Management of postchemotherapy residual masses
A CT scan was to be performed after completion of chemotherapy. Originally, the policy for the management of postchemotherapy residual masses was as follows: (1) For residual masses <3 cm, no further treatment was recommended and CT scan surveillance was to be performed (once every 3 mo for the first year and then once every
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EUROPEAN UROLOGY 65 (2014) 381–386
4 mo for the second year). (2) For residual masses 3 cm, a control CT scan was recommended approximately 2 mo later to detect a late response. In the case of a stable residual mass still 3 cm, resection was recommended. Radiation therapy was not recommended for residual masses. During the course of this study, the importance of FDG-PET for assessing postchemotherapy residual masses was progressively recognized [11,18] and implemented.
2.3.
Registration
Patients were prospectively registered by sending an inclusion form to the Biostatistics Department at the Institut Gustave Roussy, Villejuif, France.
2.4.
Statistical methods
Survival times were calculated from the date of chemotherapy initiation to the date of progression or death (progression-free survival [PFS]) and the date of death (for OS). Survival curves were estimated using the Kaplan-Meier method. Curves were compared using the log-rank test. No formal hypothesis regarding response or survival was initially put
characteristics. The median age was 37 yr (interquartile range: 33–43). Most patients had a good prognosis according to the MRC classification (n = 108) or according to the IGCCCG classification (n = 126). 3.1.
Toxicity
All 132 patients received the allocated chemotherapy regimen. Table 2 summarizes the grade 3–4 toxicity by regimen. As expected, the VIP regimen was associated with grade 3–4 hematologic toxicity more often, including neutropenic fever (23% vs 12%). One patient (0.8%) in the VIP group died of septic shock during treatment. Transfusion was more often required in patients in the VIP group (red cell transfusion: 9 [39%]; platelet transfusion: 8 [35%]) than in the EP group (10 [9%] and 1 [1%], respectively). More patients in the EP group (n = 104; 97%) were able to receive the planned four cycles than those in the VIP group (n = 21; 88%).
forward. The accrual objective was to ensure that at least 20 patients per prognostic group would be evaluable, taking into account the rarity of
3.2.
disseminated seminoma. Toxicity was assessed using National Cancer
masses
Response to chemotherapy and management of residual
Institute Common Toxicity Criteria.
3.
Results
From December 1999 to September 2008, 132 patients from 12 French centers were accrued. Table 1 lists their
Among the 128 patients assessable for response, 36 achieved a complete response to chemotherapy (defined as no detectable residual masses on CT scan): 32 of 106 (30%) in the good prognosis group and 4 of 22 (18%) in the intermediate/poor prognosis group (Fig. 1).
Table 1 – Patient population Good prognosis group (n = 108)
Intermediate/poor prognosis group (n = 24)
37 (21–67)
38 (27–63)
94 (87) 7 (6) 7 (6)
20 (83) 1 (4) 3 (13)
81 26 9 2
0 24 (100) 5 (21) 0
Age, yr, median (range) Primary tumor site, no. (%) Testis Retroperitoneum Mediastinum Staging, no. (%) Stage II Stage III Previous radiotherapy, no. (%) Previous carboplatin for stage I seminoma, no. (%) IGCCCG group, no. (%) Good risk Intermediate risk
(75) (25) (8) (2)
108 (100) 0
18 (75) 6 (25)
Overall population (n = 132) 37 (21–67) 114 (86) 8 (6) 10 (8) 81 50 14 2
(62) (38) (11) (2)
126 (95) 6 (5)
IGCCCG = International Germ Cell Cancer Collaboration Group.
Table 2 – Grade 3–4 toxicity Grade 3–4 toxicity
Neutropenia Anemia Thrombocytopenia Neutropenic fever Nausea and vomiting Renal Liver Audio Toxicity-related deaths
Good prognosis group (EP) (n = 108), no. (%) 48 5 2 13 4 0 0 1 0
(47) (5) (2) (12) (4)
(1)
Intermediate/poor prognosis group (VIP and G-CSF) (n = 24), no. (%) 8 (36) 5 (24) 5 (23) 5 (23) 1 (4) 1 (4) 1 (4) 0 1 (4) (septic shock)
EP = cisplatin-etoposide; G-CSF = granulocyte colony-stimulating factor; VIP = EP and ifosfamide.
