Neoadjuvant Platinum-Based chemotherapy and lymphadenectomy for penile cancer: an international, Multi-Institutional, Real-World study.

INTRODUCTION: This study investigated the efficacy and safety of neoadjuvant chemotherapy (NAC) for locally advance penile squamous cell carcinoma (PSCC), for which current evidence is lacking. METHODS: Included patients had locally advanced PSCC with clinical lymph node metastasis treated with at least one dose of NAC prior to planned consolidative lymphadenectomy. Objective response rates (ORR) were assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The primary and secondary outcomes were overall survival and progression-free survival, estimated by the Kaplan-Meier method. Treatment-related adverse events (trAEs) were graded per the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. RESULTS: 209 patients received NAC for locally advanced and clinically node-positive PSCC.The study population consisted of 7% of patients with stage II disease, 48% with stage III, and 45% with stage IV. Grade 2 TrAEs occurred in 35 (17%) patients, and no treatment related mortality was observed. 201 (97%) completed planned consolidative lymphadenectomy. During follow up, 106 (52.7%) patients expired, with a median OS of 37.0 months (95% CI 23.8-50.1), and median PFS of 26.0 months (95% CI 11.7-40.2). ORR was 57.2%, with 87 (43.2%) having partial response and 28 (13.9%) having a complete response. Patients with objective response to NAC had a longer median OS (73.0 vs 17.0 months, p < .01) compared to those who did not. The lymph-node pathologic complete response rate (ypN0) was 24.8% in the cohort. CONCLUSION: NAC with lymphadenectomy for locally advanced PSCC is well tolerated and active to reduce the disease burden and improve long term survival outcomes.

Long-term outcomes of penile squamous cell carcinoma in men age ≤50 years old compared with men >50 years old from a single tertiary referral centre: a propensity score matched analysis.

Penile cancer (PeCa) is rare, and the oncological outcomes in younger men are unclear. We aimed to analyse and compare oncological outcomes of men age ≤50 years (y) and >50 years with PeCa. A retrospective analysis of men ≤50 y with penile squamous cell carcinoma managed at a tertiary centre was performed. A propensity score matched cohort of men >50 y was identified for comparison. Matching was according to tumour, nodal stage and the types of primary surgery. Overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS), and metastasis-free survivals (MFS) were estimated using Kaplan-Meier plots and compared using log-rank tests. Between 2005-2020, 100 men ≤50 y (median (IQR) age, 46 y (40-49)) were identified and matched with 100 men >50 y (median (IQR) age, 65 y (59-73)). 10, 24, 32, 34 men age ≤50 y were diagnosed in 2005-2007, 2008-2012, 2013-2016 and 2017-2020 respectively. Median (IQR) follow-up was 53.5 (18-96) months. OS at 2 years: ≤50 y, 86%>50 y, 80.6%; 5 years: ≤50 y, 78.1%, >50 y, 63.1%; 10 years: ≤50 y, 72.3%, >50 y, 45.6% (p = 0.01). DSS at 2 years: ≤50 y, 87.2%>50 y, 87.8%; 5 years: ≤50 y, 80.9%>50 y, 78.2%; 10 years: ≤50 y, 78%, >50 y, 70.9% (p = 0.74). RFS was 93.1% in the ≤50 y group (vs. >50 y, 96.5%) at 2 year, and 90% (vs. >50 y, 88.5%) at 5 years, p = 0.81. Within the ≤50 y group, 2 years and 5 years MFS was 93% (vs. >50 y, 96.5%), and 89.5% (vs. >50 y, 92.7%) respectively, (p = 0.40). There were no statistical significance in DFS, RFS and MFS in men age ≤50 y and >50 y. PeCa in younger patients is fatal, public awareness and patient education are crucial for early detection and management.

Seminoma and dysgerminoma: evidence for alignment of clinical trials and de-escalation of systemic chemotherapy.

