|Year : 2015 | Volume
| Issue : 2 | Page : 313-318
Adjuvant radiotherapy in stage 1 seminoma: Evaluation of prognostic factors and results of survival
Lasif Serdar1, Emine Canyilmaz1, Turkan Ozturk Topcu2, Asli Sahbaz1, Yahyahan Memis1, Gulsen Soydemir1, Ozlem Aynaci1, Mustafa Kandaz1, Zümrüt Bahat1, Adnan Yoney1
1 Department of Radiation Oncology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
2 Department of Medical Oncology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
|Date of Web Publication||7-Jul-2015|
Department of Radiation Oncology, Faculty of Medicine, Karadeniz Technical University, Trabzon
Source of Support: None, Conflict of Interest: None
Purpose: The purpose of this study was to evaluate the prognostic factors affecting overall survival (OS), cause-specific survival (CSS), progression-free survival (PFS), and survival among patients undergoing adjuvant radiotherapy (RT) for stage-1 seminoma.
Materials and Methods: Between August 1997 and May 2013, 68 patients diagnosed with stage-1 seminoma were retrospectively evaluated. The median age was 39 (24-74) years. All patients received adjuvant RT after inguinal orchiectomy. Fifty-eight (85.3%) patients received paraaortic RT; 10 (14.7%) received dog-leg field RT. The median RT dose was 23.4 (23.4-30.6) Gy.
Results: The median follow-up period was 77.5 (6.7-198.5) months. During the follow-up period, two patients developed distant metastasis, and none developed local recurrence. Two patients died from seminoma, and three died for other reasons. The 5, 10, and 15-year OS rates were 94.7%, 89.6%, and 89.6%, respectively. The 5, 10, and 15-year CSS rates were 98.5%, 96%, and 96%, respectively. The 5, 10, and 15-year PFS rate was 96.1%. The univariate analysis showed that only histological subtype was significant for OS. The 10-year survival rate was 100% among patients with seminoma histology, 90.8% among patients with a classic seminoma histology, and 50% among patients with an anaplastic seminoma histology (P < 0.001). A multivariate analysis showed that the anaplastic seminoma was a negative prognostic indicator for OS (P = 0.042).
Conclusion: Adjuvant RT resulted in excellent long-term survival and local control in patients with stage-1 seminoma after orchiectomy. During a short follow-up, secondary malignancy (SM) and late cardiovascular morbidity were not observed. Despite those results, concern of SM and late cardiovascular morbidity remains.
Keywords: Dog-leg field, dose, paraaortic field, radiotherapy, seminom, testicular cancer
|How to cite this article:|
Serdar L, Canyilmaz E, Topcu TO, Sahbaz A, Memis Y, Soydemir G, Aynaci O, Kandaz M, Bahat Z, Yoney A. Adjuvant radiotherapy in stage 1 seminoma: Evaluation of prognostic factors and results of survival. J Can Res Ther 2015;11:313-8
|How to cite this URL:|
Serdar L, Canyilmaz E, Topcu TO, Sahbaz A, Memis Y, Soydemir G, Aynaci O, Kandaz M, Bahat Z, Yoney A. Adjuvant radiotherapy in stage 1 seminoma: Evaluation of prognostic factors and results of survival. J Can Res Ther [serial online] 2015 [cited 2018 Dec 12];11:313-8. Available from: http://www.cancerjournal.net/text.asp?2015/11/2/313/140846
| > Introduction|| |
Testicular germ-cell tumors are the most common solid tumors in men aged 15-40 years, and almost half of such tumors are seminomas. Eighty percent of testicular tumors are seminomas, most of which present as a clinical stage-I disease.  Almost all patients are cured, regardless of the treatment strategy.  The 10-year survival rates are close to 100%, and 40-year survival is ensured by each of the common treatment approaches. Therefore, the long-term health effects of the various treatment options, including posttreatment morbidity, are important for making clinical decisions regarding which treatment to use for patients with seminoma. ,
The standard treatment of stage-1 testicular seminoma is radical inguinal orchiectomy.  Options for adjuvant treatment include radiotherapy (RT) targeting the paraaortic and ipsilateral pelvic lymph nodes, single-agent carboplatin chemotherapy (CT), and follow-up monitoring.  There is controversy regarding which adjuvant therapy is the most appropriate, highlighting the need for long-term randomized studies to compare the efficacies of the alternative therapies. 
