Paclitaxel, Ifosfamide, and Cisplatin as Initial Salvage Chemotherapy for Germ Cell Tumors: Long-Term Follow-Up and Outcomes for Favorable- and Unfavorable-Risk Disease.

PURPOSE: Paclitaxel, ifosfamide, and cisplatin (TIP) is an established salvage regimen for germ cell tumors (GCT) on the basis of a phase II trial, but efficacy on a large patient cohort including patients with unfavorable risk features and long-term outcomes has not been reported. Herein, we report updated treatment efficacy and long-term follow-up with TIP. PATIENTS AND METHODS: Patients with GCT who received TIP after cisplatin-based chemotherapy were eligible. Favorable response (complete response or partial response with negative tumor markers), overall survival (OS) and progression-free survival (PFS) rates, relapse, and toxicity were determined. Disease was reclassified according to the International Prognostic Factor Study Group (IPFSG) score. RESULTS: Of the 104 patients, 87 had favorable risk factors and 17 had at least one unfavorable factor by Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Ten patients were treated for a second gonadal primary GCT. With a median follow-up of 8.9 years, the 5-year PFS and OS rates were 66% (95% CI, 55 to 74) and 69% (95% CI, 59 to 77), respectively. Among 87 patients with favorable-risk disease, 69 (79%) achieved a favorable response with 5-year PFS and OS rates of 67% (95% CI, 56 to 76) and 72% (95% CI, 61 to 80), respectively. Among 17 patients with MSKCC unfavorable-risk disease, 13 (76%) achieved a favorable response with 5-year PFS and OS rates of 59% (95% CI, 33 to 78) and 56% (95% CI, 28 to 76), respectively. After IPFSG reclassification, 5-year PFS and OS rates for patients with ≤intermediate-risk disease were 75% (95% CI, 50 to 89) and 73% (95% CI, 55 to 85), respectively. CONCLUSION: TIP is an effective second-line regimen for patients with GCT. Similar outcomes were observed in patients with favorable- and unfavorable-risk disease. The randomized TIGER trial (ClinicalTrials.gov identifier: NCT02375204) comparing TIP with high-dose chemotherapy will determine the optimal second-line treatment approach.

Primary Retroperitoneal Lymph Node Dissection for Seminoma Metastatic to the Retroperitoneum.

PURPOSE: Primary surgical treatment with retroperitoneal lymph node dissection aims to accurately stage and treat patients with node-positive pure seminoma while avoiding long-term risks of chemotherapy or radiation, traditional standard-of-care treatments. MATERIALS AND METHODS: We reported the pathologic and oncologic outcomes of patients with pure seminoma treated with primary retroperitoneal lymph node dissection in a retrospective, single-institution case series over 10 years. The primary outcome was 2-year recurrence-free survival stratified by adjuvant management strategy (surveillance vs adjuvant chemotherapy). RESULTS: Forty-five patients treated with primary retroperitoneal lymph node dissection for pure testicular seminoma metastatic to the retroperitoneum were identified. Median size of largest lymph node before surgery was 1.8 cm. Viable germ cell tumor, all of which was pure seminoma, was found in 96% (n=43) of patients. The median number of positive nodes and nodes removed was 2 and 54, respectively. Median positive pathologic node size was 2 cm (IQR 1.4-2.5 cm, range 0.1-5 cm). Four of 29 patients managed with postoperative surveillance experienced relapse; 2-year recurrence-free survival was 81%. Median follow-up for those managed with surveillance who did not relapse was 18.5 months. There were no relapses in the retroperitoneum, visceral recurrences, or deaths. Among the 16 patients who received adjuvant treatment, 1 patient experienced relapse in the pelvis at 19 months. CONCLUSIONS: Primary retroperitoneal lymph node dissection for pure seminoma with low-volume metastases to the retroperitoneum is safe and effective, allowing most patients to avoid long-term toxicities from chemotherapy or radiation.

Novel approaches to redesign surveillance strategies following orchiectomy for localized testicular cancer: a narrative review.