Malignant germ cell tumours are a group of rare cancers whose incidence peaks in late adolescence and early adulthood. Dysgerminomas of the ovary and seminomas of the testis are analogous diseases, but seminomas have a 10-fold higher incidence. The two tumours are morphologically identical and are only differentiated by surrounding organ-specific tissue or testicular germ cell neoplasia in situ. They share genetic features including KIT and RAS mutations, amplification of chromosome 12p, and expression of pluripotency markers (NANOG (Nanog homeobox), OCT3/4 (Octamer-binding transcription factor 3/4), and SAL4 (Spalt-like trascription factor 4)). Both histologies are exquisitely sensitive to platinum chemotherapy, and the combination of bleomycin, etoposide, and cisplatin (BEP) yields survival rates greater than 90%. However, BEP causes significant, lifelong toxicity (cardiovascular, renal, respiratory, and neurological) in these young patients with an expectation of cure. Here, we comprehensively review the biological features of dysgerminoma and seminoma to demonstrate that they are biologically analogous diseases. We present available clinical trial data supporting de-escalation of chemotherapy treatment. Finally, we propose that future trials should enrol men, women, and children to benefit all patients regardless of age or sex.

Outcomes of penile sarcomatoid squamous cell carcinoma from a single tertiary referral centre: a matched cohort study.

OBJECTIVE: To report the oncological survival outcomes of men with penile sarcomatoid squamous cell carcinoma (sSCC). PATIENTS AND METHODS: A retrospective analysis of men with penile sSCC diagnosed between January 2010 and January 2020 in a single centre was conducted. Disease-specific (DSS), recurrence-free (RFS) and metastasis-free (MFS) survival were evaluated. Outcomes were compared with a non-sarcomatoid penile SCC cohort matched to age, type of surgery and tumour stage. Kaplan-Meier plots were used to estimate survival outcomes. RESULTS: In all, 1286 men were diagnosed with penile SCC during the study period and of these 38 (3%) men had sSCC. The median (interquartile range) age and follow-up was 70 (57-81) years and 16 (7-44) months, respectively. Operations performed included: circumcision, one (2.6%); wide local excision, four (10.5%); glansectomy, 11 (29%); partial penectomy, 10 (26%); subtotal/total penectomy, 12 (32%). The Kaplan-Meier estimated 12-, 24- and 36-month DSS was 62% (vs non-sarcomatoid, 67%), 43% (vs non-sarcomatoid, 67%) and 36% (vs non-sarcomatoid, 67%), respectively (P = 0.03). The Kaplan-Meier estimated 12- and 24-month RFS was 47% (vs non-sarcomatoid, 60%) and 28% (vs non-sarcomatoid, 55%), respectively (P = 0.01). The MFS was 52% (vs non-sarcomatoid, 62%) at 12 months and 37% (vs non-sarcomatoid, 57%) at 24 months (P = 0.04). CONCLUSIONS: Sarcomatoid differentiation was associated with a lower DSS, RFS and MFS. Due to the rarity of its incidence and aggressiveness, expert histological review and multidisciplinary management is required in a specialist penile cancer centre.

Treatment de-escalation for stage II seminoma.

International Germ Cell Cancer Collaborative Group good-risk metastatic seminoma has cure rates of >95%. Within this risk group, patients with stage II disease exhibit the best oncological outcomes with the standard-of-care treatment strategies of radiotherapy or combination chemotherapy. However, these treatments can be associated with substantial early and late toxic effects. Therapy de-escalation aims to reduce treatment morbidity whilst preserving oncological outcomes. The evidence supporting such approaches is largely from non-randomized institutional data, and therefore this strategy is not recognized as standard of care. Current de-escalation approaches for stage II seminoma include single-agent chemotherapy, radiotherapy and surgery based on early data from clinical studies. Increased recognition of emerging data on treatment modification to reduce morbidity whilst maintaining cure rates and consideration of therapy de-escalation could improve patient survivorship outcomes.

Management of small testicular masses: outcomes from a single-centre specialist multidisciplinary team.