Adjuvant RT has been used for several years and is currently the most commonly used approach, providing excellent long-term survival outcomes. , In recent times, adjuvant CT has gained popularity as an alternative treatment approach.  In a few studies comparing adjuvant CT and RT, the effects of carboplatin CT were equivalent to those of RT. A longer follow-up period is required, however, to assess recurrence and toxicity rates. , Without treatment, the recurrence rate was 17-21% among a sample of patients with stage-1 seminoma; although recurrence was observed, the recovery rates following treatment were close to 100%.  Therefore, the main benefit of the follow-up was to monitor the 80-85% of patients who did not develop recurrence in order to protect them from toxicity secondary to treatment and adjuvant treatment. 
There are various difficulties in monitoring the results of the different seminoma treatment options, and long-term results are scant. RT is still considered to be an effective treatment approach. The 10-year cause-specific survival (CSS) among patients who received RT was 99%, and the relapse rate was 1-5%.  With adjuvant RT, the 5-year recurrence-free survival rate was 96%.  Historically, "dog-leg" RT, including RT targeting the paraaortic and ipsilateral pelvic lymph nodes, was considered part of adjuvant therapy. In recent years, after long-term survival and treatment-related morbidity were considered, there was a decrease in the use of adjuvant RT. In addition, the dosage and treatment field have been reduced. ,, Generally nowadays, a total of 20 Gy with 10 fractionation is applied to the paraaortic field over a period. ,
We monitored a sample of patients who received adjuvant RT following inguinal orchiectomy to characterize the results of RT and identify prognostic indicators for survival.
| > Materials and methods|| |
Between August 1997 and May 2013, 68 patients diagnosed with stage-1 seminoma at our clinic were evaluated retrospectively. The patient histories were obtained directly and/or by phone calls to the patients or the patients' relatives. The American Joint Committee on Cancer 7 th edition 2010 tumor node metastasis staging was used as a reference for staging purposes.
Between August 1997 and June 2011, RT was applied using 6-10 Mv photon energy from Co60 and/or linear accelerator devices in a two-dimensional planning system. After June 2011, 6-18 Mv photon energy from linear accelerator devices in a three-dimensional planning system was used. RT was applied to parallel opposed fields (anterior-posterior and posterior-anterior). The treatment field was planned from the tenth-thoracic vertebra (T10) to the level of the fifth-lumbar vertebra in the patients who received paraaortic treatment. In the patients who received dog-leg treatment, RT was administered from the T10 to the level of the obturator foramen to include the ipsilateral pelvic and iliac lymph nodes. The staging system from the radiation therapy oncology group (RTOG) was used to evaluate the treatment toxicity.
The time of general survival was calculated from the date of diagnosis to the time of last control or death, while the time of progression-free survival (PFS) was calculated from the date of diagnosis to the time of recurrence or metastasis. Statistical analysis was performed using the SPSS version 13 software. A univariate analysis of the effects of age (≤34 or >34 years), history of undescended testes, tumor localization, tumor size (≤4 or > 4 cm), histological subtype (classic, spermatocytic, or anaplastic), the spermatic cord invasion, rete testis involvement, lymphovascular invasion (LVI), stage T, stage, RT field (paraaortic or dog-leg), RT dose (≤24 or > 24 Gy), time between surgery and RT (≤30 or > 30 days), and preoperative beta-human chorionic gonadotrophin (β-hCG) level on overall survival (OS), CSS, and PFS was performed. The Kaplan-Meier survival analysis was used to analyze the distributions of survival time. The log-rank test was used to determine the differences in survival among groups, and the Bonferroni correction was used for comparisons between groups. The Chi-square and Fisher's exact tests (for smaller samples) were used to analyze the differences in frequencies between groups. Independent factors that were predictive of survival in the univariate analysis were analyzed in a multivariate analysis by Cox regression. Results with a probability of type-1 error <5% were considered to be significant.
| > Results|| |
The patient characteristics are shown in [Table 1]. The presenting symptom for all the patients was scrotal swelling. Four patients (5.9%) had undescended testes, and five (7.4%) had previous scrotal surgery. All the patients underwent inguinal orchiectomy. After orchiectomy, 58 patients (85.3%) received paraaortic RT, and 10 received dog-leg field RT. The median time between surgery and RT was 47 (18-307) days. RT was applied with 1.8 Gy/day fractionation and an overall median dose of 23.4 (23.4-30.6) Gy. The median RT dose was 23.4 (23.4-25.2) Gy among patients receiving paraaortic RT and 23.4 (23.4-30.6) Gy among patients receiving dog-leg RT.
