Clinical Outcomes of De Novo Versus Relapsed Early Metastatic Testicular Seminoma Treated With Contemporary Radiation Therapy.

PURPOSE: Chemotherapy (CHT) or radiation therapy (RT) are first-line treatments for clinical stage II (CS-II) testicular seminoma. Historically, clinical stage I (CS-I) seminoma was also treated with CHT or RT, but in the past 2 decades practice has shifted toward active surveillance for CS-I with RT or CHT reserved for patients with progression to CS-II. Limited data exist on contemporary RT techniques and patient stratification (ie, de novo [CS-II at orchiectomy] vs relapsed [CS-II diagnosed during surveillance after orchiectomy for CS-I]). We investigated outcomes in CS-II patients treated with RT in the modern era across 2 institutions. METHODS AND MATERIALS: A retrospective review identified 73 patients treated with RT for CS-II A or B seminoma between 2001 and 2022. Recurrence-free survival (RFS) was calculated by the Kaplan-Meier method and univariate analyses were performed with log-rank or Cox proportional hazard regression. Recurrence was defined as biopsy-proven metastatic seminoma after RT completion. Second malignancies were defined as a biopsy-proven malignancy originating in the prior RT field. RESULTS: Thirty-eight (52%) patients presented with de novo CS-II and 35 (48%) patients had relapsed CS-II. Median follow-up was 4.8 years (IQR: 2.3-8.1). Five-year RFS was 82% overall (92% in relapsed patients and 73% in de novo patients). Relapsed CS-II disease had lower recurrence rates after RT compared with de novo CS-II disease. All recurrences occurred outside the prior RT field and were salvaged. Disease-specific survival was 100%. Two second malignancies occurred (prostate, colorectal cancer at 67 months and 119 months post-RT, respectively). CONCLUSIONS: In patients with CS-II seminoma treated with modern RT, there were no in-field recurrences. Presentation with de novo CS-II is associated with out-of-field recurrence. Subject to further larger-scale validation, our results suggest that compared with CS-II at time of relapse, de novo CS-II may portend more aggressive or micrometastatic disease beyond the retroperitoneum, raising the possibility of benefit from CHT after radiation.

Advances in radiation therapy for testicular seminoma.

PURPOSE: Novel techniques and advances in radiation therapy (RT) have been explored to treat testicular seminoma, a highly radiosensitive and curable histology. We evaluated the historical and current indications for radiation therapy (RT) in testicular seminoma. METHODS: A narrative literature review was performed. Studies of RT for testicular seminoma were included. Additionally, recent trials testing the use of combination or surgical therapies for clinical stage (CS) II were included. Search parameters included radiation therapy, testicular seminoma, surgery, and chemoradiation. Parameters and outcomes assessed were progression-free survival (PFS), overall survival (OS), acute toxicities, long-term sequelae, and rates of secondary malignancies. RESULTS: Practice defining and changing studies in the use or omission of radiation therapy for testicular seminoma were identified along with resultant changes in National Comprehensive Cancer Network (NCCN) and European guidelines. Recent trials in combined chemoradiation and upfront surgical approaches to CS II disease were reviewed. CONCLUSION: RT has historically been used as adjuvant treatment for CS I disease and is highly effective at treating CS II (A/B) testicular seminoma. The drive to maintain therapeutic efficacy and reduce acute and long-term side effects, namely secondary malignancies, is being tested using new radiation technologies, combined modality therapy in the form of chemoradiation and with upfront surgical approaches. Also, as guidelines now "strongly prefer" surveillance instead of adjuvant RT for CS I disease, the current CS II population comprises patients presenting with CS II disease ("de novo") and those who present with CSII after relapsing post orchiectomy for CS I ("relapsed"). Emerging evidence suggests that these two groups have different outcomes with respect to RT and chemoradiation. Consequently, future trials may need to sub-stratify according to these groups.