OBJECTIVES: To report the management outcomes of men with ≤20-mm small testicular masses (STMs) and to identify clinical and histopathological factors associated with malignancy. PATIENTS AND METHODS: A retrospective analysis of men managed at a single centre between January 2010 and December 2020 with a STM ≤20 mm in size was performed. RESULTS: Overall, 307 men with a median (interquartile range [IQR]) age of 36 (30-44) years were included. Of these, 161 (52.4%), 82 (26.7%), 62 (20.2%) and 2 men (0.7%) underwent surveillance with interval ultrasonography (USS), primary excisional testicular biopsy (TBx) or primary radical orchidectomy (RO), or were discharged, respectively. The median (IQR) surveillance duration was 6 (3-18) months. The majority of men who underwent surveillance had lesions <5 mm (59.0%) and no lesion vascularity (67.1%) on USS. Thirty-three (20.5%) men undergoing surveillance had a TBx based on changes on interval USS or patient choice; seven (21.2%) were found to be malignant. The overall rate of malignancy in the surveillance cohort was 4.3%. The majority of men who underwent primary RO had lesions ≥10 mm (85.5%) and the presence of vascularity (61.7%) on USS. Nineteen men (23.2%) who underwent primary TBx (median lesion size 6 mm) had a malignancy confirmed on biopsy and underwent RO. A total of 88 men (28.7%) underwent RO, and malignancy was confirmed in 73 (83.0%) of them. The overall malignancy rate in the whole STM cohort was 23.8%. Malignant RO specimens had significantly larger lesion sizes (median [IQR] 11 [8-15] mm, vs benign: median [IQR] 8 [5-10] mm; P = 0.04). CONCLUSIONS: Small testicular masses can be stratified and managed based on lesion size and USS features. The overall malignancy rate in men with an STM was 23.8% (4.3% in the surveillance group). Surveillance should be considered in lesions <10 mm in size, with a TBx or frozen-section examination offered prior to RO in order to preserve testicular function.

Decoding germ cell tumours for clinicians.

PURPOSE OF REVIEW: Germ-cell tumours of the testis affect predominantly younger males aged between 15 and 40 years, with nearly 74,500 new cases estimated globally in 2020. Their rarity and the complex morphology, mean that, in nonexpert hands, there is a significant risk of misdiagnosis of both type and staging of these neoplasms. RECENT FINDINGS: There have been significant changes in the 2016 WHO classification of Testicular tumours that need to be understood by both pathologists and clinicians for streamlining management. Standardised structured reporting guidelines and discussion at the multidisciplinary-team meetings lead to subsequently better health outcomes and patient safety. SUMMARY: Therefore, communication with high-quality reports and understanding of clinicians of what constitutes an adequate report, is the key to ensure proper management of these patients. We attempt to discuss the key updates and pathological features that influence management and need to be communicated with clarity and precision.

Management of stage II seminoma: a contemporary UK perspective.

BACKGROUND AND AIMS: Testicular Germ Cell Tumours (TGCTs) are the commonest young adult male cancer, with excellent survival outcomes even with metastatic disease. Chemotherapy, radiotherapy, and surgery are international guideline-dictated standard of care (SOC) treatments for International Germ Cell Cancer Collaborative Group (IGCCCG) "good risk" TGCT, but are associated with significant toxicities. Therapy de-escalation aims to reduce treatment morbidity whilst preserving cure rates, and has been adopted by some centres for stage IIA/B seminoma. Here, we report on the contemporary UK treatment landscape for stage IIA/B seminoma. METHODS: A questionnaire-based survey of NHS England-designated specialist cancer centres hosting supra-regional specialist multi-disciplinary team (sMDT) services (n = 13) as well those within NHS Scotland, NHS Wales and Health and Social Care Northern Ireland. Respondents were asked to order preferences of SOC and therapy de-escalation treatments for stage IIA/B seminoma. RESULTS: We identified significant geographical heterogeneity in treatment preferences. Whilst up to a third of centres have adopted a treatment de-escalation regimen, the majority deliver combination chemotherapy or radiotherapy. CONCLUSION: A wider recognition of UK treatment heterogeneity and consideration of therapy de-escalation strategies at supra-regional sMDTs will increase stage IIA/B seminoma treatment options as part of clinical trials with oncological and quality of life endpoints.

Single-agent carboplatin AUC10 in metastatic seminoma: A multi-centre UK study of 216 patients.

