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.

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.

Dose-dense chemotherapy for untreated poor-prognosis and relapsed germ-cell tumours: an 18-year experience with GAMEC chemotherapy.

OBJECTIVE: To report a single-centre experience of the regimen GAMEC (granulocyte colony-stimulating factor, actinomycin-D, methotrexate with folinic acid rescue, etoposide and cisplatin) over 18 years in both untreated disease and relapse settings. METHODS: This retrospective cohort study was based on 162 patients who received GAMEC dose-dense chemotherapy incorporating actinomycin and high dose methotrexate. Survival outcomes were compared. Risk categorization based on (1) the International Prognostic Factor Study Group (IPFSG) criteria and (2) two factors, lactate dehydrogenase (LDH) levels greater than the upper limit of normal and age ≥35 years, were also compared in terms of survival outcomes using Cox proportional hazard regression modelling. RESULTS: Seventy-five patients with poor-prognosis disease, according to International Germ Cell Cancer Collaborative Group classification, received GAMEC as initial therapy. With a median follow-up of 63 months, the median progression-free survival (PFS) was >14 months. The 2-year PFS rate was 61.5% (95% confidence interval [CI] 49.1-71.6), and the 3-year overall survival (OS) rate was 71.9%. Seventy-six patients received GAMEC as second-line therapy (following failure of bleomycin, etoposide and cisplatin or etoposide cisplatin). The median PFS was 7.5 months (95% CI 5.2-not evaluable), the 2-year PFS rate was 43.5% (95% CI 32.1-54.4) and the 3-year OS rate was 53.7% (95% CI 41.6-64.3). In the third-line setting (n = 11), the 2-year PFS was 18.2% (95% CI 2.8-44.2). Overall, the treatment-related death rate declined from 10.5% in the first 15 years to 2.6% in the last 5 years. CONCLUSION: GAMEC was an effective regimen in untreated poor-prognosis disease and on relapse following conventional cisplatin and etoposide-based chemotherapy. Risk categorization based on LDH/age is more sensitive than that based on the updated IPFSG criteria. It is possible to identify patients who are particularly likely to benefit from this treatment, which has the important advantages of short duration and absence of bleomycin, particularly in patients with central nervous system and mediastinal disease. Low-dose induction treatment is associated with safer delivery of treatment without compromising survival.

A Prospective Audit of Intermittent Anti-Androgen verses Pituitary Blockade Suggests a Bipolar Androgen Type Strategy May Be Safe in Untreated Prostate Cancer.

OBJECTIVE: A locally advanced Gleason 4 + 4 prostate cancer patient who was on self-medication with intermittent anti-androgen monotherapy (iAAm) over 14 years suggested that raised testosterone was not dangerous and this suggestion needed investigating. PATIENTS: Others who were on AA continuously were recruited to ongoing audit of intermittent hormone therapy (IHT) and iAAm outcomes were compared with intermittent LHRH therapy (iLHRH or iMAB). RESULTS: Between 1994 and 2007, 111 patients sought IHT because of side effects of treatment. Forty-two M0 patients received IHT with iLHRHm or iMAB and 33 received iAAm (31 of these were M0). PSA nadir below 4 was necessary for entry. Overall survival was 87, 72 and 67% with iAAm and 73, 56 and 43% with iLHRH/MAB at 5, 8 and 10 years respectively. Overall survival was 61, 55 and 33% continued on iAAm and 56, 41, and 32% on iLHRH/MAB at 5, 8, and 10 years respectively. Multivariable analysis and matched case control analysis confirm that the maintenance of advantage for iAAm Testosterone levels in patients on iAAm compared to iLHRH therapy was more intense throughout treatment. CONCLUSION: These results complement recent progress in using bipolar androgen therapy to reverse castration resistance and add to the increasing acceptance that controlled testosterone exposure might be relevant in hormone-naïve patients.

Incidentally detected testicular lesions <10 mm in diameter: can orchidectomy be avoided?

OBJECTIVE: To investigate the pathology of excised testicular lesions <10 mm in size. PATIENTS AND METHODS: The pathological reports of 2 681 patients with testicular lesions from Barts Health NHS Trust and Oxford University Hospitals NHS Foundation Trust were reviewed as part of a service evaluation audit from January 2003 to May 2016. Cases in which the lesion had a maximum diameter of <10 mm were selected. Clinical features were also accessed, where available, to examine patient demographics, prediagnostic levels of serum markers, ultrasonographic findings and clinical details. RESULTS: A total of 81 patients with a lesion size <10 mm on histology were identified and, of these, 16 (20%) had a lesion diameter <5 mm. Of the 81 patients, 56 (69%) had benign lesions. Of 16 patients with a benign lesion <5 mm in diameter, 15 underwent orchidectomy and just one underwent partial orchidectomy. Preoperative tumour markers were available in 47/81 patients. None of the 16 malignant tumours in these 47 patients were associated with raised tumour markers, while seven of 31 remaining patients with benign lesions had raised α-fetoprotein and lactate dehydrogenase levels. In total there were 25/81 malignant cases (31%), which were all germ cell tumours (GCTs): 15 seminomas (60%) and 10 non-seminomatous GCTs (40%). Only one GCT had a diameter of <5 mm, and this was a regressed tumour within an 18-mm area of granulomatous inflammation. Only one GCT relapsed: a clinical stage I, embryonal carcinoma of 6 mm in maximum diameter. The 56 'benign' cases included 34 sex cord stromal tumours, including 23 Leydig cell tumours (41%), eight Sertoli cell tumours (14%) and three mixed sex cord stromal tumours (5%). None showed any malignant features. The remaining 22/56 lesions (40%) were lesions with no further follow-up. Benign lesions seemed to be associated with a small diameter, and we found <5 mm to be the best threshold for predicting benign vs malignant lesions (P = 0.002). CONCLUSION: The majority of testicular lesions <10 mm, identified by radiology, were benign, although approxmiately one-third were malignant. In the present study, 100% of lesions <5 mm in diameter were benign. Tumour markers appear to be unhelpful in the distinction of these small tumours. We suggest that regular ultrasound surveillance be more widely used for testicular lesions of this size. Testicular tumours now have a very high cure rate and changes in size of lesions may be monitored prospectively with minimal risk of increased morbidity. Patients who undergo an orchidectomy for lesions <5 mm are 'victims of modern imaging technology'. If surgery is undertaken in lesions 5-10 mm, patients should be counselled that two-thirds of cases are benign.

