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1 DOI: /jkstro Is Radiotherapy Necessary for Stage 1 Testicular Seminoma? Jung Ae Lee, M.D.*, Won Park, M.D., Ph.D.*, Do Hoon Lim, M.D., Ph.D.*, Yong Chan Ahn, M.D., Ph.D.*, Seung Jae Huh, M.D., Ph.D.*, Jeong Il Yu, M.D.*, Han Yong Choi, M.D., Ph.D., Hyun Moo Lee, M.D., Ph.D. and Eun Yoon Cho, M.D., Ph.D. Departments of * Radiation Oncology, Urology, Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Purpose: To report on the clinical outcome of patients with stage I testicular seminoma by postoperative radiotherapy (PORT) or surveillance after radical inguinal orchiectomy. Materials and Methods: This study is a retrospective review of 32 stage I pure seminoma patients treated between 1996 and 2005 at the Samsung Medical Center. Twenty two of the patients were treated by PORT, which was directed at the paraaortic lymphatics with a median dose of 25.2 Gy in 14 fractions for 3 weeks. The 10 remaining patients were managed by surveillance. The median follow-up period was 96 months with a range of 24 to 155 months. Results: Clinically, most patients presented with a testicular mass or discomfort. Two of the patients had a history of undescended testes. Pathologically, 23 of the patients had intratubular germ cell neoplasia with seminoma. Both recurrence-free survival (RFS) and overall survival (OS) rates of patients treated by PORT were. In the control group, 1 of the 10 patients suffered a para-aortic lymph node relapse. The RFS and OS rates of the surveillance group were 88.9% and, respectively. Conclusion: No difference in survival was observed between the two groups. Moreover, symptom recurrence was only observed in 1 patient in the control group. The use of PORT may reduce the risk of relapse. With the availability of effective diagnostic and salvage modalities, surveillance monitoring may be considered for patients in good compliance. Key Words: Seminoma, Radical orchiectomy, Radiation therapy, Surveillance Introduction Testicular germ cell tumors (GCT) account for 1 2% of all male malignancies. These tumors are the most common malignancy among young men, with a median age at diagnosis of approximately 34 years old. Testicular seminomas account for 40 60% of all testicular GCTs, and 75% of the patients are diagnosed with stage I disease. Fifteen to 20% of patients with stage I disease have subclinical metastases, usually in the paraaortic lymph nodes. The incidence of testicular GCT has doubled during last three decades, with unknown etiology. 1) Despite the increased incidence, testicular Submitted April 8, 2009, accepted May 7, 2009 Reprint requests to Won Park, Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Irwon-dong, Gangnam-gu, Seoul , Korea Tel: 02) , Fax: 02) wonro.park@samsung.com seminoma is one of the most curable solid neoplasms, with a 5-year cancer-free survival approaching nearly, due to remarkable treatment advances that began in the late 1970s. 2) Postoperative radiotherapy (PORT) directed to the retroperitoneal and ipsilateral pelvic nodes is traditionally the standard treatment for patients with stage I seminoma. However, there is a trend towards decreased treatment intensity or even therapeutic abstention (i.e. surveillance) due to the risks of longterm treatment-related morbidity and a benefit of only 15% to 20% of the patients with subclinical disease. 3) The main concern of recent studies has been to maintain a high cure rate while minimizing treatment-related complications. The 1999 British Medical Research Council (MRC) trial TE10 4) demonstrated that PORT is comparable to the classical dog-leg field, with lower toxicity when directed to the paraaortic field. The 2005 British MRC trial TE18 3) demonstrated a dose equivalence between 20 and 30 Gy. Furthermore, according to the Princess Margaret Hospital, 5,6) surveillance results in an