BACKGROUND: Radiotherapy and cisplatin-based combination chemotherapy are accepted standard-of-care treatments for metastatic seminoma with excellent survival outcomes but with established short- and long-term morbidity. Carboplatin monotherapy may be a less toxic alternative; however early historic studies at AUC7 showed inferior outcomes. OBJECTIVES: To evaluate multi-institutional data on and toxicity and longer-term survival for metastatic seminoma patients treated with the single-agent carboplatin AUC10. METHODS: We undertook a multi-institutional analysis incorporating all men with the International Germ Cell Cancer Collaborative Group good-prognosis metastatic seminoma treated until 2018. Carboplatin AUC10 was given every 21 days. Toxicity, progression-free survival (PFS), disease-specific survival (DSS) and overall survival were noted. Variables predictive of progression were identified. RESULTS AND LIMITATIONS: 216 patients were treated. The three-year PFS rate was 96.5%, and five-year DSS was 98.3%. There were seven relapses, of which 5 were successfully salvaged with further chemotherapy ± surgery, and three non-seminoma-related deaths. There were no treatment-related deaths. Of 148/216 evaluable patients for toxicity, 37% and 27% suffered >/ = grade III neutropenia and thrombocytopenia, respectively. Twelve percent of patients needed a platelet or blood transfusion (or both). The incidence of febrile neutropenia was 5%. CONCLUSION: For metastatic seminoma, carboplatin AUC10 harbours a similar oncological efficacy to established therapies, with a low failure risk. The major acute toxicity was myelosuppression. Our study establishes carboplatin AUC10 as another standard-of-care treatment option for good-prognosis metastatic seminoma, with a potentially lower toxicity profile than other therapies.

A comparative study of peri-operative outcomes for 100 consecutive post-chemotherapy and primary robot-assisted and open retroperitoneal lymph node dissections.

PURPOSE: To describe and compare differences in peri-operative outcomes of robot-assisted (RA-RPLND) and open (O-RPLND) retroperitoneal lymph node dissection performed by a single surgeon where chemotherapy is the standard initial treatment for Stage 2 or greater non-seminomatous germ cell tumour. METHODS: Review of a prospective database of all RA-RPLNDs (28 patients) and O-RPLNDs (72 patients) performed by a single surgeon from 2014 to 2020. Peri-operative outcomes were compared for patients having RA-RPLND to all O-RPLNDs and a matched cohort of patients having O-RPLND (20 patients). Further comparison was performed between all patients in the RA-RPLND group (21 patients) and matched O-RPLND group (18 patients) who had previous chemotherapy. RA-RPLND was performed for patients suitable for a unilateral template dissection. O-RPLND was performed prior to the introduction of RA-RPLND and for patients not suitable for RA-RPLND after its introduction. RESULTS: RA-RPLND showed improved peri-operative outcomes compared to the matched cohort of O-RPLND-median blood loss (50 versus 400 ml, p < 0.00001), operative duration (150 versus 195 min, p = 0.023) length-of-stay (1 versus 5 days, p < 0.00001) and anejaculation (0 versus 4, p = 0.0249). There was no statistical difference in complication rates. RA-RPLND had lower median lymph node yields although not significant (9 versus 13, p = 0.070). These improved peri-operative outcomes were also seen in the post-chemotherapy RA-RPLND versus O-RPLND analysis. There were no tumour recurrences seen in either group with median follow-up of 36 months and 60 months, respectively. CONCLUSIONS: Post-chemotherapy RA-RPLND may have decreased blood loss, operative duration, hospital length-of-stay and anejaculation rates in selected cases and should, therefore, be considered in selected patients. Differences in oncological outcomes require longer term follow-up.

The potential of using circulating tumour cells and their gene expression to predict docetaxel response in metastatic prostate cancer.

Background: Docetaxel improves overall survival (OS) in castration-resistant prostate cancer (PCa) (CRPC) and metastatic hormone-sensitive PCa (mHSPC). However, not all patients respond due to inherent and/or acquired resistance. There remains an unmet clinical need for a robust predictive test to stratify patients for treatment. Liquid biopsy of circulating tumour cell (CTCs) is minimally invasive, can provide real-time information of the heterogeneous tumour and therefore may be a potentially ideal docetaxel response prediction biomarker. Objective: In this study we investigate the potential of using CTCs and their gene expression to predict post-docetaxel tumour response, OS and progression free survival (PFS). Methods: Peripheral blood was sampled from 18 mCRPC and 43 mHSPC patients, pre-docetaxel treatment, for CTC investigation. CTCs were isolated using the epitope independent Parsortix® system and gene expression was determined by multiplex RT-qPCR. We evaluated CTC measurements for post-docetaxel outcome prediction using receiver operating characteristics and Kaplan Meier analysis. Results: Detection of CTCs pre-docetaxel was associated with poor patient outcome post-docetaxel treatment. Combining total-CTC number with PSA and ALP predicted lack of partial response (PR) with an AUC of 0.90, p= 0.037 in mCRPC. A significantly shorter median OS was seen in mCRPC patients with positive CTC-score (12.80 vs. 37.33 months, HR= 5.08, p= 0.0005), ≥3 total-CTCs/7.5mL (12.80 vs. 37.33 months, HR= 3.84, p= 0.0053), ≥1 epithelial-CTCs/7.5mL (14.30 vs. 37.33 months, HR= 3.89, p= 0.0041) or epithelial to mesenchymal transitioning (EMTing)-CTCs/7.5mL (11.32 vs. 32.37 months, HR= 6.73, p= 0.0001). Significantly shorter PFS was observed in patients with ≥2 epithelial-CTCs/7.5mL (7.52 vs. 18.83 months, HR= 3.93, p= 0.0058). mHSPC patients with ≥5 CTCs/7.5mL had significantly shorter median OS (24.57 vs undefined months, HR= 4.14, p= 0.0097). In mHSPC patients, expression of KLK2, KLK4, ADAMTS1, ZEB1 and SNAI1 was significantly associated with shorter OS and/or PFS. Importantly, combining CTC measurements with clinical biomarkers increased sensitivity and specificity for prediction of patient outcome. Conclusion: While it is clear that CTC numbers and gene expression were prognostic for PCa post-docetaxel treatment, and CTC subtype analysis may have additional value, their potential predictive value for docetaxel chemotherapy response needs to be further investigated in large patient cohorts.