Background and Objective: Surveillance is the preferred management strategy for most men with clinical stage I testicular cancer after orchiectomy. However, frequent office visits, imaging tests, and laboratory studies place a significant burden on patients, which may contribute to poor compliance with guideline-recommended surveillance regimens. Identifying strategies to overcome these barriers may help improve quality of life, reduce costs, and improve adherence for patients. We reviewed evidence for three strategies that may help with surveillance redesign: telemedicine, implementing microRNA (miRNA) as a biomarker, and novel imaging protocols. Methods: A web-based literature search for novel imaging strategies, diagnostic utility of miRNA, and telehealth as they relate to early-stage testicular germ cell cancer was completed during the month of August 2022. We focused our search on contemporary PubMed-indexed and Google Scholar-registered manuscripts written in English. Supportive data sourced from current guideline statements were also included. Evidence was compiled for narrative review. Key Content and Findings: Telemedicine is a safe and acceptable platform for urologic cancer follow-up care, but it requires further study specifically among men with testicular cancer. Access to care may either be improved or reduced depending on system- and patient-level characteristics and should be implemented with this in mind. miRNA may potentially be a helpful biomarker for men with localized disease, but further research on diagnostic accuracy and marker kinetics are needed before implementing it into routine surveillance strategies or using it to deviate from long-standing surveillance regiments. Novel imaging strategies with less frequent imaging and the use of magnetic resonance imaging (MRI) instead of computed tomography (CT) appear to be non-inferior in clinical trials. However, use of MRI requires expert radiologist availability and may be more costly with a lower ability to detect small, early recurrences when used in routine practice. Conclusions: Using telemedicine, integrating miRNA as a tumor marker, and adopting less intensive imaging strategies may improve guideline-concordant surveillance for men with localized testicular cancer. Future studies are needed to assess the risks and benefits of using these novel approaches separately or together.

Analytical Validation and Performance Characteristics of Molecular Serum Biomarkers, miR-371a-3p and miR-372-3p, for Male Germ Cell Tumors, in a Clinical Laboratory Setting.

Detection of serum embryonic miRNAs miR-371a-3p and miR-372-3p has been proposed to aid in diagnosis, prognosis, and management of patients with testicular germ cell tumors (GCTs). This study describes the analytical validation and performance of a laboratory-developed test to detect these miRNA targets by stem loop real-time quantitative RT-PCR (RT-qPCR) in serum from patients with GCTs. The assay was standardized using an exogenous spike-in control of nonhuman miRNA from Caenorhabditis elegans (cel-miR-39-3p) to assess extraction efficiency, and an endogenous housekeeping miRNA, miR-30b-5p, to control for miRNA normalization. miRNA results were expressed as relative expression level, using the comparative threshold cycle method (2ΔΔCT). Analytical sensitivity of miR-371a-3p and miR-372-3p was 12.5 and 1.25 copies/µL, respectively. Clinical accuracy was evaluated using GCT patients with (n = 34) and without (n = 17) active disease. Positive/negative cutoffs and indeterminate findings were established on the basis of results from healthy volunteers (n = 25) and assay precision. miR-371a-3p and miR-372-3p exhibited a sensitivity of 81.8% and 87.5%, respectively, and a specificity of 100% and 94%, respectively, and an area under the receiver operating characteristic curve of 0.93 and 0.95, respectively. Taken together, RT-qPCR testing for serum miR-371a-3p and miR-372-3p represents a robust, sensitive, and specific clinical assay to aid in the clinical management of patients with GCT.

Four Cycles of Etoposide plus Cisplatin for Patients with Good-Risk Advanced Germ Cell Tumors.