2 average recurrence rate of 15 to 20% with early detection of recurrences and a high salvage rate. Hence, this retrospective study was conducted with the following objectives: (1) to analyze clinical characteristics of stage 1 adult testicular seminoma and (2) to identify future directions of treatment by assessing PORT versus active surveillance after radical inguinal orchiectomy. Materials and Methods We retrospectively analyzed 34 patients treated at Samsung Medical Center between January 1996 and September 2005 for stage I testicular seminoma. Medical records of all patients were reviewed according to the following: histologic diagnosis of pure seminoma after radical inguinal orchiectomy, clear spermatic cord resection margins, no clinical or radiologic evidence of regional or distant metastasis, and normal postoperative serum α-fetoprotein (AFP) and β-human chorionic gonadotropin (β-hcg) levels. Orchiectomy specimens were fully reviewed by one pathologist to confirm a diagnosis of pure seminoma. Radiologic exams included chest X-ray and computed tomography (CT) of the abdomen and pelvis, and were performed in all patients. Thirty two patients with pure seminoma except 2 spermatocytic seminoma patients were analyzed in terms of demographics, clinical characteristics, T stage, postoperative management, recurrence, and survival. PORT was administered after orchiectomy in 22 patients, and no adjuvant treatment was given to the 10 patients in the surveillance group. There were no specific criteria to divide patients into PORT or surveillance group. Surgeon s preference was mainly influenced on the subsequent treatment after orchiectomy. Radiotherapy was delivered to the paraaortic lymphatics, with a median dose of 25.2 Gy (range Gy) at Gy per fraction and with 10 or 15 megavoltage photon. Paraaortic lymphatic pathway was covered from L1 to L5 vertebra. For left-sided tumors, the left renal hilum was included in the field. Toxicity evaluation was based on the Radiation Therapy Oncology Group toxicity criteria. For surveillance, patients underwent a regular outpatient follow up with a physical examination, serum tumor marker tests, chest X-ray, and CT of the abdomen and pelvis. Statistical analysis was made using the Kaplan-Meier method, and relapse-free survival rates were calculated from the date of surgery. Results 1. Patient characteristics Table 1 lists the patient characteristics. The median age was 34 years old and ranged from 22 to 58 years. All patients underwent inguinal orchiectomy for testicular seminoma. The most common presentation was a scrotal mass or swelling in 29 (90.6%) of 32 cases. Two of these patients also suffered from scrotal discomfort, and one of these 32 patients also suffered from abdominal pain. Two patients had a past medical history of cryptorchidism. Twenty-four of the 32 patients had intratubular germ cell neoplasia (ITGN) with pure seminoma. Preoperative serum β-hcg levels were elevated in 7 of the 32 patients and were normal in the rest. Preoperative serum LDH levels were elevated in 10 patients, normal in 11 patients, and not measured in 11 patients. Initial serum AFP levels were within normal limits in all patients. Most of the patients had a T1 disease status. The median tumor size was 6 cm and ranged from 2.5 to 12 cm. The median tumor size of patients treated by PORT was 6.8 cm, and that for the control group was 5 cm. Nineteen of 22 (86.4%) PORT-treated patients and 6 out of 10 (60%) control patients had a tumor larger than 4 cm (Table 1). 2. Relapse and survival All patients were alive at a median follow up of 96 months (range, months), which was measured from the date of orchiectomy (Table 2). The median follow up of two groups was different, 112 months (range, months) for PORT group and 46 months (range, months) for control group, respectively. The five-year RFS for all patients was 96.8% (Fig. 1). None of the PORT-treated patients had recurrent disease, and thus had a RFS (Fig. 2). One control patient developed a nodal recurrence in the left paraaortic area 27 months after orchiectomy. This patient was 40 years old with a 5 cm by 4.5 cm T1 stage tumor. Salvage chemotherapy with the combination of bleomycin, etoposide and cisplatin (BEP) was performed, and no evidence of disease was observed up to 18 months after treatment (Fig. 3). To evaluate prognostic factors for recurrence, parameters including age, tumor size, and T stage were assessed, and none of the factors had a statistically significant influence on