Overall population (n = 132), no. (%) 56 10 7 18 5 1 1 1 1
(45) (8) (5) (14) (4) (0.8) (0.8) (0.8) (0.8)
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EUROPEAN UROLOGY 65 (2014) 381–386
[(Fig._1)TD$IG]
Table 3 – Reported outcome in metastatic seminoma treated with chemotherapy (95% confidence intervals)
Patients evaluable after chemotherapy (n = 128)
IGCCCG 1997 [11] Complete responses (n = 36; 28%)
Surveillance (n = 65; 71%)
Residual masses postchemotherapy (n = 92; 72%)
Surgical resection (n = 20; 21%)
Radiotherapy (n = 4; 4%)
Resection plus radiotherapy (n = 1; 1%)
PFS, % (range) 3 yr 5 yr OS, % (range) 3 yr 5 yr
MRC 1997 [12]
Present study
NA 81 (78–84)
84 (80–88) NA
91 (84–95) 85 (76–91)
NA 85 (82–88)
85 (81–89) NA
96 (91–99) 92 (83–96)
IGCCCC = International Germ Cell Cancer Collaboration Group; MRC = Medical Research Council; NA = not available; OS = overall survival; PFS = progression-free survival.
Viable seminoma (n = 1) Teratoma (n = 1)
3.3.
Progression-free survival and overall survival
Fig. 1 – Patient management after chemotherapy.
Among the 92 patients with postchemotherapy residual masses on CT scan, the median size of masses was 29 mm (range: 7–200 mm). Postchemotherapy treatment in these 92 patients was as follows: surveillance (65), resection of residual masses (20), radiotherapy (4), resection plus radiotherapy (1), and missing information (2). Overall, 76 patients underwent an 18F-FDG PET after chemotherapy (CT scan had detected residual masses in 60 of them), which was deemed normal in 58 (76%). Postchemotherapy treatment consisted of surveillance in 54 of 58 patients (93%) with a normal FDG-PET.
[(Fig._2)TD$IG] (a)
100% 80%
The median follow-up is 4.5 yr (range: 0.4–11.6 yr). Eight patients experienced progression or a relapse, three of whom subsequently died. The 3-yr PFS rate was 93% (range: 85–97%) in the good prognosis group treated with EP and 83% (range: 63–93%) in the intermediate/poor prognosis group treated with VIP ( p = 0.03 for PFS). The 5-yr PFS rate was 88% (range:77–93%) and 76% (range: 53–90%), respectively (Fig. 2). The 3-yr OS rate was 99% (range: 92–100%) in the good prognosis group treated with EP and 87% (range: 67–95%) in the intermediate/poor prognosis group treated with VIP ( p < 0.005 for OS). The 5-yr OS rate was 93% (range: 83–97%) and 87% (range: 67–95%), respectively. Table 3 shows the PFS and OS data for the overall population. The causes of the nine deaths included two seminomas, one first-line chemotherapy-related toxicity, one salvage chemotherapy–related toxicity, one second cancer (carcinoma of the larynx), two other causes, and two unknown causes.
60%
4.
40% p = 0.0334 20% 0% 0 95 23
At risk
(b)
1 86 21
2 71 16
3 60 14
4 49 9
5 34 6
6 23 4
Years
100% 80% 60% 40%
p = 0.0044
20% 0% At risk
0 107 23
1 95 22
2 80 17
3 66 15
4 55 11
5 37 8
6 Years 25 5
Fig. 2 – (a) Progression-free survival and (b) overall survival by risk group (red curve: good-risk; blue curve: intermediate/poor risk).
Discussion
Advanced seminoma requiring chemotherapy is a rare situation. There are only a few reported prospective studies comprising >100 patients [6,19]. We report here the results of a national treatment policy applied prospectively in 132 patients over a decade, with the treatment burden adapted to the prognosis. This strategy led to an OS of 96%, with ultimately only two patients dying of progressive seminoma. According to published evidence and guidelines [1,10], patients requiring first-line cisplatin-based chemotherapy are those with a bulky clinical stage II seminoma (with an ongoing debate over what the lymph node diameter cut-off should be for the choice between radiotherapy and chemotherapy), extraretroperitoneal lymph node dissemination, or a primary mediastinal seminoma [4]. These patients with advanced seminoma represented only 9% (29 patients) of the 339 patients included in a recently reported European Organization for Research and Treatment of Cancer phase 3 trial focusing on IGCCCG intermediate-risk advanced GCT [20]. In the large (n = 1384) Swedish and Norwegian testicular cancer group (SWENOTECA) program collecting virtually all patients with seminoma treated in these two countries from 2000 to 2006, only 73 patients (5%)
EUROPEAN UROLOGY 65 (2014) 381–386
and 42 patients (3%) with stage IIA–B and stage IIC–D seminoma, respectively, were treated with EP-based chemotherapy [21]. This rarity makes it unlikely that a randomized phase 3 trial will be conducted specifically in these patients. The two regimens currently recommended for patients with good-risk advanced seminoma are four cycles of the EP regimen or three cycles of the BEP regimen [1,10]. Four cycles of EP were administered in most of the published studies [7–9,14,21], and this regimen was chosen in the current trial. With a 3-yr OS rate of 99% (range: 92–100%) in the good prognosis group, our data indicate that this treatment is appropriate for most patients, and they also raise the question as to whether a decrease in the chemotherapy burden could be