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Pure seminoma is a rare pathology of the young adult, often discovered in the early stages. Its prognosis is generally excellent and many therapeutic options are available, especially in stage I tumors. High cure rates can be achieved in several ways: standard treatment with radiotherapy is challenged by surveillance and chemotherapy. Toxicity issues and the patients’ preferences should be considered when management decisions are made. This paper describes firstly the management of primary seminoma and its nodal involvement and, secondly, the various therapeutic options according to stage. Keywords: Seminoma, treatment, radiotherapy, chemotherapy, surveillance Testicular cancers, 95% of which are germ-cell tumors Diagnosis and surgical management (GCT), are the most common solid malignancies affect- Testicular cancer commonly presents as a unilateral ing males between the ages of 15 and 35 years, although lump or painless swelling noticed incidentally. Pain is it accounts for only about 1% of all cancers in men . less common, with a third of patients presenting with a In 2010 it caused an estimated 350 deaths with 8480 dull ache, and acute pain is uncommon, occurring in new cases diagnosed in the United States alone . In 10% of patients at presentation. Testis cancers uncom- Switzerland, and particularly in the Vaud canton, its monly present with symptoms related to metastatic dis- prevalence is one of the world’s highest, and is still ease . The clinical examination may uncover a increasing . Nevertheless its origin remains poorly testicular enlargement, and ultrasound examination con- understood, although some environmental or genetic firms the existence of an intrascrotal tumor . Pure risk factors are suspected . It is also known to be testicular seminomas do not have specific serum tumor bilateral in 3% of cases . GCT may consist of one pre- markers, but in certain cases can produce a small dominant histologic pattern or represent a mixture of amount of bHCG (b-subunit of human chorionic gona- multiple histologic types. For treatment purposes, two dotropin) . broad categories are recognized: pure seminoma (no High inguinal orchiectomy is the standard initial treat- nonseminomatous elements present), and all others, ment for suspected testicular carcinoma . This strategy which together are termed nonseminomatous germ-cell allows accurate staging and histological diagnosis of the tumors (NSGCT). Seminoma, 80% of which are diag- tumor, while ensuring the best local control and minimiz- nosed at stage I (Table 1), is highly sensitive to both ing treatment morbidity. Nonstandard surgical approaches radiotherapy (RT) and chemotherapy (CHT) and, there- (scrotal violations), including scrotal orchiectomy, open fore, unlike many malignant neoplasms, cure is an testicular biopsy and fine needle aspiration, have histori- expected outcome in the majority of cases, even with cally been condemned as significantly compromising prog- metastatic disease at presentation . Its prognosis is nosis. Patients with scrotal violation are often subjected to generally good, but the treatment-induced morbidity potentially morbid or disfiguring local therapies. In addi- must not be underestimated. tion, patients with scrotal violations are usually disqualified from surveillance protocols . Several groups have proposed organ-sparing orchiect- * Correspondence: email@example.com omy as an alternative option for a small group of † Contributed equally patients with bilateral testicular tumors, lesions in a soli- Department of Radiation Oncology, Centre Hospitalier Universitaire Vaudois tary testis, or metachronous contralateral tumors. This (CHUV), Bugnon 46, CH-1011 Lausanne, Switzerland Full list of author information is available at the end of the article © 2011 Boujelbene et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Boujelbene et al. Radiation Oncology 2011, 6:90 Page 2 of 12 http://www.ro-journal.com/content/6/1/90 Table 1 Classification of seminomas according to UICC/AJCC and IGCCCG [7,61] Clinical TNM (UICC/AJCC) Category Blood tumor markers Stage (S) T N M S LDH bHCG AFP (mIU/ (ng/ ml) ml) 0 pTis carcinoma in situ N0 M0 - - - - IA pT1 Limited to the testis and/or epididym, without lymphatic or N0 M0 Any Any Any Norm. vascular invasion, the tumor can infiltrate the tunica albuginea but S LDH bHCG not the tunical vaginalis level level level IB pT2 Limited to the testis and/or epididym, without lymphatic or N0 M0 Any Any Any Norm. vascular invasion, or spread through the tunica albuginea and S LDH bHCG invasion of the tunica vaginalis level level level pT3 Infiltration of the spermatic cord pT4 Infiltration of the scrotal wall IIA Any N1 (≤ M0 Any Any Any Norm. T 2 cm) S LDH bHCG stage level level level IIB Any N1 (> M0 Any Any Any Norm. T 2- 5 S LDH bHCG stage cm) level level level IIC Any N1 (> M0 Any Any Any Norm. T 5 cm) S LDH bHCG stage level level level IIIA/B/C Any Any N M1a (non-regional Any Any Any Norm. T stage nodes or lung S LDH bHCG stage metastasis) level level level IIIC Any Any N