3 Table 1. Patients Characteristics of Stage 1 Testicular Seminoma Jung Ae Lee, et al: Radiotherapy in Stage I Testicular Seminoma Parameter Total (%) PORT* group (n=22) Surveillance group (n=10) p-value Age (years) <34 34 Site Right Left Serologic marker bhcg LDH AFP T stage T1 T2 T3 Tumor size <4 cm 4 cm ITGN Yes No Unknown 14 (43.8%) 18 (56.2%) 13 (40.6%) 19 (69.4%) (90.6%) 2 (6.3%) 1 (3.1%) 7 (21.9%) 25 (78.1%) 24 (75.0%) 5 (15.6) 3 (9.4%) 10 (45.5%) 12 (54.5%) 12 (54.5%) 10 (45.5%) (90.9%) 2 (9.1%) 0 (0%) 3 (13.6%) 19 (86.4%) 16 (72.7%) 4 (18.2%) 2 (9.1%) 4 (40%) 6 (60%) 1 (10.0%) 9 (90.0%) (90.0%) 0 (0%) 1 (10%) 4 (40%) 6 (60%) 8 (80.0%) 1 (10%) 1 (10%) NS p<0.05 NS NS p<0.05 NS *postoperative radiation therapy, beta human chorionic gonadotrophin, lactate dehydrogenase, alpha fetoprotein, intratubular germ cell neoplasia, not significant Table 2. Survival Results of Each Group Total PORT* group Surveillance group Median f/u (months)(range) 5 year RFS (%) 5 year OS (%) 96 (24 155) 96.8% 112 (35 155) 46 (24 119) 88.9% *postoperative radiation therapy, recurrence free survival, overall survival Fig. 2. Recurrence free survival of each group. RFS (Table 3). In PORT-treated patients, radiotherapy morbidity was limited to Grade I acute gastrointestinal side effects, with nausea in five patients and vomiting in one patient. However all PORT-treated patients tolerated treatment with no interruption during radiotherapy. Fig. 1. Recurrence free survival of all patients

Prognostic Factor Evaluation for Paraaortic Recurrence Parameter Age (years) <34 34 T stage T1 T2 or T3 Tumor size <4 cm 4 cm Number 18 14 29 3 7 25 *recurrence free survival 5 year RFS* (%) 100 92.

4 Fig. 3. Computed tomography of left paraaortic recurrence. (A) A nodal recurrence 27 months after orchiectomy in the left paraaortic area (arrow). (B) Complete remission state after salvage chemotherapy with the combination of bleomycin, etoposide and cisplatin (BEP). Table 3. Prognostic Factor Evaluation for Paraaortic Recurrence Parameter Age (years) <34 34 T stage T1 T2 or T3 Tumor size <4 cm 4 cm Number *recurrence free survival 5 year RFS* (%) p-value (univariate) Discussion and Conclusion p-value (multivariate) There is a wide variation in worldwide incidence of testicular seminoma, with the highest incidence in northern European countries and the lowest incidence in eastern Europe and Asia, which explains why almost all large studies are from western countries. There are few studies on Asian males with testicular seminoma. Our study may be the largest study regarding stage 1 seminoma in Asian patients, and may indicate a clinical direction for the treatment of this subset of patients in Asia. Historically, early stage seminoma was treated with orchiectomy followed by inguinal and paraaortic radiotherapy, and sometimes included mediastinal radiotherapy. However, prophylactic mediastinal radiotherapy was not performed after the 1970s due to significantly increased cardiac mortality. 7) Zagars et al. from The University of Texas M.D. Anderson Cancer Center reported on the long term treatment-related mortality of 477 men with stage I or II testicular seminoma treated by postorchiectomy radiotherapy between 1951 and ) The cardiac and cancer standardized mortality ratio were 1.61 and 1.91, respectively, and were significant after 15 years of follow-up (p<.01). A significant risk of death resulting from cardiac disease or secondary cancers was observed among long-term survivors of PORT-treated seminoma patients. After the 1970s, the dog-leg field became standard and included paraaortic and ipsilateral iliac lymphatics with a 30 Gy dose at 2 Gy per fraction. The 1999 British MRC trial TE10 4) compared the relapse rates and toxicity associated with paraaortic field or dog-leg field (30 Gy/15 fractions/3 weeks) for 478 men with