BACKGROUND: The National Comprehensive Cancer Network recommends either three cycles of bleomycin, etoposide, and cisplatin or four cycles of etoposide and cisplatin (EPx4) as initial chemotherapy for the treatment of good-risk germ cell tumors (GCTs). To assess the response, toxicity, and survival outcomes of EPx4, we analyzed our experience. MATERIAL AND METHODS: Response and survival outcomes, selected toxicities, and adherence to chemotherapy dose and schedule were assessed in patients with good-risk GCT who received EPx4 at Memorial Sloan Kettering Cancer Center between 1982 and 2016. The results were compared with our past results and published data. RESULTS: Between 1982 and 2016, 944 patients with GCT were treated with EPx4, 289 who were previously reported plus 655 treated between January 2000 and August 2016. A favorable response was achieved in 928 of 944 patients (98.3%). Five-year progression-free, disease-specific, and overall survival rates were 93.9%, 98.6%, and 97.9%, respectively. Median follow-up was 7.3 years (range, 2.8 months to 35.5 years). Viable, nonteratomatous malignant GCT was present in 3.5% of 432 postchemotherapy retroperitoneal lymph node dissection specimens from patients with nonseminomatous GCT. Febrile neutropenia and thromboembolic events occurred in 16.0% and 8.9%, respectively, with one treatment-related death. In the more recent 655-patient cohort, full-dose EPx4 was administered to 631 (96.3%), with deviations from planned treatment driven mainly by vascular (n = 13), hematologic (n = 11), renal (n = 7), or infectious (n = 5) events. CONCLUSION: EPx4 is highly effective and well tolerated in patients with good-risk GCTs and remains a standard of care. IMPLICATIONS FOR PRACTICE: Four cycles of etoposide and cisplatin (EPx4) is a standard-of-care regimen for all patients with good-risk germ cell tumors with a favorable response rate and disease-specific survival of 98%. Full-dose administration of etoposide and cisplatin and complete resection of residual disease lead to optimal outcomes. EPx4 should be the recommended regimen in active smokers, patients with reduced or borderline kidney function, and patients aged 50 years or older, which are patient groups at increased risk for bleomycin pulmonary toxicity. Because of a risk of acquired severe pulmonary illness, EPx4 may also be favored for patients who vape or use e-cigarettes and during ongoing transmission of severe acute respiratory syndrome coronavirus 2.

Thoracic Metastasectomy in Germ Cell Tumor Patients Treated With First-line Versus Salvage Therapy.

BACKGROUND: Outcomes after thoracic metastasectomy in patients with testicular germ cell tumors (GCTs) who received first-line chemotherapy alone versus salvage chemotherapy remain unexplored. METHODS: We conducted a retrospective review of patients who underwent thoracic metastasectomy for residual GCT between 1997 and 2019 at a single tertiary center. Factors associated with progression-free survival (PFS) and overall survival (OS) were assessed using multivariable Cox regression. RESULTS: Of 251 patients, 191 received only first-line chemotherapy (76%) and 60 received salvage chemotherapy (24%). Median follow-up was 3.45 years (interquartile range, 1-7.93 years). Among first-line patients without teratoma in the primary tumor, with necrosis in the retroperitoneal nodes and normalized or decreasing serum tumor markers, 17 of 20 had intrathoracic necrosis (85%). Among first-line and salvage patients, respectively, 5-year OS was 93% (95% confidence interval [CI], 89%-98%) versus 63% (95% CI, 51%-78%; P < .001), and 5-year PFS was 69% (95% CI, 62%-77%) versus 40% (95% CI, 29%-56%; P < .001). On multivariable analysis, multiple lung lesions (hazard ratio [HR] = 3.01; 95% CI, 1.50-6.05; P = .002) and brain metastasis (HR = 4.51; 95% CI, 2.34-8.73; P < .001) at diagnosis, salvage chemotherapy (HR = 1.85; 95% CI, 1.10-3.13; P = .021), teratoma (HR = 2.68; 95% CI, 1.50-4.78; P = .001), and viable malignancy (HR = 4.34; 95% CI, 2.44-7.71; P < .001) were associated with worse PFS. CONCLUSIONS: Although GCT patients treated with salvage chemotherapy followed by thoracic metastasectomy have more aggressive disease and poorer PFS, they can achieve encouraging OS. Our findings highlight the integral role of aggressive thoracic metastasectomy in the treatment of GCT patients with residual thoracic disease after first line-only or salvage chemotherapy.