Dose comparison of robustly optimized intensity modulated proton therapy (IMPT) vs IMRT and VMAT photon plans for testicular seminoma.

BACKGROUND: Patients with stage II seminoma have traditionally been treated with photons to the retroperitoneal and iliac space, which leads to a substantial dose bath to abdominal and pelvic organs at risk (OAR). As these patients are young and with excellent prognosis, reducing dose to OAR and thereby the risk of secondary cancer is of utmost importance. We compared IMPT to opposing IMRT fields and VMAT, assessing dose to OAR and both overall and organ-specific secondary cancer risk. MATERIAL AND METHODS: A comparative treatment planning study was conducted on planning CT-scans from ten patients with stage II seminoma, treated with photons to a 'dog-leg' field with doses ranging from 20 to 25 Gy and a 10 Gy sequential boost to the metastatic lymph node(s). Photon plans were either 3-4 field IMRT (Eclipse) or 1-2 arc VMAT (Pinnacle). Proton plans used robust (5 mm; 3.5%) IMPT (Eclipse), multi field optimization with 3 posterior fields supplemented by 2 anterior fields at the level of the iliac vessels. Thirty plans were generated. Mean doses to OARs were compared for IMRT vs IMPT and VMAT vs IMPT. The risk of secondary cancer was calculated according to the model described by Schneider, using excess absolute risk (EAR, per 10,000 persons per year) for body outline, stomach, duodenum, pancreas, bowel, bladder and spinal cord. RESULTS: Mean doses to all OARs were significantly lower with IMPT except similar kidney (IMRT) and spinal cord (VMAT) doses. The relative EAR for body outline was 0.59 for IMPT/IMRT (p < .05) and 0.33 for IMPT/VMAT (p < .05). Organ specific secondary cancer risk was also lower for IMPT except for pancreas and duodenum. CONCLUSION: Proton therapy reduced radiation dose to OAR compared to both IMRT and VMAT plans, and potentially reduce the risk of secondary cancer both overall and for most OAR.

Consolidative radiation in partial responders/unresectable/recurrent disease after first-line/salvage chemotherapy in poor-risk nonseminomatous germ cell tumor prolongs survival: A new paradigm?

The role of radiotherapy (RT) in partial radiographic response (PR)/unresectable has not been evaluated earlier in nonseminomatous germ cell tumor (NSGCT). Can the PR/unresectable be treated with consolidation RT instead of surgery? This approach will allow avoidance of surgical morbidity and be an additional tool for treatment. We report a series of five cases with poor prognosis NSGCT, who were treated with consolidation RT after PR/un-resectable disease and complete serum marker decline. The median survival of these patients was 52 months (range 21-112 months).

Retroperitoneal lymph-node dissection (RPLND) as upfront management in stage II germ-cell tumours: Evaluation of safety and efficacy.

INTRODUCTION: Patients with stage II germ-cell tumours (GCT) usually undergo radiotherapy (seminoma only) or chemotherapy. Both strategies display a recognised risk of long-term side effects. We evaluated retroperitoneal lymph node dissection (RPLND) as exclusive treatment in stage II GCT. METHODS: Between 2008 and 2019 included, 66 selected stage II GCT patients underwent primary open (O-) or laparoscopic (L-)RPLND. Type of procedure and extent of dissection, operative time, node rescue, hospital stay, complications (according to Clavien-Dindo), administration of chemotherapy, relapse and site of relapse were evaluated. RESULTS: Five patients had pure testicular seminoma. Nineteen (28.8%) had raised markers prior to RPLND; 48 (72.7%), 16 (24.2%) and two (3.0%) were stage IIA, IIB and IIC, respectively. O-RPLND and unilateral L-RPLND were 36 and 30 respectively. Six stage II A patients (12.5%) had negative nodes. Four patients underwent immediate adjuvant chemotherapy. One patient was lost at follow-up. After a median follow-up of 29 months, 48 (77.4%) of the 62 patients undergoing RPLND alone remained recurrence-free; one patient had an in-field recurrence following a bilateral dissection. According to procedure, number of rescued nodes (O-RPLND: 25. IQR 21-31; L-RPLND: 20, IQR 15-26; p: 0.001), hospital stay (L-RPLND: 3 days, IQR 3-4; O-RPLND: 6 days, IQR 5-8; p: .001) and grade ≥2 complications (L-RPLND 7%, O-RPLND 22%; p: 0.1) were the only significant differences. CONCLUSION: Primary RPLND is safe in stage II GCT, including seminoma, and may warrant a cure rate greater than 70%. When feasible, L-RPLND may be as effective as O-RPLND with better tolerability.