stage I testicular seminoma. With the 3-year RFS over 96% and significantly reduced hematologic, gastrointestinal, and gonadal toxicity, the paraaortic field only is comparable to the classical dog-leg field, if the lymphatic drainage is undisturbed. However, the paraaortic field resulted in a slightly higher risk of pelvic recurrence. Importantly, the median time to recovery in sperm counts was 13 months with the paraaortic field and 20 months with the dog-leg field if sperm counts were normal before radiotherapy, and was 24 and 37 months, respectively, if sperm counts were abnormal before radiotherapy. Also, the 2005 British MRC trial TE18 3)

5 Jung Ae Lee, et al: Radiotherapy in Stage I Testicular Seminoma demonstrated a dose equivalence between 20 and 30 Gy. Two dose schedules of 20 Gy in 10 fractions or 30 Gy in 15 fractions in 625 patients with stage I seminoma were evaluated and, 10 and 11 relapses, respectively, were reported in the 30 Gy and 20 Gy groups with a median follow up of of 61 months. Reductions in morbidity enabled patients to return to work more rapidly, with 5% moderate to severe lethargy in patients treated with 20 Gy compared to 20% in patients treated with 30 Gy 4 weeks after PORT. Thus, there is a shift towards decreasing treatment morbidity. More recently, a surveillance strategy has begun overtaking PORT as a treatment modality, due to radiation-related late complications such as secondary malignancies 7) or infertility. The study from Netherlands 8) with median follow up of 7.7 years for 1909 testicular cancer patients has shown that the relative risk of gastrointestinal malignancies increases after radiation therapy or radiation therapy plus chemotherapy and is greatest after 10 years. An excess of soft tissue sarcoma has also been observed in other study. 9) The Princess Margaret Hospital 5,6) and Danish Testicular Cancer Study Group 10) have reported on the surveillance strategy with average recurrence rates of 15 to 20%. Early detection of recurrence and high salvage rates make this strategy feasible. In the current study, PORT was directed to paraaortic lymphatics with a median radiation dose of 25.2 Gy. Radiotherapy gave excellent results that were comparable with other clinical series. One of 10 patients managed by surveillance had recurrence with a RFS of 88.9%. However, the median follow up of two groups was different, 112 months (range, months) for PORT group and 46 months (range, months) for control group, respectively. Although the majority of relapses are known to occur within 2 years after surgery, the recurrence rate of surveillance group may increase with longer follow up because control group had shorter follow up period than PORT group. There was no survival difference between the two groups. PORT may reduce the chance of recurrence, although there was no statistical significance. Prognostic factors for recurrence have been studied often. 6,11) The size of the primary tumor ( 4 cm vs. >4 cm) and invasion of the rete testis are statistically significant prognostic factors for relapse in the pooled analysis of 638 patients from the four largest surveillance studies. 6) Also, the second Spanish Germ Cell Cancer Cooperative Group reported a prospective study of 314 patients. 11) Tumor size ( 4 cm vs. >4 cm) and rete testis involvement were also risk factors for relapse, and patients without these risk factors were managed by surveillance. This risk-adapted management may be a reasonable treatment paradigm. In our series, the recurrence was only observed in one patient managed by surveillance who had a tumor of 5 cm. However, we can not conclude that tumor size is the most important factor of regional recurrence or that PORT is needed for large tumors due to the small sample set, and there were no statistically significant risk factors. Currently, PORT is applied to the patients with stage I seminoma with lymphovascular invasion in our institution. Meanwhile, because chemotherapy is effective for more advanced disease, several studies analyzed the use of chemotherapy for stage I