attempted. To test this hypothesis, a GETUG trial exploring the role of FDG-PET for the early assessment of response after two cycles of EP is ongoing, specifically to limit the number of chemotherapy cycles and thus the risk of long-term ototoxicity and peripheral neurotoxicity [22]. Although numerous studies indicate that bleomycin should be used in good-risk nonseminoma and that three cycles of the BEP regimen should be preferred over four cycles of EP (with 5 vs 12 deaths reported in a randomized trial comparing the two regimens [23]), such evidence has not been conclusively provided in metastatic seminoma. However, there is a clear demonstration that single-agent carboplatin therapy is not as efficient as cisplatin-based combination regimens for patients with advanced seminoma [6]. The 3-yr OS rate of 99% (range: 92–100%) achieved in the good prognosis advanced seminoma group in this study indicates that almost universal cure can be obtained when these patients are adequately treated with four cycles of EP. Only very limited published data are available for patients with intermediate prognosis seminoma according to the IGCCCG [12] classification or poor prognosis seminoma according to the MRC [13] classification. For example, in the SWENOTECA experience of 1384 patients with seminoma, only 6 (0.4%) had intermediate prognosis disease according to the IGCCCG [21]. Guidelines recommend four cycles of the BEP regimen for these patients [1], although this is based on an analogy with intermediate prognosis nonseminoma and not on a randomized trial focusing on seminoma or even on large prospective noncomparative data. In this study, 24 patients with intermediate/poor prognosis seminoma (according to IGCCCG or MRC classifications) were prospectively treated with four cycles of the VIP regimen plus G-CSF. The rationale for replacing bleomycin with ifosfamide in the triplet was based on the well-recognized activity of ifosfamide in seminoma [15]. Four cycles of VIP is a recognized alternative to four cycles of BEP for intermediate or poor prognosis metastatic germ cell tumors [1,24,25]. The 3-yr PFS rate of 83% (range: 63–3%) achieved in the present study with four cycles of VIP compares favorably with the 56% rate reported in poor prognosis seminoma by the MRC [13]. This possible increased efficacy of four cycles of VIP is to be balanced with the wellrecognized toxicity of this regimen, including one death due to septic shock in this study. Whether standard
385
treatment should be four cycles of VIP or four cycles of BEP in intermediate prognosis seminoma will likely be impossible to sort out with a phase 3 trial given the rarity of this situation. Both regimens should be considered possible options based on the available evidence. The management of postchemotherapy residual masses has evolved during the last 2 decades: FDG-PET avoids a high number of unnecessary resections and is now a recognized standard. Extensive experiences reported a high negative predictive value [11], although false-positive results have recently been reported to occur more often than originally thought [26]. The timing of FDG-PET is critical to avoid false positives; it should not be performed before 6 wk after day 21 of the last chemotherapy cycle [11]. In a rare disease like metastatic seminoma, which is almost universally curable with inexpensive cheap and widely available drugs, cumulative data indicate that guidelines are not properly followed in many countries, thus potentially reducing the chances of curing patients [27,28]. Although no progress in germ cell tumors has been directly demonstrated by randomized trials during the last 25 yr [29], an indirect and unrecognized benefit of performing national or international multicenter prospective studies may well be the improvement of the quality of care for patients with these rare tumors, probably because physicians may be more inclined to follow protocol rules than to refer to guidelines. 5.
Conclusions
The 96% OS rate achieved in the present study shows that excellent results can be obtained in a multicenter setting when treating metastatic seminoma in regional cancer centers or university hospitals if a rigorous protocol is followed. Author contributions: Karim Fizazi had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Fizazi, Culine, Laplanche. Acquisition of data: Fizazi, Delva, Caty, Chevreau, Kerbrat, Rolland, Priou, Geoffrois, Rixe, Beuzeboc, Malhaire, Culine, Aubelle, Laplanche. Analysis and interpretation of data: Fizazi, Laplanche, Aubelle. Drafting of the manuscript: Fizazi. Critical revision of the manuscript for important intellectual content: Fizazi, Delva, Caty, Chevreau, Kerbrat, Rolland, Priou, Geoffrois, Rixe, Beuzeboc, Malhaire, Culine, Aubelle, Laplanche. Statistical analysis: Aubelle, Laplanche. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Fizazi. Other (specify): None. Financial disclosures: Karim Fizazi certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
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