Testicular germ cell tumour arising 15 years after radiotherapy with 18 Gy for germ cell neoplasia in situ.

PURPOSE: Germ cell neoplasia in situ (GCNis), the precursor of adult testicular germ cell tumours (GCTs), is found in 5-6% of contralateral testicles in patients with testicular GCT and in the tumour-surrounding tissue of > 90% of testes undergoing testis-sparing surgery (TSS) for GCT. Local radiotherapy to the testis with 18-20 Gy eradicates GCNis while preserving Leydig cells. The frequency of treatment failures is so far unknown. METHODS: A 22-year-old patient with right-sided seminoma clinical stage I and contralateral GCNis received radiotherapy with 18 Gy to his left testicle. Fifteen years later he underwent orchiectomy of the irradiated testis for seminoma with adjacent GCNis. The patient is well 1 year postoperatively while on testosterone-replacement therapy. The literature was searched for further cases with GCTs arising despite local radiotherapy. RESULTS: Six failures of radiotherapy have been reported previously. An estimated total number of 200 and 100 radiotherapeutic regimens with 18-20 Gy applied to cases with contralateral GCNis and with TSS, respectively, are documented in the literature. CONCLUSION: Cumulative experience suggests that radiotherapy with 18-20 Gy to the testis may fail with an estimated frequency of around 1%. Reasons for failure are elusive. A primary radioresistant subfraction of GCNis is hypothesized as well as technical failures regarding application of the radiotherapeutic dose volume in small and mobile testes. Caregivers of patients with TSS and contralateral GCNis should be aware of local relapses occurring after intervals of > 10 years.

Treatment results of Para-Testicular Rhabdomyosarcoma (PT-RMS) using radiation as an alternative to retro-peritoneal nodal dissection: A single Institution experience.

BACKGROUND: Para-testicular Rhabdomyosarcoma (PT-RMS) has a favorable treatment outcome adopting multidisciplinary management; resection, namely high inguinal orchiectomy ± retro-peritoneal lymph node dissection (RPLND) followed by standard or intensive chemotherapy ± adjuvant radiation therapy. PATIENTS AND METHODS: This is a retrospective study including all patients with pathologically proven PT-RMS, presented to the National Cancer Institute, Cairo University, during the period from 2005 to 2020. Endpoints included overall survival, disease free survival and patterns of failure of different treatment modalities. RESULTS: Forty one patients were identified. Median age in our cohort was 15 years (range: 2-54 years). After a median follow up of 26 months (range, 3-75 months) ,two and five years OS were 100% and 91.7% respectively and median survival was not reached. Patients who underwent retro-peritoneal nodal dissection had a 5-year DFS rate of 100% versus 73% for those who received radiation to para-aortic nodes (p = 0.185). Limitations include retrospective nature and deviation from COG protocol. CONCLUSIONS: This study shows promising results suggesting that less aggressive local treatment modalities including radiation to para-aortic chain could be an option in PT-RMS, given the excellent results of this subtype. However further validation in a prospective study is warranted.

Surveillance versus Adjuvant Treatment with Chemotherapy or Radiotherapy for Stage I Seminoma: A Systematic Review and Meta-Analysis According to EAU COVID-19 Recommendations.