M1b (other Any Any Any Norm. T stage metastasis sites) S LDH bHCG stage level level level IIIC Mediastinal primary tumor Any N Any M stage Any Any Any Norm. stage S LDH bHCG level level level LDH: lactate deshydrogenase, bHCG: Beta Human chorionic gonadotrophin, AFP: alpha-fetoprotein, T: tumor, N: nodes, M: metastasis, S:blood marker, AJCC: American Joint Committee on Cancer, UICC: International Union Against Cancer, IGCCCG: International Germ Cell Cancer Collaborative Group approach allows endocrinological, fertility, and psycholo- normal endogenous serum testosterone levels and did gical advantages for the patient, especially in younger not need exogenous androgen replacement . men . The German Testicular Cancer Intergroup and Anatomic studies and detailed mapping studies of ret- others have reported prospective data on partial orch- roperitoneal lymph node dissections have increased our iectomy for GCT in a small subset of carefully selected understanding of testicular lymphatic drainage and have patients with a solitary testis or bilateral testicular sharpened the focus of clinical staging and treatment by tumors . Selection criteria in these studies included: identifying the most likely sites of metastatic disease. organ-confined disease with no infiltration of the rete- The first echelon of lymph nodes draining the right tes- testis; a mass of < 2 cm in order to preserve testoster- tis is located in the inter-aortocaval region, followed by one-producing parenchyma; a negative postresection the precaval and pre-aortic nodes . Regarding left- biopsy of the tumor bed; and conditions of cold ische- sided tumors, the first nodal stations include the pre- mia to preserve the function of Sertoli and Leydig cells. aortic and para-aortic lymph nodes, left renal hilar Heidenreich et al. have treated 73 patients with GCT nodes followed by the inter-aortocaval nodes . Con- with partial orchiectomy using these criteria. Among tralateral spread is common with right-sided tumors but these, 17 were synchronous, 52 were metachronous and is rarely seen with left-sided tumors and is usually asso- 4 occurred in a solitary testicle. After a median follow- ciated with bulky disease . More caudal deposits of up of 91 months, 98.6% of patients had no evidence of metastatic disease usually reflect retrograde spread to diseaseand onediedofsystemictumor progression. distal iliac and inguinal lymph nodes secondary to a The presence of carcinoma in situ was described in large volume of disease and, more rarely, aberrant testi- cular lymphatic drainage. 82.3% of patients. Eighty-five percent of all patients had Boujelbene et al. Radiation Oncology 2011, 6:90 Page 3 of 12 http://www.ro-journal.com/content/6/1/90 Data comparing para-aortic nodal spread between studies [11,12,14-16]. Some authors consider spread to seminomatous and nonseminomatous testicular tumors the rete-testis as a negative prognostic factor [12,14,16] do not exist. From a theoretical point of view, we con- even it is not yet validated. The almost optimal cure sider that the primary zone of spread of testis tumors is rate in these patients is close to 100%, regardless of similar, and is not dependent on the histology . In these features. This can be achieved with one of three all cases, those nodal areas are in close proximity to the treatment options: surveillance with treatment only in L1-L4 sympathetic roots of the superior hypogastric the case of relapse, adjuvant RT, or adjuvant single- plexus. When oncologically possible, they should be agent carboplatin CHT [11,17,18]. With a cause-specific spared at least unilaterally to preserve the ejaculation survival rate of 100%, the question is no longer ‘how function.Thisgoesagainst theancient dogmathat can the disease be cured?’ but rather ‘how can we retain required a systematic and extended bilateral node dis- this excellent cure rate with theleastriskofshort-and section. Contrary to NSGCT, retroperitoneal lymph long-term consequences?’. Decisions regarding the man- node dissection (RPLND) is no longer regarded as a agement of stage I seminoma in any individual are thus valid therapeutic option in seminomas . complex, and we need to take into account concerns A good knowledge of the pathways of lymphatic nodal about long-term complications of RT and CHT, as well spread is essential for the radiation oncologist in the as the patient’s ability to comply with intensive planning of the radiation treatment of the retroperito- surveillance. neal region. Active surveillance Histology Surveillance policies offer the opportunity to detect Seminoma can be divided into three pathologic cate- relapsing patients early whilst avoiding the morbidities gories: classical, spermatocytic, and seminoma with syn- and risks of treatment for most . No prospective cytiocytotrophoblastic cells. The spermatocytic type is studies exist comparing surveillance alone versus adju- rare, occurs in older men, and may have a better prog- vant treatment (RT or CHT). Several large prospective nosis. The classical and the syncytiocytotrophoblastic nonrandomized studies of