Germ Cell Tumor Molecular Heterogeneity Revealed Through Analysis of Primary and Metastasis Pairs.

PURPOSE: Although primary germ cell tumors (GCTs) have been extensively characterized, molecular analysis of metastatic sites has been limited. We performed whole-exome sequencing and targeted next-generation sequencing on paired primary and metastatic GCT samples in a patient cohort enriched for cisplatin-resistant disease. PATIENTS AND METHODS: Tissue sequencing was performed on 100 tumor specimens from 50 patients with metastatic GCT, and sequencing of plasma cell-free DNA was performed for a subset of patients. RESULTS: The mutational landscape of primary and metastatic pairs from GCT patients was highly discordant (68% of all somatic mutations were discordant). Whereas genome duplication was common and highly concordant between primary and metastatic samples, only 25% of primary-metastasis pairs had ≥ 50% concordance at the level of DNA copy number alterations (CNAs). Evolutionary-based analyses revealed that most mutations arose after CNAs at the respective loci in both primary and metastatic samples, with oncogenic mutations enriched in the set of early-occurring mutations versus variants of unknown significance (VUSs). TP53 pathway alterations were identified in nine cisplatin-resistant patients and had the highest degree of concordance in primary and metastatic specimens, consistent with their association with this treatment-resistant phenotype. CONCLUSION: Analysis of paired primary and metastatic GCT specimens revealed significant molecular heterogeneity for both CNAs and somatic mutations. Among loci demonstrating serial genetic evolution, most somatic mutations arose after CNAs, but oncogenic mutations were enriched in the set of early-occurring mutations as compared with VUSs. Alterations in TP53 were clonal when present and shared among primary-metastasis pairs.

Treatment of Chylous Ascites with Peritoneovenous Shunt (Denver Shunt) following Retroperitoneal Lymph Node Dissection in Patients with Urological Malignancies: Update of Efficacy and Predictors of Complications.

PURPOSE: We investigated the efficacy and analyzed the complication risk factors of peritoneovenous shunt in treating refractory chylous ascites following retroperitoneal lymph node dissection in patients with urological malignancies. MATERIALS AND METHODS: From April 2001 to March 2019 all patients with refractory chylous ascites after retroperitoneal lymph node dissection treated with peritoneovenous shunt were reviewed. Demographic characteristics, technical success, efficacy, patency period and complications were studied. Univariate and multivariate logistic regression analysis was performed to identify predictors of complications. RESULTS: Twenty patients were included in this study. Testicular cancer was the most common malignancy (85%). The mean number of days from surgery to detection of chylous ascites was 21 days (SD 15, range 4 to 65). Ascites permanently resolved after peritoneovenous shunt in 18 patients (90%), leading to shunt removal in 17 patients (85%) between 46 and 481 days (mean 162, SD 141). The mean serum albumin level increased 24% after shunt placement (mean 3.0±0.6 gm/dl before, 3.9±0.8 gm/dl after, p <0.05). The most common complication was occlusion (30%). Relative risk of complications increased significantly when shunt placement was more than 70 days after surgery and in patients with more than 5 paracenteses before peritoneovenous shunt placement (AR 0.71% vs 0.25%, RR 2.9, p <0.048 and AR 0.6% vs 0.125%, RR 4.8, p <0.04, respectively). CONCLUSIONS: Peritoneovenous shunt permanently treated chylous ascites in 90% of patients after retroperitoneal lymph node dissection. Peritoneovenous shunt was removed in 85% of patients. Shunt placement is an effective and safe treatment option for refractory chylous ascites. These patients might benefit from earlier intervention, after 4 to 6 weeks of conservative management as opposed to 2 to 3 months.

Adjuvant Chemotherapy With Etoposide Plus Cisplatin for Patients With Pathologic Stage II Nonseminomatous Germ Cell Tumors.