Background and Objectives: During the coronavirus disease 2019 (COVID-19) outbreak, the European Association of Urology (EAU) Guidelines Office Rapid Reaction Group (GORRG) recommended that patients with clinical stage I (CSI) seminoma be offered active surveillance (AS). This meta-analysis aimed to evaluate the efficacy of AS versus adjuvant treatment with chemotherapy or radiotherapy for improving the overall survival (OS) of CSI seminoma patients. Materials and Methods: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The PubMed/Medline, EMBASE, and Cochrane Library databases were searched. The primary outcome was 5-year OS, and the secondary outcome was the 5-year relapse-free survival (RFS). The outcomes were analyzed as odds ratios (ORs) and 95% confidence intervals (CIs). Results: A total of 14 studies were included. Overall, the quality scores were relatively high, and little publication bias was noted. In terms of the 5-year OS, 7 studies were analyzed; there was no significant difference between AS and adjuvant treatment (OR, 0.99; 95% CI, 0.41−2.39; p = 0.97). In terms of 5-year RFS, 12 studies were analyzed. Adjuvant treatment reduced the risk of 5-year recurrence by 85% compared with AS (OR, 0.15; 95% CI, 0.08−0.26; p < 0.001). Conclusions: In terms of the OS in CSI seminoma patients, no intergroup difference was noted, so it is reasonable to offer AS, as recommended by the EAU GORRG until the end of the COVID-19 pandemic. However, since there is a large intergroup difference in the recurrence rate, further research on the long-term (>5 years) outcomes is warranted.

Single-dose carboplatin followed by involved-node radiotherapy for stage IIA and stage IIB seminoma (SAKK 01/10): a single-arm, multicentre, phase 2 trial.

BACKGROUND: Standard treatment options for patients with stage IIA or stage IIB seminoma include either para-aortic and pelvic radiotherapy or three to four cycles of cisplatin-based combination chemotherapy. These options result in 3-year progression free survival rates of at least 90%, but bear risks for acute and late toxic effects, including secondary malignancies. We tested a novel approach combining de-escalated chemotherapy with de-escalated involved node radiotherapy, with the aim of reducing toxicity while preserving efficacy. METHODS: In the single-arm, multicentre, phase 2 SAKK 01/10 trial, patients with stage IIA or IIB classic seminoma (either at primary diagnosis or at relapse during active surveillance for stage I) were enrolled at ten centres of the Swiss Group for Clinical Cancer Research and ten centres of the German Testicular Cancer Study Group. WHO performance status 0-2, age 18 years or older, and adequate bone marrow and kidney function were required for eligibility. Treatment comprised one cycle of carboplatin (area under the curve 7) followed by involved-node radiotherapy (30 Gy in 15 fractions for stage IIA disease and 36 Gy in 18 fractions for stage IIB disease). The primary endpoint was 3-year progression-free survival. Efficacy analyses were done on the full analysis set, which comprised all patients who signed the informed consent, were registered in the trial, initiated trial treatment, and met all medically relevant inclusion or exclusion criteria. Safety was assessed in all patients who were treated at least once with one of the trial treatments. The study is ongoing but no longer recruiting, and is registered with Clinicaltrials.gov, NCT01593241. FINDINGS: Between Oct 18, 2012, and June 22, 2018, 120 patients were registered in the study. 116 patients were eligible and started treatment according to the study protocol (46 patients with stage IIA disease and 70 with stage IIB disease). After a median follow-up of 4·5 years (IQR 3·9-6·0), 3-year progression-free survival was 93·7% (90% CI 88·5-96·6). With a target progression-free survival of 95% at 3 years, the primary endpoint was not met. Acute treatment-related adverse events of any grade were noted in 58 (48%) of 116 patients, and grade 3 or 4 treatment-related adverse events occurred in the form of neutropenia in five (4%) patients, thrombocytopenia in three (3%) patients, and vomiting in one (1%) patient. No treatment-related deaths and no late treatment-related adverse events were reported. Serious adverse events were reported in five (4%) of 116 patients (one transient creatinine increase and four second primary tumours). INTERPRETATION: Despite the fact that the primary endpoint was not met, we observed favourable 3-year progression-free survival with single-dose carboplatin area under the curve 7 and involved-node radiotherapy, with minimal toxic effects. Our findings might warrant discussion with patients about the SAKK 01/10 regimen as an alternative to standard-of-care treatment, but more research on this strategy is needed. FUNDING: Swiss State Secretariat for Education, Research and Innovation and Rising Tide Foundation for Clinical Cancer Research.