surveillance have been con- types of seminoma behave similarly, although the syncy- ducted over the past 15 years. Reports have demon- tiocytotrophoblastic subtype is associated with increased strated the feasibility of surveillance protocols, serum bhCG levels. Occasionally, seminoma may con- particularly when associated with effective salvage regi- tain numerous mitotic figures. When three or more mens . Retrospective series from the Royal Marsden mitotic figures are identified per high power field Hospital London, from the Princess Margaret Hospital throughout the tumor, it is designated as seminoma (PMH), Toronto, and from a national collaboration in with high mitotic index or anaplastic seminoma. Denmark, have all concluded that surveillance is a rea- Historically, anaplastic seminoma was thought to be a sonable policy, albeit with some practical difficulties in more aggressive subtype of seminoma but subsequent view of the lack of sensitivity of specific serum markers data failed to confirm this finding [12,13]. As an exam- [15,20,21]. Consensus guidelines accept surveillance as ple, in a retrospective analysis of prognostic factors for an option, which can be offered to stage I seminoma relapse among 638 men with stage I seminoma, there patients following orchiectomy . A recent paper was only a trend towards worse five-year relapse-free which analyses retrospectively a total of 649 patients survival with anaplastic as compared to classical histol- reports the evolution of treatment with an increased use ogy (83 vs 71%, p = 0.056); in multivariate analysis, only of active surveillance for stage I disease (545 patients) tumor size and rete-testis invasion were significant pre- without deaths related to seminoma . The predomi- dictors of outcome . Most seminomas are confined nant site of relapse is in the para-aortic lymph nodes to the testicle. Spread beyond the tunica into the sper- and most patients are asymptomatic at the time of matic cord occurs only in a minority of patients. detection. In the DATECA (Danish Testicular Carci- noma Study Group) and in the PMH retrospective stu- Stage I seminoma dies, 41 of 49 relapses (82%) and 54 of 67 relapses (89%) Seminoma patients with clinical stage I (about 85% of all occurred in the para-aortic lymph nodes, respectively. stages) have a substantial risk of locoregional lymph Other sites of relapse included the pelvic lymph nodes node micrometastases with a 20% risk of disease pro- (approximately 3% overall), and very rarely the inguinal gression if no adjuvant therapy is administered after nodes and the lungs [19,21]. orchiectomy. A primary tumor size of 4 cm or more Active surveillance permits avoiding development of a and invasion of the rete testis have been identified as second malignancy which is a concern for anyone independent factors associated with an increased risk of exposed to RT or CHT, especially in men with early stage seminoma who are expected to survive for decades relapse in multivariate analysis in many retrospective Boujelbene et al. Radiation Oncology 2011, 6:90 Page 4 of 12 http://www.ro-journal.com/content/6/1/90 following treatment [23-25]. Data on the association of willingness and ability to adhere to a surveillance pro- infradiaphragmatic RT with subsequent cardiovascular gram. Patients and families should also be informed of disease are conflicting [26,27]. The largest study to date the salvage treatment options and their potential risks. has included 40.576 testicular cancer survivors from 14 population-based tumor registries in Europe and North Radiation therapy America . More than 7800 were followed for 20 Seminoma cells are extremely radiosensitive, and radia- years and 2065 for 30 years. An increased risk of second tion therapy has been widely used for more than 60 solid cancers was seen among men treated with RT years, and has an excellent long-term track record. This alone (RR 2.0), CHT alone (RR 1.8), and with both mod- modality is still a standard management in pure semino- alities (RR 2.9) [23,24]. Other rare complications may mas in the United States, and in Europe it is used quite happen, such as renal artery stenosis after RT . often [33,34]. The main drawback of surveillance is the need for Historically, RT was delivered by a cobalt source using intensive follow-up and repeated imaging for at least 5 two parallel opposed anterior and posterior treatment to 10 years after radical orchiectomy. Disadvantages fields, were defined with the help of bony landmarks. include expensive imaging tests, radiation exposure, Thedosewas 30 Gy using15 fractions.The treated anxiety related to the risk of recurrence and the poten- areas were the para-aortic, homolateral external iliac tial for patients to be noncompliant with follow-up nodes and the orchiectomy scar. This technique was [29,30]. While there is a high rate of cure for patients known as the «dog-leg». The fields spread generally up who experience recurrence and undergo definitive treat- to the superior aspect of D11 or D10 down to the ingu- ment , they are likely to require combination CHT, inal