Bone metastases in germ cell tumours: lessons learnt from a large retrospective study.

OBJECTIVE: To determine the characteristics of patients with germ cell cancer and bone metastases. PATIENTS AND METHODS: The case records of patients with known germ cell tumours (GCTs) within the Anglian Germ Cell Cancer Group database between January 2005 and March 2011 were reviewed retrospectively. Data were collected for histopathology, presence of bone metastases at diagnosis or relapse, site of bone metastases and imaging method used to confirm bone metastases, treatment received, response to treatment and overall survival. We present here the largest unselected cohort of bone metastases in patients with GCTs. RESULTS: In all, 2550 cases of GCTs were reviewed and there was bone involvement in 19 cases. The primary site was either testicular (13/19), mediastinal (1/19) or unknown (5/19). Most cases were non-seminomatous GCTs (11/19, 58%) and only three cases of seminomatous GCTs (3/19, 16%) with five cases in which diagnosis was based on clinical history and significantly raised GCT markers (5/19, 26%). In all of these five cases ß-human chorionic gonadotrophin was raised and in three α-fetoprotein was raised, consistent with non-seminomatous GCT. There were bone metastases at diagnosis (0.51%, 13/2550) or at relapse (0.24%, 6/2550). The sites of bone metastases were the vertebrae (15/19, 79%), pelvis (3/19, 16%), ribs (3/19, 16%) and femur (2/19, 11%). Ten patients (53%) had solitary, and nine patients (47%) had multiple, sites of bone metastases. In patients presenting with bone metastases at diagnosis compared with relapse, the mortality rate was 23% (3/13) and 50% (3/6), respectively. After receiving one line of chemotherapy, nine patients (47%) remained in remission not requiring further treatment, six (32%) required further chemotherapy due to subsequent relapse, three (16%) died after first-line chemotherapy and one was lost to follow-up. At the time of data collection and based on the last clinic follow-up, six patients (32%) had died with a median (interquartile range, IQR) follow-up of 11.5 (4.3, 24.8) months and 10 (53%) remained alive with a median (IQR) follow-up of 26 (13.5, 48) months Three patients were lost to follow-up. Of the known patients alive, eight (42%) remained in remission and two (11%) had recurrent disease requiring further treatment. CONCLUSION: Although bone disease in germ cell cancer is rare, awareness of this condition is important and there is a need for prospective evaluation of patient characteristics, treatment approaches and survival outcome in this group of patients.

Carboplatin AUC 10 for IGCCCG good prognosis metastatic seminoma.

OBJECTIVE: Metastatic seminoma is a highly curable disease. Standard treatment comprises of combination chemotherapy. The short- and long-term toxicities of this treatment are increasingly recognised and the possibility of over treatment in such a curable disease should be considered. We have therefore assessed the use of single agent carboplatin at a dose of AUC 10 in patients with good prognosis metastatic seminoma. MATERIALS AND METHODS: Patients with good prognosis metastatic seminoma treated with carboplatin (AUC 10) were identified at our institution and affiliated institutions. Treatment was three weekly for a total of three or four cycles. Outcome and toxicities were analysed. RESULTS: With a median follow-up of 36 months, 61 patients in total were treated with carboplatin AUC 10, all good prognosis by the IGCCCG criteria. Forty-eight percent had stage IIA/IIB disease and 52% had greater than stage IIB disease. Thirty-one patients (51%) had a complete response following treatment. Three-year survival was 96.3% with a three-year progression free survival of 93.2%. The main treatment toxicity was haematological with 46% having grade 3, 24% having grade 4 neutropenia and 54% experiencing grade 3/4 thrombocytopenia. There were no treatment related deaths. CONCLUSION: Single agent carboplatin at a dose of AUC 10 is an effective treatment for good prognosis metastatic seminoma. The outcome compares favourably to previously published outcomes of combination chemotherapy. Although haematological toxicity is a concern, single agent carboplatin treatment for good prognosis metastatic seminoma could be considered a treatment option and is associated with less toxicity than combination regimens currently used.