Patterns of Disease Progression and Outcome of Patients With Testicular Seminoma Who Relapse After Adjuvant or Curative Radiation Therapy.

PURPOSE: Radiation therapy is a possible treatment strategy for patients with testicular seminoma after orchiectomy in clinical stage I or II disease. Little is known about the outcome of patients who experience a relapse after radiation therapy. METHODS AND MATERIALS: Data from 61 patients who relapsed after adjuvant or curative radiation therapy from 17 centers in 11 countries were collected and retrospectively analyzed. Primary outcomes were disease-free and overall survival. Secondary outcomes were time to relapse, stage at relapse, treatment for relapse, and rate of febrile neutropenia during chemotherapy for relapse. RESULTS: With a median follow-up of 9.9 years (95% confidence interval [CI], 7.5-10.9), we found a 5-year disease-free survival of 90% (95% CI, 79-95) and a 5-year overall survival of 98% (95% CI, 89-100). Sixty-six percent of patients had stage III disease at time of relapse and 93% of patients fell into the good prognosis group per the International Germ Cell Cancer Collaborative Group classification. The median time to relapse after radiation therapy was 15.6 months (95% CI, 12-23). Twenty-two (36%) patients relapsed more than 2 years after radiation therapy and 7 (11.5%) patients relapsed more than 5 years after radiation therapy. One-third of relapses was detected owing to patients' symptoms, whereas two-thirds of relapses were detected during routine follow-up. The majority (93%) of cases were treated with cisplatin-based chemotherapy. The rate of febrile neutropenia during chemotherapy was 35%. Five patients experienced a second relapse. At last follow-up, 55 patients (90%) were alive without disease. Only 1 patient died owing to disease progression. CONCLUSIONS: Cisplatin-based chemotherapy for patients with seminoma who have relapsed after treatment with radiation therapy alone leads to excellent outcomes. Patients and physicians should be aware of possible late relapses after radiation therapy.

Increased risk of high-grade prostate cancer among testicular cancer survivors.

INTRODUCTION: Testicular cancer survivors (TCS) have an increased risk of additional cancers, including prostate cancer. Our understanding of the natural history of prostate cancer in testicular cancer survivors is very limited due to its rare incidence. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) Registry from 1978 to 2011, we identified 282 TCS with subsequent prostate cancer and examined the tumor grade and clinical outcomes in contrast to men with primary prostate cancer in the general population. RESULTS: TCS with a subsequent prostate cancer diagnosis were more likely to be diagnosed at a younger age than men with primary prostate cancer (65.2% vs. 37.6% for age ≤65, 34.8% vs. 62.4% for age >65, p<0.001) and were more likely to have grade III/IV tumors (46.2% vs. 37.0%, p<0.002). Longer latency between testicular and prostate cancer diagnoses was associated with a higher risk of grade III/IV (p<0.001) cancer. Despite the increased risk for high-grade tumors, 10-year prostate cancer-specific survival and overall survival were not significantly different between TCS and men with primary prostate cancer. Based on the available information in SEER, we found that prior history of radiotherapy for testicular cancer had no impact on tumor grade or survival outcomes. CONCLUSIONS: Prostate cancer in TCS was more likely to be diagnosed at a younger age and with higher grades. Risks of grade III/IV disease increased with longer latency between testicular and prostate cancer diagnoses. Radiotherapy for testicular cancer did not appear to have a significant impact on the outcome of subsequent prostate cancer.