ligament. This was the standard method until the which has a greater toxicity risk than adjuvant treatment beginning of the 1980’s. Since the 1990’s, following the with RT or single-dose carboplatin . There is no low pelvic relapse rates reported in stage I tumors (less consensus regarding the optimum follow-up for these than 5%), the indication for pelvic irradiation was chal- patients . Currently, patients at PMH are followed lenged [10,35,36]. The results of this new approach were up with regular physical examination, measurement of excellent with a low pelvic relapse rate [37-39]. The serum tumor markers, and imaging for retroperitoneal reduced volume permits limiting the area, preserving and chest disease. Patients are followed up at 4-monthly the remaining testicular function and will hopefully intervals for the first 3 years, 6-monthly intervals in decrease the secondary cancer rate [40,41]. However years 4-7, and yearly intervals thereafter. At each visit, a this strategy is still debated  in spite of the very well CT scan of the abdomen and pelvis is performed. Chest conducted randomized study by the Medical Research x-rays are obtained at alternate visits. Serum tumor Council (MRC) Testicular Cancer Working Party. In marker levels are measured at each visit for the first 3 this trial 478 patients were randomized between para- years of surveillance . Some clinicians feel that there aortic and pelvic RT versus para-aortic RT alone. The is an unnecessary number of CT scans with this scheme. dose was 30 Gy in 15 fractions in both arms. The The healthy testis must be closely watched during fol- relapse rate was 3.4% in the first group, and all recur- low-up, as the long-term risk of developing a contralat- rences were localized above the diaphragm versus 4% in eral testis cancer after a previous seminoma is about 2- the second group with 1.6% in the pelvis. Gastrointest- 5%. This usually occurs within the first 6 years and the inal side effects were less important in the second risk decreases with time . During clinical examina- group. Patients with a scrotal, inguinal or pelvic surgical tion, the palpation of the testis must be systematic. historywereexcludedfromthetrial[43,44].A recent Teaching of auto-palpation techniques is also interesting retrospective Australian study contradicts this irradia- and efficient, and should be done whenever possible. In tion option, arguing that despite the proven efficiency of high-risk patients (fertility problems, testis atrophy, his- the irradiation in the patients known to have had cryp- tory of cryptorchidism, contralateral testis microcalcifi- torchidism, surveillance alone or chemotherapy are still cations on the ultrasound), an annual doppler valid options . ultrasound exam can be advised to detect early relapse, Looking for a way to combine those two treatment and allows conservative treatment . In the mean- options, Thomas et al. have proposed a para-aortic and while, risk assessment for recurrence based on rete-testis common iliac vessel (inferior limit at the acetabulum) involvement and tumor size is the best model until now. irradiation field. This technique is used at the PMH This model has never been validated independently, but , and allows the inclusion of most of these possible we believe it can help us to assess risk of recurrence in relapse regions . our daily practice. In the context of potential risks and However, we note that the irradiation of the para-aor- benefits of treatment, physicians should consult with the tic nodes alone yields good results and that the risk of patient, and family if necessary, to determine the nodal relapse exists but is quite low. We find that a Boujelbene et al. Radiation Oncology 2011, 6:90 Page 5 of 12 http://www.ro-journal.com/content/6/1/90 clinical target volume (CTV) on the right side, compris- short- and long-term complications [24,46,52-54]. The ing the paracaval, precaval and inter aortocaval nodes is development of new medical imaging and exploration justified. The left side should comprise, additionally, the techniques has also greatly improved the quality of latero-aortic, pre-aortic and left renal hilar nodes treatment. Currently, irradiation is delivered by a high- [6,7,10,35]. The inguinal orchiectomy scar and ipsilateral energy linear accelerator with a conformational techni- scrotal contents are not treated unless scrotal violation que, allowing the shaping of the treatment fields to the has occurred during surgery. We propose a planned tar- expected target volume which was planned with CT- get volume (PTV) as the CTV plus a 0.5 cm margin in scan images and 3D reconstruction (RT3D). With the all directions. help of multiple irradiation beams, this technique allows The optimal RT dose is also still a matter of contro- a better definition of the target volumes and a maximal versy . Generally, the recommended dose is between sparing of the neighboring critical organs such as kid- 25 and30 Gy in15to20fractions.The MRCtrialis neys, spinal cord..... Computerized dosimetry and dose- the only randomized study that evaluates a dose