A patient-centric pathway for testicular cancer - A multicentre study investigating the uptake of semen cryopreservation and impact on treatment.

BACKGROUND: The option of semen cryopreservation following a diagnosis of testicular cancer shows a variable uptake with the option to cryopreserve before surgery often dependent on the preference of the treating clinician and the fertility laboratory resources available. OBJECTIVES: To assess whether the introduction of a patient-centric pathway for managing suspected testicular cancer increases the uptake of semen cryopreservation and the impact of this on surgical waiting times. MATERIALS AND METHODS: A multicentre retrospective analysis of patients treated as part of a patient-centric pathway was conducted for suspected testicular cancer at two specialist centres within a one-stop testicular clinic. Clinical information, including semen cryopreservation acceptance rate, time intervals to surgery and CT scan, TNM stage, histology and age, was recorded from an institutional database. RESULTS: Eighty nine patients (median age: 34 years (range: 14-89)) underwent orchidectomy for suspected testicular cancer over a 15-month period after the introduction of a patient-centric testicular cancer pathway at two UK centres. The overall uptake of semen cryopreservation was 68.5% (n = 61) with all men under the age of 33 years accepting this option. A microdissection oncoTESE was performed in 9/61 (14.8%) patients who attempted cryopreservation but were found to be azoospermic. Pre-operative CT imaging was completed for 85.4% of patients, and the median time from initial outpatient consultation to orchidectomy was 9 days. DISCUSSION AND CONCLUSIONS: A patient-centric pathway ensures that the uptake of semen cryopreservation remains high particularly for those men within the common age for paternity. It also identifies men who may benefit from microdissection oncoTESE for complex cases such as tumours in solitary testicles, bilateral tumours or an atrophic contralateral testicle as well as those diagnosed with de novo azoospermia. The additional time taken for semen cryopreservation to be performed did not significantly delay orchidectomy or influence the decisions for adjuvant treatment.

Management of penile cancer patients during the COVID-19 pandemic: An eUROGEN accelerated Delphi consensus study.

OBJECTIVES: To develop an international consensus on managing penile cancer patients during the COVID-19 acute waves. A major concern for patients with penile cancer during the coronavirus disease 2019 (COVID-19) pandemic is how the enforced safety measures will affect their disease management. Delays in diagnosis and treatment initiation may have an impact on the extent of the primary lesion as well as the cancer-specific survival because of the development and progression of inguinal lymph node metastases. MATERIALS AND METHODS: A review of the COVID-19 literature was conducted in conjunction with analysis of current international guidelines on the management of penile cancer. Results were presented to an international panel of experts on penile cancer and infection control by a virtual accelerated Delphi process using 4 survey rounds. Consensus opinion was defined as an agreement of ≥80%, which was used to reconfigure management pathways for penile cancer. RESULTS: Limited evidence is available for delaying penile cancer management. The consensus rate of agreement was 100% that penile cancer pathways should be reconfigured, and measures should be developed to prevent perioperative nosocomial transmission of COVID-19. The panel also reached a consensus on several statements aimed at reconfiguring the management of penile cancer patients during the COVID-19 pandemic. CONCLUSIONS: The international consensus panel proposed a framework for the diagnostic and invasive therapeutic procedures for penile cancer within a low-risk environment for COVID-19.