Therapy of clinical stage IIA and IIB seminoma: a systematic review.

PURPOSE: The optimal treatment for clinical stage (CS) IIA/IIB seminomas is still controversial. We evaluated current treatment options. METHODS: A systematic review was performed. Only randomized clinical trials and comparative studies published from January 2010 until February 2021 were included. Search items included: seminoma, CS IIA, CS IIB and therapy. Outcome parameters were relapse rate (RR), relapse-free (RFS), overall and cancer-specific survival (OS, CSS). Additionally, acute and long-term side effects including secondary malignancies (SMs) were analyzed. RESULTS: Seven comparative studies (one prospective and six retrospective) were identified with a total of 5049 patients (CS IIA: 2840, CS IIB: 2209). The applied treatment modalities were radiotherapy (RT) (n = 3049; CS IIA: 1888, CSIIB: 1006, unknown: 155) and chemotherapy (CT) or no RT (n = 2000; CS IIA: 797, CS IIB: 1074, unknown: 129). In CS IIA, RRs ranged from 0% to 4.8% for RT and 0% for CT. Concerning CS IIB RRs of 9.5%-21.1% for RT and of 0%-14.2% for CT have been reported. 5-year OS ranged from 90 to 100%. Only two studies reported on treatment-related toxicities. CONCLUSIONS: RT and CT are the most commonly applied treatments in CS IIA/B seminoma. In CS IIA seminomas, RRs after RT and CT are similar. However, in CS IIB, CT seems to be more effective. Survival rates of CS IIA/B seminomas are excellent. Consequently, long-term toxicities and SMs are important survivorship issues. Alternative treatment approaches, e.g., retroperitoneal lymph node dissection (RPLND) or dose-reduced sequential CT/RT are currently under prospective investigation.

Radiotherapy after testis-sparing surgery for seminoma in monorchid patients: safety and efficacy.

PURPOSE: To evaluate local control and longitudinal endocrine data in monorchid patients treated with testicular-sparing surgery and adjuvant radiotherapy (RT) for seminomatous germ-cell tumors. METHODS: We searched our database established in 2009 for patients with seminoma who received testis irradiation following partial orchiectomy up to 2018. Eleven patients were identified. All had associated germ cell neoplasia in situ (GCNIS) in surrounding parenchyma. Analysis focused on local control and testosterone levels preservation after RT. We considered age, baseline (pre-RT) testosterone and luteinizing hormone (LH) levels, residual testicular volume, tumor size, and testosterone and LH levels trend over time in order to identify any association with endocrine impairment leading to hormonal replacement need. RESULTS: After a median follow-up of 21 months, no local or distant relapses were observed and hormonal function was maintained in 54.5% of patients (6/11). No significant interactions were observed for the investigated covariates. Notably, we observed an association between higher baseline testosterone levels and a decreased risk of exogenous androgen replacement (hazard ratio [HR] 0.409, 95% confidence interval [CI] 0.161-1.039, p = 0.060), whereas tumor size was associated with an increased risk of exogenous androgen replacement (HR 1.847, 95% CI 0.940-3.627, p = 0.075). CONCLUSIONS: Radiotherapy after testicular sparing surgery is effective in preventing local disease relapse in presence of GCNIS in the medium term. This strategy allows a preservation of adequate endocrine function in about half of patients. More patients and longer follow-up are needed to confirm these findings.

Paternity After Treatment for Testicular Germ Cell Cancer: A Danish Nationwide Population-Based Cohort Study.