de- volume histograms are now commonly used . In our escalation. It compared a dose of 20 Gy versus 30 Gy institution, we have treated several cases of seminoma with conventional fractionation in 625 patients. Ten per- by Intensity-Modulated Radiation Therapy (IMRT) (Fig- cent of the patients were treated with a « dog-leg » field, ure 1). Many institutions tend to use the knowledge and 90% with para-aortic fields. The relapse rates after a provided by functional imaging, associated with conven- median follow-up of a little more than five years were tional imaging to better define the target volumes. Stu- not significantly different. The 20 Gy arm showed a dies on the role of PET/CT (positron emission slightly lower acute toxicity rate (moderate asthenia 5% tomography coupled with a CT-scan) in the determina- vs 20%, work incapacity 28 vs 46%). The only death due tion of treatment volumes are also under way . to the primary disease was in the 20 Gy arm . Following this MRC publication,wealsouse the20 Chemotherapy Gy dose option with a two-week treatment time, which Cisplatin-based combination CHT is the gold standard is now the standard in our institution. in treating advanced testicular cancer, including both The long term specific survival rate after RT reaches seminomatous and nonseminomatous tumors. Carbopla- 100% and the disease free survival about 95-97% tin is often preferred because of its better toxicity pro- [15,43,46,47]. The RT regimen is well tolerated by most file. In a phase II study, Oliver et al. were the first to of the patients. The rare deaths in most of the series are describe the use of carboplatin in stage I seminomas. usually due to intercurrent disease. In older studies Seventy-eight patients were included (53 with two where patients received prophylactic mediastinal and cycles, 25 with one), and after a 44-month median fol- supraclavicular node irradiation, a significant number of low-up, only one relapse was observed . In 2005, deaths were due to secondary cancers and radiation- induced cardiac toxicity. In single or multicenter studies with a sufficient num- ber of patients, the relapse rates were below 5% and the relapses within the RT field were rare [19,43,48,49]. In those cases, a biopsy was needed to avoid missing a dif- ferent histology, such as a nonseminomatous tumor. Relapses were located mostly in the mediastinum, the supraclavicular region and the lungs. The inguinal region was seldom involved (about 0.5%) and only in particular cases such as after a prior inguinal surgery . In many ways, RT was a victim of its own success, because given the very high cure rates and the fact that many men were diagnosed with testicular cancer at a young age (< 30 years), patients lived long enough to develop late RT toxicities RT . Interest of new radiotherapy techniques In most of the old seminoma series, treatment was Figure 1 Axial view showing planning target volume and based on 2D irradiation techniques with cobalt isodose distribution using TomoTherapy, sparing kidneys and machines and at higher doses compared to current spinal cord in the case of stage I seminoma. recommendations. All this could be the cause of many Boujelbene et al. Radiation Oncology 2011, 6:90 Page 6 of 12 http://www.ro-journal.com/content/6/1/90 Oliver et al. reported the results of a multicenter rando- acid) radio isotope clearance rate. This product is not mized study. The latter included 1477 patients, and Food and Drug Administration (FDA) authorized yet compared adjuvant para-aortic RT (para-aortic strip or but other products exist today such as the iodine-125 dog-leg field and 20 or 30 Gy depending on the center) iothalamate sodium or more simply the 24 hours versus a single-cycle carboplatin CHT (area under curve proteinuria. (AUC) of 7 mg/ml/min) (Table 2) . This non-infer- Current recommendation is to administer either a sin- iority trial showed a comparable 3-year disease-free sur- gle carboplatin dose (that must be properly dosed with the help of renal scintigraphy) or two cycles spaced vival time between both arms (94.8 vs 95.9%; p=0.32) three weeks apart . Although these recommenda- . These results were still comparable after a 6.5 years follow-up . As a general rule, both treatments tions are not yet supported by randomized studies, sev- were well tolerated but with different toxicity profiles. eral phase II studies have evaluated the use of a 2-cycle With a little less asthenia, acute toxicity was somewhat carboplatin regimen. These results appear promising but less severe in the CHT arm. Long-term toxicity profiles longer follow-up and a phase III study are still needed. are however, not yet available . Only one seminoma- Although the therapeutic equivalence between carbo- related death was recorded in the radiotherapy arm. platin and classic RT is well established, its long-term Interestingly, there were significantly less contralateral effects are still unknown. The sites of relapse after car- germinal cell tumors in the CHT arm (p = 0.003). boplatin and surveillance alone are comparable: both are Among relapses, there was