The impact of a supranetwork multidisciplinary team (SMDT) on decision-making in testicular cancers: a 10-year overview of the Anglian Germ Cell Cancer Collaborative Group (AGCCCG).

BACKGROUND: The germ cell supranetwork multidisciplinary team (SMDT) for the Anglian Network covers a population of 7.5 million. METHODS: We reviewed 10 years of SMDT discussion and categorised them into five domains ((1) overall outcome, (2) chemotherapy regimens-untreated disease and salvage therapy, (3) radiology, (4) pathology and (5) complex cases) to assess the impact of the SMDT. RESULTS: A total of 2892 new cases were reviewed. In the first 5 years, patients with good prognosis disease had poorer survival in low-volume vs high-volume centres (87.8 vs 95.3, p = 0.02), but the difference was no longer significant in the last 5 years (93.3 vs 95.1, p = 0.30). Radiology review of 3206 scans led to rejection of the diagnosis of progression in 26 cases and a further 10 cases were down-staged. There were 790 pathology reviews by two specialised uropathologists, which lead to changes in 75 cases. 18F-fluorodeoxyglucose (18FDG) PET-CT was undertaken during this time period but did not help to predict who would have viable cancer. A total of 26 patients with significant mental health issues who were unable to give informed consent were discussed. CONCLUSION: SMDT working has led to an improvement in outcomes and refining of treatment in patients with germ cell tumours.

Neutropenic sepsis rates in patients receiving bleomycin, etoposide and cisplatin chemotherapy using olanzapine and reduced doses of dexamethasone compared to a standard antiemetic regimen.

OBJECTIVE: To investigate whether the use of a steroid-sparing antiemetic protocol (substituting dexamethasone with olanzapine) affects the incidence of neutropenia and associated hospital admissions in patients receiving bleomycin, etoposide and cisplatin (BEP) chemotherapy. PATIENTS AND METHODS: Records from 108 patients who received BEP at St Bartholomew's Hospital, London were divided into two groups according to antiemetic regimen. Group 1 (treated 2008-2013) were treated with a steroid-containing antiemetic protocol and group 2 (treated 2014-2017) were treated according to a steroid-sparing protocol, i.e. using olanzapine. Outcomes included incidence of neutropenia at nadir blood count, severity of neutropenia, hospital admissions attributable to febrile neutropenia (FN) and baseline risk factors associated with FN. Statistical analyses were performed using two-sided chi-squared tests. RESULTS: The baseline characteristics of the two groups were balanced with regard to age, gender, histology, and proportion of patients with International Germ Cell Cancer Collaborative Group poor-risk disease. The incidence of neutropenia of any grade (group 1, 96.2%; group 2, 98.1%) was similar, although group 2 had more patients with severe neutropenia than group 2 (77.7% vs 88.8%). There was a significant difference in FN incidence (group 1, 22%; group 2 7.5%; P = 0.030). Most cases of FN occurred in cycle 1. Two baseline characteristics were over-represented in patients who developed FN: female sex and age ≥50 years. CONCLUSION: By comparing two cohorts who received prophylactic antibiotics, our audit suggests that rates of FN-related admissions were lower in the cohort of patients in whom we employed a steroid-sparing antiemetic protocol.

Management of Late Relapses After Chemotherapy in Testicular Cancer: Optimal Outcomes with Dose-intense Salvage Chemotherapy and Surgery.

BACKGROUND: Late relapse (LR) in testicular cancer is defined as disease recurrence more than 2yr after primary treatment. Optimal management for this rare group is unknown. OBJECTIVE: To identify prognostic factors relevant to outcomes in a large LR series following primary treatment with platinum-based chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective analysis of all patients treated for advanced testicular cancer within the Anglian Germ Cell Cancer Network between 1995 and 2016. We identified 53 cases of LR following initial treatment for metastatic disease with platinum-based chemotherapy, and collected data on patient and tumour characteristics, treatments, and outcomes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Progression-free survival (PFS) and overall survival (OS) were calculated for all patients. Survival curves were plotted according to the Kaplan-Meier method and univariate analysis of descriptive variables was performed using the log-rank method. RESULTS AND LIMITATIONS: Across the cohort, PFS at 36 mo was 41% and OS was 61%. Multiple factors were correlated with PFS. Use of dose-intense or high-dose chemotherapy was associated with better PFS compared to conventional-dose chemotherapy (PFS 48 vs 9.8 mo; p=0.0036). Resection of residual disease post-relapse chemotherapy was associated with better PFS (hazard ratio 3.46; p=0.0076). There was a nonsignificant trend towards worse PFS in very late (>7 yr) relapses. The study is limited by its retrospective nature and selection bias cannot be excluded. CONCLUSIONS: This study provides new insight into prognostic factors in LR. It confirms that surgery is critical to optimal outcomes, and suggests that dose-intense or high-dose chemotherapy in multisite nonresectable disease should be considered wherever feasible. PATIENT SUMMARY: We studied patients with testicular cancer that recurred at least 2yr after initial treatment with chemotherapy. We found that patients who are able to have surgery to remove cancer and who have more intensive chemotherapy may be more likely to live longer.