BACKGROUND: Testicular germ cell cancer (TC) incidence peaks during reproductive age, but knowledge on fertility after treatment is insufficient. The aim was to evaluate paternity after today's TC treatment. METHODS: Clinical data were extracted from the Danish Testicular Cancer database, and patients were divided into 4 groups: 1) surveillance; 2) bleomycin, etoposide, and cisplatin (BEP); 3) BEP + postchemotherapy retroperitoneal surgery (BEP + surgery); and 4) abdominal radiotherapy. For each patient, 10 men matched on date of birth were randomly sampled from the normal population. Paternity was defined as date of birth of first child after TC treatment with or without the use of assisted reproductive technology and was assessed by linkage to the Danish Medical Birth Register and the Danish in vitro fertilization register. RESULTS: We included 4846 unilateral TC patients and 48 456 men from the normal population. The 20-year predicted chance of obtaining fatherhood for a 30-year-old man was 39.7% in TC patients compared with 42.5% in the normal population. The chance of obtaining fatherhood was statistically significantly decreased after BEP (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.78 to 0.97) and BEP + surgery (HR = 0.74, 95% CI = 0.63 to 0.87), but not after radiotherapy (HR = 0.89, 95% CI = 0.75 to 1.06) or surveillance (HR = 0.95, 95% CI = 0.89 to 1.02). The risk of needing assisted reproductive technology to obtain fatherhood was increased after all treatment modalities. CONCLUSIONS: The chance of obtaining fatherhood after TC treatment was substantially higher than previously reported. Patients followed on a surveillance program had a similar chance of obtaining fatherhood as noncancerous men.

Testicular Cancer in the Cisplatin Era: Causes of Death and Mortality Rates in a Population-Based Cohort.

PURPOSE: Using complete information regarding testicular cancer (TC) treatment burden, this study aimed to investigate cause-specific non-TC mortality with impact on previous treatment with platinum-based chemotherapy (PBCT) or radiotherapy (RT). METHODS: Overall, 5,707 men identified by the Cancer Registry of Norway diagnosed with TC from 1980 to 2009 were included in this population-based cohort study. By linking data with the Norwegian Cause of Death Registry, standardized mortality ratios (SMRs), absolute excess risks (AERs; [(observed number of deaths - expected number of deaths)/person-years of observation] ×10,000), and adjusted hazard ratios (HRs) were calculated. RESULTS: Median follow-up was 18.7 years, during which non-TC death was registered for 665 (12%) men. Overall excess non-TC mortality was 23% (SMR, 1.23; 95% CI, 1.14 to 1.33; AER, 11.14) compared with the general population, with increased risks after PBCT (SMR, 1.23; 95% CI, 1.07 to 1.43; AER, 7.68) and RT (SMR, 1.28; 95% CI, 1.15 to 1.43; AER, 19.55). The highest non-TC mortality was observed in those < 20 years at TC diagnosis (SMR, 2.27; 95% CI, 1.32 to 3.90; AER, 14.42). The most important cause of death was non-TC second cancer with an overall SMR of 1.53 (95% CI, 1.35 to 1.73; AER, 7.94), with increased risks after PBCT and RT. Overall noncancer mortality was increased by 15% (SMR, 1.15; 95% CI, 1.04 to 1.27; AER, 4.71). Excess suicides appeared after PBCT (SMR, 1.65; 95% CI, 1.01 to 2.69; AER, 1.39). Compared with surgery, increased non-TC mortality appeared after 3 (HR, 1.47; 95% CI, 0.91 to 2.39), 4 (HR, 1.41; 95% CI, 1.01 to 1.99), and more than four (HR, 2.04; 95% CI, 1.25 to 3.35) cisplatin-based chemotherapy cycles after > 10 years of follow-up. CONCLUSION: TC treatment with PBCT or RT is associated with a significant excess risk of non-TC mortality, and increased risks emerged after more than two cisplatin-based chemotherapy cycles after > 10 years of follow-up.

Radiotherapy role in non-seminomatous germ cell tumors, radiobiological and technical issues of an unexplored scenario.