PURPOSE: The relapse rate after primary retroperitoneal lymph node dissection (RPLND) for patients with pathologic stage (PS) IIA nonseminomatous germ cell tumors (NSGCTs) is 10%-20% but increases to ≥ 50% for PS IIB disease. We report our experience with 2 cycles of adjuvant etoposide plus cisplatin (EP×2) after therapeutic primary RPLND. PATIENTS AND METHODS: All patients with PS II NSGCT seen at Memorial Sloan Kettering Cancer Center from March 1989 to April 2016 and who were planned to receive EP×2 were included. Each cycle consisted of cisplatin 20 mg/m2 and etoposide 100 mg/m2 on days 1 through 5 at 21-day intervals. Demographic characteristics, histopathologic features, therapeutic and survival outcomes were recorded. RESULTS: Of 156 patients, 30 (19%) had pathologic N1, 122 (78%) had pathologic N2 (pN2), and 4 (3%) had pathologic N3 (pN3) disease. The median number of involved lymph nodes was 3 (range, 1-37 nodes), and the median size of the largest involved node was 2.0 cm (range, 0.4-7.0 cm); extranodal extension was present in 69 patients (45%). Embryonal carcinoma was the most frequent RPLND histology, present in 143 patients (92%). One hundred fifty patients (96%) received EP×2, five received EP×1 and one received EP×4. With a median follow-up of 9 years, 2 patients (1.3%; 1 patient each with pN2 and pN3 disease) experienced relapse; both patients remain continuously disease free at more than 5 and 22 years after salvage chemotherapy. Three patients died, all unrelated to NSGCT, yielding 10-year disease-specific, relapse-free, and overall survival rates of 100%, 98%, and 99%, respectively. CONCLUSION: Adjuvant EP×2 for PS II NSGCT is highly effective, has acceptable toxicity, and incurs less drug cost than 2 cycles of bleomycin, etoposide, and cisplatin. Inclusion of bleomycin in this setting is not necessary.

Impact of Teratoma on the Cumulative Incidence of Disease-Related Death in Patients With Advanced Germ Cell Tumors.

PURPOSE: In men with metastatic germ cell tumors (GCTs), risk-directed treatment is determined, in part, by a distinction between seminoma and nonseminomatous GCT (NSGCT). The importance of NSGCT cell type is uncertain. We evaluated the long-term impact of teratoma on survival in patients with NSGCT. METHODS: Prechemotherapy, primary tumors from patients who received platinum-based chemotherapy were studied, and the histology was confirmed by a genitourinary pathologist. The cumulative incidence of disease-related death (CIDD) was the primary end point, and a competing-risk analysis was performed. RESULTS: Tumors were available from 232 patients, including 193 with NSGCT. An element of teratoma was present in 82 NSGCT primary tumors (42%). With a median follow-up of 17 years (range, 0.3 to 35 years), 58 patients with NSGCT died, 47 as a result of GCT and 11 as a result of other causes. Most GCT deaths occurred within the first 5 years and were associated with pretreatment risk status (P < .001). Death as a result of other causes rose steadily after 15 years and was not associated with risk status (P = .66). A higher CIDD was observed in patients who had NSGCT with teratoma than those with NSGCT without teratoma and seminoma (5-year CIDD rate, 27.4%, 17.4%, and 10.3%, respectively; P = .03). A higher CIDD was observed in patients who had NSGCT with mature teratoma compared with those with either NSGCT with immature teratoma or NSGCT without teratoma (5-year CIDD rate, 38.1%, 19.9%, and 17.4%, respectively; P = .01). CONCLUSION: The presence of teratoma, particularly mature teratoma, in an NSGCT primary tumor is associated with a higher CIDD, consistent with the hypothesis that differentiation is associated with adverse outcomes. Death as a result of non-GCT causes is not associated with risk status and must be separated from GCT death when evaluating long-term survival.

Diagnosis and Treatment of Early Stage Testicular Cancer: AUA Guideline.