more para-aortic (74 vs 9%) often isolated and retroperitoneal . and pelvic nodal relapse (31 vs 0%) in the para-aortic In conclusion, the efficiency of the three different RT arm, showing the importance of RT in the preven- therapeutic options presented here seems to be equiva- tion of those relapses [18,58]. One criticism about this lent. RT series, being the reference treatment, have a study was that it was designed to exclude a 3% relapse longer track record compared to the two newer options risk in the carboplatin arm - it achieved an exclusion (Table 3, 4). power of only 3.6% (95% confidence interval), the main goal consequently not being achieved. Stage II seminoma There is a slightly increased relapse risk with the sin- Stage II seminoma are usually managed with RT or pla- gle-dose carboplatin regimen, as seen in one prospective tinum-based combination CHT following orchiectomy. study (9% vs 0%) . This was also the case in the Obviously, surveillance is not an appropriate option for update of the MRC/EORTC (European Organization for these men, and therapeutic RPLND has been largely Research and Treatment of Cancer) trial . replaced by CHT and/or RT . No prospective rando- Generally, the Calvert formula ("Calvert formula total mized trial has been published to date for the treatment carboplatin dose (mg) = (target AUC) × (GFR+25)”)is of stage II seminoma. The optimal treatment depends used to find the optimal dose of carboplatin . The on the spread of lymph node invasion. calculated glomerular filtration rate (GFR) based on In old series, a difference between “bulky” and “non- the blood creatinin level is often underestimated. This bulky” disease was often made, but its precise definition can lead to a wrong dose. The MRC/EORTC trial used varied between different centers. Mostly bulky disease a chromium-51 EDTA (Ethylenediaminetetraacetic was characterized by masses less than 7, most often, 5 Table 2 Relapses and survival in randomized controlled trials in stage 1 seminoma Reference/No. of Treatment Total No. pelvic Relapse-free survival Other patients relapses relapses  20 Gy RT (n = 313) 11 3 At 2 years: 97% 8/9 pelvic relapses occurred in the PA n = 625 RT field group 30 Gy RT (n = 312) 10 6 At 5 years: 97%*  DL RT (n = 242) 9 0 At 3 years: 96.6% At 5 3-years OS: 100% n = 478 years: 96.2%* PA RT (n = 236) 9 4 At 3 years: 96% At 5 3-years OS: 99.3% years: 96.1%* [18,58] RT: PA or DL, 20 or 30 36 10 At 3 years: 95.9% At 5 - All pelvic relapses occurred in the PA RT n = 1477 Gy (n = 904) years: 96%* group - 74% of relapses in the carboplatin group occurred in the PA nodes 1 cycle carboplatin 29 0 At 3 years: 94.8% At 5 (n = 573) years: 94.7%* RT: radiation therapy; DL: Dog-Leg; PA: para-aortic; OS: overall survival;* data retrieved in update. Boujelbene et al. Radiation Oncology 2011, 6:90 Page 7 of 12 http://www.ro-journal.com/content/6/1/90 Table 3 Outcome of patients treated for seminoma from 1999 to 2008  Stage Treatment Number of 5-Year Second 5-Year disease- 5-Year overall Dead of disease/ Death other patients relapse rate relapse, n specific survival (%) survival (%) treatment, n (%) cause, n (%) (%) Surv 313 19.3 3 (1%) 100 99 0 2 (1) I RT 159 2 0 100 99.3 0 1 (1) Carb 73 2 0 100 100 0 0 RT 19 8.3 0 100 92.3 0 1 (3) II CHT 65 4.5 0 100 90.7 3 (5%) 2 (3) Other 3 0 0 100 100 0 0 III CHT 17 0 0 100 100 0 0 a: After RT for first relapse. Carb, single-agent carboplatin; CHT, primary combination chemotherapy; Other, other treatment modalities or combination of treatment modalities; RT, radiation; Surv, surveillance. cm in diameter. This corresponds to the latest TNM of PEB or PE CHT represents a valid option depending classification of N1-N2 and N3 stages (Table 1) . of the prognostic group . Unlike stage I disease, a After orchiectomy, the treatment of stage IIA and IIB single agent carboplatin CHT is not proven to be effi- seminomas with less than 2.5 cm nodal involvement cient compared to combined cisplatin-based CHT . (N2 < 2.5 cm) classically consists of RT which remains A retrospective study by Domont et al., showed a sig- to this day the standard treatment [7,33]. These patients nificantly increased relapse rate after RT, especially with generally respond well to curative RT, and their clinical lymph nodes of more than 3 cm in diameter. Therefore, outcome is favorable in most cases. The need of che- CHT plays an important role in stages IIB and beyond motherapy for these patients is still questioned. Plati- . Ching et al., in a retrospective study including 79 num-based CHT (PEB: cisplatin, etoposide, bleomycin for 3 cycles or PE: cisplatin, etoposide for 4 cycles, if cases, concluded with absence of proof for “prophylac- there are arguments against bleomycin) were also used tic” left supraclavicular nodal RT; this volume of RT in some centers [7,33]. Prognosis remains good both being of little use in 97% of the patients . Mediast- with RT and CHT treatment. Five-year survival rates are inal RT can be toxic for cardiac function, and was aban- about 95-100% [11,62-64]. doned after the retrospective studies of Hanks et