The RTOG criteria were used as a reference to detect early side effects of RT. Grade 1-2 gastrointestinal (GIS) toxicity was seen in 28 patients (41.2%). None of the patients exhibited grade 3-4 disease-related toxicity. GIS toxicity was seen in 23 (39.7%) patients who received paraaortic RT and in 4 (40%) patients who received dog-leg RT. There was no statistically significant difference in the toxicity rate between the two groups of patients.
Local and distant recurrence
The median follow-up period was 77.5 (6.7-198.5) months. Two patients (2.9%) developed distant metastasis in the bone and lung, respectively. The median time to metastasis was 30.7 (5.16-56.25) months. None of the patients developed local recurrence. The patient diagnosed with classic-type seminoma who developed bone metastasis underwent a bone biopsy, which confirmed that the metastasis was related to the seminoma.
During the follow-up period, two patients (2.9%) died due to seminoma, and three died due to other causes. Sixty-three patients (92.6%) survived through the follow-up period without evidence of further disease. The median OS time was 182.8 months (95% CI: 169.7-195.9). The 5, 10, and 15-year OS rate was 94.7% (SE: ±0.03%), 89.6% (SE: ±0.05%), and 89.6% (SE: ±0.05%), respectively [Figure 1].
The median CSS time was 192.2 (95% CI: 183.6-200.8) months. The 5, 10, and 15-year CSS rate was 98.5% (SE: ±0.02%), 96% (SE: ±0.03%), and 96% (SE: ±0.03%), respectively [Figure 2]. The median PFS time was 192.2 (95% CI: 183.4-200.8) months. The 5, 10, and 15-year PFS rate was 96.1% (SE: ±0.03%) for all patients [Figure 3].
Only histological subtype was found to be a significant prognostic indicator for OS. The 10-year survival rate was 90.8% among patients with a classic seminoma histology, 100% among patients with the spermatocytic seminoma histology, and 50% among patients with an anaplastic seminoma histology (P < 0.001).
None of the factors in the univariate analysis significantly affected CSS. In the multivariate analysis of factors affecting CSS and PFS, only high preoperative β-hCG level was marginally significant: The 10-year PFS rate was 66.7% among patients with elevated β-hCG levels and 93.8% among patients with normal β-hCG levels (P = 0.05). A multivariate analysis of the prognostic factors affecting OS indicated that only a histologic finding of the anaplastic seminoma was a poor prognostic indicator (P = 0.042).
| > Discussion|| |
Spermatocytic seminomas are seen less frequently than classic seminomas and makeup 10% of all seminomas. They are generally seen in patients more than 50 years of age and have an excellent prognosis due to their low rate of metastasis and a high degree of differentiation.  In our study, histological subtype was a statistically significant prognostic indicator for OS. The 10-year OS rate was 100% among patients with spermatocytic seminoma, 90.8% among patients with classic seminoma, and 50% among patients with an anaplastic seminoma (P < 0.001). Having the anaplastic seminoma was the only factor found by multivariate analysis to be a poor prognostic indicator for OS.
Seminoma progresses slowly, and its lymphatic spread occurs sequentially. Recurrences in previous studies generally occurred outside the treatment area in supradiaphragmatic locations including the mediastinal nodes, lungs, and supra clavicular fossa. , Fewer than 50% of relapses appeared due to radiographic abnormalities, and most were seen in the first 2 years after treatment.  Late relapses were observed within 10 years following treatment.  In our study, the median follow-up period was 77.5 (6.7-198.5) months, and none of the patients experienced local recurrence.
At present, the late morbidity of RT is of interest, given the high-cure rates and longer survival times among patients receiving RT. Secondary malignancy (SM), cardiovascular disease (CVD), peptic ulcer, bowel obstruction, nephrotoxicity, and hypogonadism and infertility are late sequelae of testicular cancer and resulting in treatment. ,,, SM and late cardiovascular toxicity risks have been shown in larger studies with longer follow-up periods. , Infradiaphragmatic RT causes a two-fold or greater increase in the risk of CVD over the 15 years following treatment.  In other studies, peptic ulcer rates were higher than expected among patients who underwent RT. ,, Travis et al.  reported long-term results demonstrating a significantly higher risk of SM in organs inside 13% the field of RT. Those patients received dog-leg RT, however, with high-radiation doses applied to large areas, and few of them received concurrent CT. Independent of the dose-response model, the risk of SM among patients receiving paraaortic RT was lower by one-half to one-third than the risk of SM among patients receiving dog-leg RT.  The median time to GIS SM diagnosis in the previous study was 22 years. Because the follow-up period in our study was much shorter, we did not monitor the development of GIS SM.