Historically, non-seminomatous germ cell tumor (NSGCT) has been considered a radio-resistant disease, excluding radiotherapy (RT) from curative strategies. However, case series exploring the use of radiation treatment in this setting are often outdated, and prospective ongoing studies testing new radiotherapeutic approaches in NSGCT are lacking. Considering that tremendous advances in radiotherapy technology have enabled improved precision in RT delivery as well as dose escalation while decreasing treatment-related morbidity, we overviewed the currently available literature to explore the radiobiological basis, the technical issues, and potential strategies for implementation of RT in the management of this clinical entity. The purpose of the present overview is to provide insight for future research in this unexplored scenario. In summary, the biological rationale for RT use and potential implementation with systemic therapies exist, especially considering the advantage of new technologies, which were unavailable in the era of early literature reports. The NSGCT radioresistance paradigm could be based only on the fact that effective treatment schedules were simply undeliverable with older RT techniques due to toxicity issues, but the availability of actual techniques may prompt further exploration to offer treatment alternatives to these patients. Ongoing trials on this issue are lacking, but potential areas of research are platinum-refractory disease and consolidation therapy for residual masses after PST.

177Lu-PSMA Therapy for Metastatic Testicular Mixed Germ Cell Tumor.

ABSTRACT: Prostate-specific membrane antigen (PSMA) overexpression in various tumors are demonstrated in both in vitro and in vivo studies. Prostate-specific membrane antigen-directed radionuclide therapies are generally used in prostate cancer and could be also useful in PSMA-avid other malignancies. Herein, we present a case of a 46-year-old male patient who had progressive metastatic testicular mixed germ cell tumor, despite repeated operations and treatments. 68Ga-PSMA PET/CT was performed to assess eligibility for 177Lu-PSMA therapy. Patient had intense PSMA uptake in metastatic lesions, and 177Lu-PSMA has been given to control of disease. However, α-fetoprotein level progressed, and mixed therapy response was detected in 68Ga-PSMA PET/CT.

Radiotherapy for Post-Chemotherapy Residual Mass in Advanced Seminoma: A Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography-Based Risk-adapted Approach.

AIMS: There is a lack of consensus regarding the management of post-chemotherapy residual mass in classical seminoma. The use of fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) may aid the detection of residual masses harbouring viable disease and help to tailor therapy. The aim of this study was to evaluate if PET-CT could identify patients who will benefit from locoregional radiotherapy. MATERIALS AND METHODS: This ethics-approved study included patients with advanced classical seminoma primarily treated with standard platinum-based first-line chemotherapy. Patients were either observed or given adjuvant radiotherapy based on the clinician's preference and followed up. For this study, patients were stratified into two groups based on FDG PET-CT residual nodal maximum standardised uptake value (SUVmax): low risk (SUVmax <3) and high risk (SUVmax ≥3). Further subgroup analysis was carried out for patients with residual nodal size ≥3 cm and SUVmax ≥3, and this was considered as the very high risk group. The diagnostic accuracy of FDG PET-CT was assessed and survival was compared between the different groups. RESULTS: Sixty-nine patients were included in the study: 48 patients were observed and 21 received radiotherapy. The low and high risk groups contained 50.7% and 49.3% of the patients, respectively. The very high risk subgroup had 24 patients. At a median follow-up of 44 months, locoregional failures in the radiotherapy and observation cohorts were 0% and 30% (P = 0.059) in the very high risk subgroup and 5.8% and 29.4% (P = 0.078) in the high risk group. The positive predictive value for the very high risk and high risk groups was 30% and 17.1%, respectively. The benefit of locoregional control failed to translate into overall survival benefit. CONCLUSION: A tailored, FDG PET-based risk-adapted treatment approach can refine the management of post-chemotherapy residual masses in seminoma. In this study, with the largest cohort of advanced seminoma patients treated with radiotherapy reported to date, radiotherapy seems to benefit patients with post-chemotherapy residual mass SUVmax ≥3.