al. and Patients with more advanced disease with more than Ledermann et al. [53,69]. Chung et al. recommend a 2.5 cm nodes (IB stage with N2 between 2.5 and 5 or classical infra-diaphragmatic RT including the para-aor- IIC stage) respond better to combined chemotherapy, tic and same side (± contralateral) iliac nodes. Protec- despite a greater risk of toxicity compared to RT . tion of the contralateral testis is fundamental to In these patients and in patients refusing RT, 3-4 cycles preserve fertility of often young patients. There is no Table 4 Advantages and disadvantages of different management options in the treatment of stage I seminoma Management option Advantage Disadvantage Surveillance - Excellent cancer cure rate - Frequent follow-up CT, with associated long- - No treatment-related toxicity term risks - Excellent salvage rate - Anxiety related to the risk of recurrence - Avoids overtreatment for most patients Radiation Dog-leg - Excellent cancer cure rate - Most patients are overtreated therapy - No need for routine CT - Second malignancy risk - Lower recurrence rates compared with patients managed by - Cardiotoxicity surveillance - Fertility impairment Para- - Excellent cancer cure rate - Frequent follow-up CT, with associated long- aortic - Lower recurrence rate than patients managed by surveillance term risks - Second malignancy risk - Cardiotoxicity - Most patients are overtreated Chemotherapy - Excellent cancer cure rate - Long-term survival and toxicity unknown - Lower acute toxicity than radiation therapy - Frequent follow-up CT, with associated long- term risks - Most patients are overtreated CT: computerised tomography Boujelbene et al. Radiation Oncology 2011, 6:90 Page 8 of 12 http://www.ro-journal.com/content/6/1/90 proof that to include the contralateral iliac, inguinal, or following the treatment of testicular cancer in general scrotal regions in the RT volume is of any benefit. Scro- and after CHT in particular . Cisplatin dose-intensi- tal irradiation was advised in the past in case of undes- fied CHT does not seem to be superior to standard BEP cended testis, previous scrotal or inguinal surgery, or or RT . Post therapeutic follow-up modalities consist pT3 and pT4 tumors . The role of the RT-CHT of a four-week post CHT thoraco-abdomino-pelvic CT- association is presently being evaluated . scan . The subsequent management depends on the In general, we have a longer follow-up with patients size of the residual mass. If the latter is less than 3 cm treated with RT than CHT especially with the newer in diameter, a simple surveillance in advised. If it is lar- ger, a PET/CT exam is recommended. If the latter drugs. Because of this, short term results can overesti- mate the true effect of the treatment. remains positive, a definitive confirmation by biopsy is In a phase II nonrandomized prospective study, Krege necessary. If the PET/CT is negative, surveillance may et al. showed that a monochemotherapy with carbopla- be sufficient [33,83]. In the presence of active residual tin (AUC7) does not allow the full eradication of the tumoral tissue, RT or CHT remains the treatment of retroperitoneal metastases in stage II seminomas . choice [5,33]. Gilbertetal.,inalettertothe editor, published results on 81 patients showing the superiority of RT given in Management of relapse association with carboplatin compared to RT alone . Treatment of relapse depends on different parameters This confirms the results of a previous study by Patter- such as the nature of the initial treatment and the sub- son et al. . sequent response, the localization, and the time since In stage IIA and IIB seminoma, the RT dose is treatment. Most of the stage I seminoma patients who between 30-36 Gy, depending on the size of the positive are under surveillance can be salvaged by RT or cispla- nodes . The gross tumor volume (GTV) is defined on tin CHT alone. Surgery is not an option [14,21]. the planning CT-scan (computerised tomography). A In case of relapse after RT, it will almost always be firstclinicaltarget volume(CTV1)includesthe GTV outside the previous treatment volume. The recom- with a 0.5 cm margin, and a second (CTV2) includes mended treatment scheme is a CHT identical to that the lymphatic risk areas (identical to CTV in stage I dis- used in stage IIC and III, which is efficient in the major- ease). We propose that the PTV should comprise both ity of the patients . Reirradiation is also possible if the the CTV1 and CTV2 with a 0.5 cm margin [7,62-64,73]. relapse is late, localized, and represent a small volume, In stage IIC Seminoma, although local control is possi- such as a solitary adenopathy. In this case, some groups blewith RT, thereis a50% risk of distant metastasis, recommend pelvic nodal dissection . Our opinion is and salvage may not be possible in all cases . RT, that it is by far not the best option in stage I disease therefore, has no major role in this stage of metastatic relapse. seminoma, as BEP combination CHT cures 95% of In the case of relapse after CHT, and if it occurs less patients . In addition, RT to the involved