In a recent study by the Medical Research Council (MRC) TE 10, the treatment volume and dose of the RT were reduced to prevent RT-related late morbidity; paraaortic RT was provided instead of dog-leg RT, lowering the rate of acute toxicity and quickening there is the recovery of sperm count.  There was no difference in that study between paraaortic and dog-leg RT in terms of the 5-year relapse-free survival rate (96.1% vs. 96.2%, respectively). The application of paraaortic RT instead of classic-field RT reduced the treatment area, which was predicted by a linear dose-response model to reduce the risk of SM by 45%.  On the other hand, sequential lymphatic drainage was impaired in patients who underwent ipsilateral pelvic or scrotal surgery, so the application of dog-leg RT was preferable to that of paraaortic RT, and the pelvic lymph nodes were included in the RT field. 
In our study, there was no significant difference between paraaortic and dog-leg RT in terms of survival and progression patterns. The MRC TE 18 study demonstrated that low-dose paraaortic RT (a total of 20 Gy with 10 fractionation) and high-dose RT (a total of 30 Gy with 15 fractionation) had the same results.  The median dose of RT in our study was a total of 23.4 (23.4-30.6) Gy, and there was no statistically significant correlation between the RT dose (≤24 or >24 Gy) and survival.
Another way to decrease RT-related morbidity is the use of proton RT. Proton RT has the potential significantly to decrease the dosage in normal tissues such as the stomach, liver, pancreas, intestine, colon, and rectum, , which reduces the risk of GIS morbidity and SM. A previous study comparing proton and photon plans using the radiation-induced SM risk model found that the risk of SM was significantly lower among patients with proton plans than among those with photon plans. 
Due to the potential for RT-related late morbidity, there is an increasing interest in investigating new treatment strategies for testicular cancer seminoma. , The new strategies aim to minimize late GIS morbidity and obtain high-cure rates. Long-term monitoring and carboplatin CT are treatment options for stage-1 seminoma.  The MRC TE19 study showed that outcomes of carboplatin CT were not worse than those of paraaortic or dog-leg RT using a total dose of 20-30 Gy.  In another randomized study, carboplatin CT was as effective as RT.  Unfortunately, the long-term efficacy and toxicity of CT have not been reported.
Avoiding excessive treatment for patients with stage-1 seminoma decreases the risk of long-term toxicity. Previous studies found no clear predictors of relapse among patients who were monitored after orchiectomy; however, LVI, tumor size, and rete testis invasion increased the risk of relapse. , Although Warde et al.  described rete testis invasion and tumor size (>4 cm) as possible adverse prognostic indicators in their analysis, a validation study found that rete testis invasion and tumor size were not significant prognostic factors.  The rate of relapse in a recent study of patients with stage-1 disease was 10-30%. , The relapses were detected early, and good long-term survival results were obtained with salvage therapy. , According to a study by Aparicio et al.,  more reliable predictive factors are required so that risk-adjusted treatments can be applied. Patient compliance must be rigorous for monitoring to be effective. If patient compliance was not present, the mode of monitoring remained inadequate. In the previous studies, the relapse rates after treatment were very low among patients who underwent postoperative adjuvant RT, making it difficult to analyze the relationships between adverse pathological features and relapse. In our study, we did not observe any relapses and were, therefore, unable to analyze tumor size, rete testis invasion, and LVI as factors predicting relapse. When we analyzed the effects of those factors on OS, none were statistically significant.
Our study was limited by the short median follow-up duration and the retrospective method of evaluation. Despite those shortcomings, our data support the efficacy of adjuvant RT in patients undergoing treatment for stage-1 seminoma.
| > Conclusion|| |
Adjuvant RT after orchiectomy for stage-1 seminoma resulted in excellent survival and local control rates. A histologic finding of the anaplastic seminoma was a poor prognostic indicator for survival. Recurrence after RT was rare and was only observed outside the field of treatment. However, there is still concern regarding the late morbidity associated with RT. Patients with seminoma generally have good long-term survival outcomes, making them susceptible to late treatment effects. The adjuvant treatment load is an important issue for patients who are unlikely to develop recurrence and expect to have a good long-term survival outcome. Monitoring the development of adverse long-term treatment effects is appropriate for many patients, but the ability to perform such monitoring is limited due to a lack of high-quality evidence for choosing the optimal treatment strategy.
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[Figure 1], [Figure 2], [Figure 3]