Pathological predictors of metastatic disease in testicular non-seminomatous germ cell tumors: which tumor-node-metastasis staging system?

Pathological risk factors for metastatic disease in patients with testicular non-seminomatous germ cell tumors are debated. The tumor-node-metastasis (TNM) classification eighth edition for testicular cancers includes divergent versions, by the International Union Against Cancer (UICC) and by the American Joint Committee for cancer (AJCC). We investigated pathological predictors of metastatic disease at presentation in 219 non-seminomatous germ cell tumors with reference to both classifications. Age, tumor size, percentage of embryonal carcinoma, lymphovascular invasion, invasion of stromal rete testis, hilar soft tissue, epididymis, spermatic cord, and tunica vaginalis, as well as tumor at spermatic cord margin, were assessed and correlated with clinical stage at presentation. Of the 219 NSGCT cases, 151 (69%) were clinical stage I, 68 (31%) were clinical stage II/III. On univariate analysis, tumor size (P = 0.028), percentage of embryonal carcinoma (P = 0.004), lymphovascular invasion (P = 0.001), stromal rete testis invasion (P = 0.001), hilar soft tissue invasion (P = 0.010), epididymis invasion (P = 0.010), direct spermatic cord invasion (P = 0.001), and tumor at spermatic cord margin ((P = 0.009) were associated with higher clinical stage. On multivariate analysis, lymphovascular invasion (P = 0.003), tumor size (P = 0.005), percentage of embryonal carcinoma (P = 0.005), stromal rete testis invasion (P = 0.008) remained significant. A tumor size of 6 cm and an embryonal carcinoma percentage of 70% were the significant cut-off values. We conclude that in addition to lymphovascular invasion, stromal rete testis invasion, tumor size, and embryonal carcinoma percentage are strong predictors of metastatic disease at presentation and their inclusion should be considered in any future TNM revision. Further, our results support the changes in the AJCC TNM eighth edition as invasion of the epididymis and hilar soft tissue were both univariately significant.

ctDNA monitoring using patient-specific sequencing and integration of variant reads.

Circulating tumor-derived DNA (ctDNA) can be used to monitor cancer dynamics noninvasively. Detection of ctDNA can be challenging in patients with low-volume or residual disease, where plasma contains very few tumor-derived DNA fragments. We show that sensitivity for ctDNA detection in plasma can be improved by analyzing hundreds to thousands of mutations that are first identified by tumor genotyping. We describe the INtegration of VAriant Reads (INVAR) pipeline, which combines custom error-suppression methods and signal-enrichment approaches based on biological features of ctDNA. With this approach, the detection limit in each sample can be estimated independently based on the number of informative reads sequenced across multiple patient-specific loci. We applied INVAR to custom hybrid-capture sequencing data from 176 plasma samples from 105 patients with melanoma, lung, renal, glioma, and breast cancer across both early and advanced disease. By integrating signal across a median of >105 informative reads, ctDNA was routinely quantified to 1 mutant molecule per 100,000, and in some cases with high tumor mutation burden and/or plasma input material, to parts per million. This resulted in median area under the curve (AUC) values of 0.98 in advanced cancers and 0.80 in early-stage and challenging settings for ctDNA detection. We generalized this method to whole-exome and whole-genome sequencing, showing that INVAR may be applied without requiring personalized sequencing panels so long as a tumor mutation list is available. As tumor sequencing becomes increasingly performed, such methods for personalized cancer monitoring may enhance the sensitivity of cancer liquid biopsies.