fields after than three months after one CHT cycle, the disease is CHT has not been shown in a retrospective analysis to still considered to be sensitive to a platinum-based CHT add any survival benefit . Today BEP CHT, as in salvage treatment . The chemosensitivity persists even more advanced stages, remains the standard of care, but after the second or third CHT cycles . Cisplatin is increasing attention has been given to late toxicity of the fundamental drug that must be part of any salvage the treatment, and there is increased interest in further CHT [77,85]. The most used first line salvage protocols studies of a single agent CHT . are the VIP (cisplatin, etoposide, ifosfamide), TIP (pacli- taxel, ifosfamide, cisplatin) or VeIP (vinblastine, ifosfa- Stage III seminoma mide, cisplatin) schedules . In fact, relapse after a Most of the studies on advanced germinal cancer platinum-based CHT is very rare, and about 50% of include both seminoma and nonseminomatous tumors them are cured by a salvage CHT [84,86]. . There is no evidence that their chemosensitivity is Dose-intensification CHT has not been shown to be of any different [79,80]. As there is no bad prognostic sub- any interest in first or second line salvage treatments type for advanced pure seminomas, most of the centers . Post CHT salvage surgery must not be used too tend to treat them in the same way as the bad prognos- promptly, as a retarded regression of the residual masses tic subtypes of nonseminoma. The current standard is frequently observed [83,87]. Surgery can possibly be treatment consists of 3-4 cycles of BEP or EP CHT considered in case of CHT failure, although it is mainly [5,34]. The most recent European consensus evaluates used in nonseminomatous tumors [88,89]. the risk of complications . The retrospective Dutch Up to now, surgery has only been considered only for study of Belt-Dusebout et al. establishes the risk of sec- residual masses over 3 cm. The use of FDG-PET/CT (18F-fluorodeoxyglucose positron emission tomography) ondary cancer and cardiovascular complications Boujelbene et al. Radiation Oncology 2011, 6:90 Page 9 of 12 http://www.ro-journal.com/content/6/1/90 scanning allowed a change in this recommendation . treatment. For advanced stages, the treatment includes An FDG-PET/CT fixing lesion can be surgically RT, but the mainstay is platinum based CHT: Trials on removed. Even if technically difficult, resection must be combined RT and CHT are under way. bHCG secreting complete. seminoma is arareformofpureseminoma, andits In patients resistant to CHT, such as those who have prognosis and treatment is comparable to those of non- never normalized their markers after a first course of secreting seminoma. In case of relapse, salvage options CHT or who have not responded to salvage CHT, there depend on previous treatments. Presently, FDG-PET/CT is presently no standard treatment. Some authors advise is an important imaging modality in the therapeutic decision in case of post CHT residual masses. Dose- the use of new drugs such as gemcitabine and paclitaxel. Dose-intensification CHT is under investigation. The intensification CHT regimens are still being investigated. place of surgery has yet to be defined . Author details bHCG secreting seminoma Department of Radiation Oncology, Centre Hospitalier Universitaire Vaudois bHCG secreting seminoma is a rare form of pure semi- (CHUV), Bugnon 46, CH-1011 Lausanne, Switzerland. Department of noma with an incidence of about 10-20% . An Radiation Oncology, Centre Hospitalier Universitaire Habib Bourguiba, 3000 Sfax, Tunisia. Department of Pathology, Institut Gustave-Roussy, 94805 increase in serum bhCG primarily reflects higher tumor Villejuif, France. Department of Radiation Oncology, Hôpital de Sion-CHCVs, burden but not necessarily a greater metastatic potential CH-1950 Sion, Switzerland. Department of Pathology, Hôpital . It has the same clinical and evolutive characteris- HabibThameur, 1089 Tunis, Tunisia. tics as the non-secreting seminoma. Its treatment is Authors’ contributions controversial but two studies have been able to deter- NB, AZ: conception and design. NB drafted the manuscript, AC, NB, KK, SB, mine that its prognosis is identical to that of the non- EH, ROM, MO and AZ criticized the manuscript. All authors read and approved the final manuscript. secreting form [94,95]. In stage I, the concentration of this glycoprotein should return to normal after surgery Competing interests . If not, it is strongly suggestive of disease of at least The authors declare that they have no competing interests. stage II . In this case, the blood level of bHCG Received: 7 April 2011 Accepted: 8 August 2011 should be normalized after an adjuvant RT or CHT Published: 8 August 2011 treatment . In older series, stage I bHCG secreting seminoma was References 1. Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin considered to carry a worse prognosis . 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Radiation Oncology – Springer Journals
Published: Aug 8, 2011
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