seminoma. In the 2005 British MRC trial TE19, 12) comparable outcomes were achieved with a single dose of carboplatin or PORT. The 3-year relapse-free survival was 95% with carboplatin treatment and 96% with PORT. In conclusion, PORT may reduce the risk of relapse, especially for larger tumors. There were no significant prognostic factors due to small sample size. However, it could be a reasonable approach to apply PORT according to the risk factors and further study should be needed. With the availability of effective diagnostic and salvage modalities, surveillance may be considered for patients with good compliance. Acknowledgments All the authors participated in the design, execution, and analysis of this paper and approved the final version. There is no conflict of interest in connection with this paper and the material described is not under publication or consideration for publication elsewhere. References 1. McGlynn KA, Devesa SS, Sigurdson AJ, Brown LM, Tsao L, Tarone RE. Trends in the incidence of testicular germ cell tumors in the United States. Cancer 2003;97: Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, CA Cancer J Clin 2007;57: Jones WG, Fossa SD, Mead GM, et al. Ra ndomiz ed tria l of 30 versus 20 Gy in the adjuvant treatment of stage I

6 Testicular Seminoma: a report on Medical Research Council Trial TE18, European Organisation for the Research and Treatment of Cancer Trial (ISRCTN ). J Clin Oncol 2005;23: Fossa SD, Horwich A, Russell JM, et al. Optimal planning target volume for stage I testicular seminoma: A Medical Research Council randomized trial. Medical Research Council Testicular Tumor Working Group. J Clin Oncol 1999; 17: Choo R, Thomas G, Woo T, et al. Long-term outcome of postorchiectomy surveillance for Stage I testicular seminoma. Int J Radiat Oncol Biol Phys 2005;61: Warde P, Specht L, Horwich A, et al. Prognostic factors for relapse in stage I seminoma managed by surveillance: a pooled analysis. J Clin Oncol 2002;20: Zagars GK, Ballo MT, Lee AK, Strom SS. Mortality after cure of testicular seminoma. J Clin Oncol 2004;22: van Leeuwen FE, Stiggelbout AM, van den Belt- Dusebout AW, et al. Second cancer risk following testicular cancer: a follow-up study of 1,909 patients. J Clin Oncol 1993;11: Jacobsen GK, Mellemgaard A, Engelholm SA, Moller H. Increased incidence of sarcoma in patients treated for testicular seminoma. Eur J Cancer 1993;29A: Daugaard G, Petersen PM, Rorth M. Surveillance in stage I testicular cancer. Apmis 2003;111: Aparicio J, Germa JR, Garcia del Muro X, et al. Risk-adapted management for patients with clinical stage I seminoma: the Second Spanish Germ Cell Cancer Cooperative Group Study. J Clin Oncol 2005;23: Oliver RT, Mason MD, Mead GM, et al. Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial. Lancet 2005;366: 국문초록 제 1 병기성인고환정상피종에대한임상적고찰및치료결과분석 성균관대학교의과대학삼성암센터방사선종양학교실 *, 비뇨기과학교실, 병리학교실 이정애 * ㆍ박원 * ㆍ임도훈 * ㆍ안용찬 * ㆍ허승재 * ㆍ유정일 * ㆍ최한용 ㆍ이현무 ㆍ조은윤 목적 : 제 1 병기성인고환정상피종환자에대한임상적고찰과함께근치적고환절제술후보조적방사선치료와고환절제술단독치료의결과를후향적으로분석비교하고자하였다. 대상및방법 : 1996 년 1월부터 2005 년 9월까지삼성서울병원에서제 1 병기정상피종으로진단을받은환자 32명의순수정상피종 (pure seminoma) 환자를대상으로하였다. 근치적고환절제술후 22명은보조적방사선치료를시행하였고, 10명은추가치료없이종양표지자와복부골반전산화단층촬영을이용한정기적추적관찰을행하였다. 방사선치료는 MV 광자선을사용하였으며일일치료선량 Gy로총 Gy ( 중앙값, 25.2 Gy) 를대동맥주위림프절 (L1 L5) 에이문조사하였다. 전체추적관찰기간은근치적고환절제술시행일을기준으로 개월 ( 중앙값, 96개월 ) 이었다. 결과 : 환자의연령은 22 58세 ( 중앙값 34세 ) 였고, 임상적으로진단전주증상은음낭종괴및불편감이대부분이었다. 이중 2명에서잠복고환의병력이있었으며, 병리적으로 32명중 23명에서정상피종에관내배아세포종 (intratubular germ cell neoplasia) 이동반되어있었다. 술후보조적방사선치료를시행한군은분석시점에모든환자가무병상태로 의국소제어율및생존율을보였다. 술후추적관찰만을시행한군은 10명중 1명에서좌측대동맥주위림프절에재발하여구제항암화학요법후완전관해되었으며국소제어율 88.9%, 생존율 를보였다. 결론 : 제 1 병기정상피종에서근치적고환절제술후보조적방사선치료를시행한군과추적관찰만을시행한군간에생존율의차이는없었다. 환자수가적고추적관찰기간이짧기는하지만재발후항암화학요법으로구제가잘되고, 방사선치료시이차암의가능성이있음을고려한다면정기적인추적관찰이가능한환자에서수술후방사선치료를생략할수도있겠다. 핵심용어 : 정상피종, 근치적고환절제술, 방사선치료, 정기적추적관찰

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( )Jkstro011.hwp 비인강암의방사선치료결과및생존율에관한예후인자분석 2005 2 1 2005 3 28. :, Tel: 053)250-7665, Fax: 053)250-7984 E-mail: jhkim@dsmc.or.kr 정영연외 2 인 : 비인강암의예후인자분석 정영연외 2 인 : 비인강암의예후인자분석 Carcinoma of the nasopharynx treated by radiotherapy