PURPOSE: Testis cancer is the most common solid malignancy in young males. The purpose of this guideline is to provide a useful reference on the effective evidence-based treatment of early stage testicular cancer. METHODS: The systematic review utilized to inform this guideline was conducted by a methodology team at the Johns Hopkins University Evidence-based Practice Center. The methodology team searched using PubMed®, Embase®, and the Cochrane Central Register of Controlled Trials (CENTRAL) from January 1980 through August 2018. The evidence review team also reviewed relevant systematic reviews and references provided by the panel to identify articles that may have been missed by the database searches. RESULTS: When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low). Such evidence-based statements are provided as Strong, Moderate, or Conditional Recommendations. In instances of insufficient evidence, additional guidance is provided as Clinical Principles and Expert Opinions. CONCLUSIONS: This guideline attempts to improve a clinician's ability to evaluate and treat patients with testicular cancer, but higher quality evidence in future trials will be essential to improve level of care for these patients.

Surgical Management of Patients with Advanced Germ Cell Tumors Following Salvage Chemotherapy: Memorial Sloan Kettering Cancer Center (MSKCC) Experience.

OBJECTIVE: To characterize clinical and pathologic outcomes of cisplatin-refractory or relapsed germ cell tumor (GCT) patients who underwent retroperitoneal lymph node dissection (RPLND) following salvage chemotherapy with either conventional or high dose regimens. METHODS: Data were reviewed to identify all patients treated with TIP or TICE salvage chemotherapy between 1994 and 2011(n = 184) at our institution. We report clinicopathologic and outcomes data on 131 patients who were further managed with surgical resection. Using Cox-proportional hazards models, predictors of disease-specific survival (DSS) were analyzed. RESULTS: Median follow-up was 7.3 years. Of the 112 patients who underwent postsalvage chemotherapy RPLND, histology was reported as viable GCT in 30 (27%), teratoma only in 26 (23%) and fibrosis in 56 (50%). 5-year DSS for the entire cohort was 74% (95% confidence interval 63%-80%). On multivariable analysis, viable GCT histology at RPLND or extra-RPLND resection predicted for worse DSS (hazard ratio 7.37, P = .003). CONCLUSIONS: Our data suggest that approximately half of the patient with cisplatin-refractory or relapsed GCT salvaged with TIP or TICE chemotherapy and evidence of residual disease are at risk of harboring either viable GCT or teratoma. This finding underlines the critical role of surgery in the multimodality approach to the management of this advanced disease entity. If retroperitoneal disease exists prior to salvage chemotherapy, we recommend postchemotherapy resection in all eligible patients.

Current controversies on the role of retroperitoneal lymphadenectomy for testicular cancer.

Retroperitoneal lymph node dissection (RPLND) is an important component of the multimodal treatment which cures most patients diagnosed with testicular germ cell tumors. Considering the high cure rates achieved, research focus in recent years has been directed toward improving quality of life and decreasing long-term treatment related sequelae. Consequently, the role of RPLND has evolved over the past 3 decades in both low-stage and advanced testicular cancer. The use of RPLND in clinically stage I and low volume stage II disease may offer the advantages of treating retroperitoneal teratoma which is present in 15% to 20% of patients, avoiding chemotherapy and reducing the need for frequent imaging during follow-up. Similarly, ongoing studies are evaluating the safety and effectiveness of RPLND for the treatment of early stage seminoma to avoid the long-term effects of chemotherapy and radiotherapy. RPLND is traditionally used for the treatment of residual masses >1 cm after completion of chemotherapy. Its role in subcentimeter residual masses remains somewhat controversial given the fact that 25% to 30% of these patients are found to harbor either teratoma or viable nonteratomatous germ cell tumors. The presence of teratoma increases the probability of teratoma in metastatic sites. Modified unilateral templates were developed based on early mapping studies with the aim of preserving antegrade ejaculation. Recent data suggests initial mapping studies underestimated the risk of contralateral retroperitoneal metastases which may reach 32%. Furthermore, antegrade ejaculation may be preserved in >95% of patients undergoing bilateral nerve sparing primary RPLND and >80% undergoing nerve-sparing PC-RPLND, which, in our view is the more prudent oncologic approach. Recently, multiple series have demonstrated the safety and short-term efficacy of minimally invasive RPLND; however, larger studies with prolonged follow-up are required to validate the long-term oncologic efficacy of newer techniques.