Phase II study of Disulfiram and Cisplatin in Refractory Germ Cell Tumors. The GCT-SK-006 phase II trial.

BACKGROUND: Multiple relapsed/refractory germ cell tumor (GCT) patients have extremely poor prognosis. Cisplatin resistant testicular GCTs overexpress aldehyde-dehydrogenase (ALDH) isoforms and inhibition of ALDH activity by disulfiram is associated with reconstitution of cisplatin sensitivity in vitro as well as in animal model. This study aimed to determine the efficacy and toxicity of ALDH inhibitor disulfiram in combination with cisplatin in patients with multiple relapsed/refractory GCTs. METHODS: Disulfiram was administered at a dose of 400 mg daily until progression or unacceptable toxicity, cisplatin was administered at dose 50 mg/m2 day 1 and 2, every 3 weeks. Twelve evaluable patients had to be enrolled into the first cohort, and if 0 of 12 patients had treatment response, the study was to be terminated. The results of the first stage of the trial are presented in this report. RESULTS: Twelve patients with multiple relapsed/refractory GCTs were enrolled in the phase II study from May 2019 to September 2021. Median number of treatment cycles was 2 (range 1-6). None of patients achieved objective response to treatment, therefore the study was terminated in first stage. Median progression-free survival was 1.4 months, 95% CI (0.7-1.5 months), and median overall survival was 2.9 months 95% CI (1.5-4.7 months). Disease stabilization for at least 3 months was observed in 2 (16.7%) patients. Treatment was well tolerated, however, 5 (41.7%) of patients experienced grade 3/4 fatigue, 4 (33.3%) thrombocytopenia, 3 (25.0%) anemia, while 2 (16.7%) experienced neutropenia, nausea and infection. CONCLUSIONS: This study failed to achieve its primary endpoint and our data suggest limited efficacy of disulfiram in restoring sensitivity to cisplatin in multiple relapsed/refractory GCTs.

Gemcitabine, carboplatin and veliparib in multiple relapsed/refractory germ cell tumours: The GCT-SK-004 phase II trial.

Background Patients with multiple relapsed/refractory germ cell tumours (GCTs) have an extremely poor prognosis. PARP (poly-ADP-ribose polymerase) is overexpressed in GCTs compared to normal testes, and PARP overexpression is an early event in GCT development. This study aimed to determine the efficacy and toxicity of gemcitabine, carboplatin and the PARP inhibitor veliparib in patients with multiple relapsed/refractory GCTs. Methods Fifteen patients with multiple relapsed/refractory GCTs were enrolled in this phase II study from October 2016 to October 2020. Gemcitabine was administered at a dose of 800 mg/m2 on days 1 and 8 every 3 weeks; carboplatin at a target AUC of 4 on day 1 every 3 weeks; and veliparib at a dose of 250 mg b.i.d. throughout. The primary end point was 12-month progression-free survival (PFS). Results The median number of treatment cycles was 4 (range 2-8). Twelve-month PFS was achieved in 1 (6.7 %) patient. The median PFS was 3.1 months (95 % CI 2.2-3.9), and the median overall survival was 10.5 months (95 % CI 8.9-11.1). Partial remission was achieved in 4 (26.7 %) patients, and disease stabilization was observed in 5 (33.3 %) patients. A favourable response was achieved in 3 (20.0 %) patients. Treatment was well tolerated; however, 11 (73.3 %) patients experienced grade 3/4 neutropenia, 10 (66.7 %) experienced thrombocytopenia, 5 (33.3 %) anaemia and 2 (13.3 %) febrile neutropenia. Conclusions This study failed to achieve its primary endpoint, and our data suggest limited efficacy of gemcitabine, carboplatin and veliparib for multiple relapsed/refractory GCTs. ClinicalTrials.gov Identifier: NCT02860819, registered August 9, 2016.

Phase II study of avelumab in multiple relapsed/refractory germ cell cancer.

Background Germ cell tumors (GCTs) are highly curable diseases; however, not all patients can be cured. Patients in their second relapse have especially poor prognoses. PD-L1 expression is significantly higher in GCTs than in normal testicular tissue, and high PD-L1 expression is associated with a poor prognosis. This study aimed to determine the efficacy and safety of avelumab, a PD-L1 inhibitor, in patients with GCTs. Methods In this phase 2 study, patients with multiple relapsed and/or refractory GCTs were treated with avelumab at a dose of 10 mg/kg administered biweekly until progression or unacceptable toxicity. The primary endpoint was 12-week progression-free survival (PFS). Fifteen evaluable patients had to be enrolled in the first cohort, and if <8 of 15 patients had 12-week PFS, the study was to be terminated. Here, we report the results of the first stage of the trial. Results From November 2017 to January 2018, 8 patients with a median age of 29 years (range, 22 to 52 months) were enrolled. Patients were pretreated with a median of 5 (range, 1 to 6) previous lines of platinum-based therapies; 5 tumors (62.5%) were absolutely refractory to cisplatin, and 5 patients (62.5%) had visceral nonpulmonary metastases. At a median follow-up period of 2.6 months (range, 0.3 to 14.4), all the patients experienced disease progression, and 7 patients (87.5%) died. The twelve-week PFS was 0%, median PFS was 0.9 months (95% CI 0.5-1.9), and median OS was 2.7 months (95% CI 1.0-3.3). Avelumab was well tolerated, and no severe adverse events were observed. Conclusions This study failed to achieve its primary endpoint. Our data suggest a lack of avelumab efficacy in unselected multiple relapsed/refractory GCTs.

Patterns of relapse in poor-prognosis germ-cell tumours in the GETUG 13 trial: Implications for assessment of brain metastases.

BACKGROUND: The GETUG 13 phase III trial tested personalised chemotherapy based on tumour marker decline in patients with poor-prognosis germ-cell tumour (GCT) and demonstrated that a dose-dense regimen improves progression-free survival in patients with an unfavourable decline. We investigated the pattern of relapse for patients included in GETUG 13. METHODS: We conducted an analysis of relapse events in patients from GETUG 13. Baseline procedures before inclusion in the trial comprised a thoraco-abdomino-pelvic computed tomography scan and a magnetic resonance imaging of the brain. RESULTS: With a median follow-up of 4.1 years (0.3; 8.8 years), a progression event was observed in 109/254 patients (43%). First event consisted in a marker progression only in 47 patients (43%), a radiographic progression only in 35 patients (32%), a mix progression on both markers and imaging in 12 patients (11%) and death in 15 patients (14%). In patients with radiographic progression only, brain was the predominant site (n = 19/35, 54%). Among patients with unfavourable decline who experienced a radiographic progression (as first and subsequent progression event, n = 58), brain was a site of progression in 28 patients (48%): 12/30 (40%) in patients treated with cisplatin, bleomycin and etoposide and 16/28 (57%) in those treated with dose-dense chemotherapy. CONCLUSIONS: Brain metastases develop often, early and frequently as the only site of relapse in the course of poor-prognosis GCT. This raises the question of early detection and optimal treatment of brain metastases in these patients, e.g. by integrating a systematic brain MRI after 2-3 months of chemotherapy.

Differences in Incidence and Biological Characteristics of Breast Cancer between Roma and Non-Roma Patients in Slovakia.

BACKGROUND: Roma (Gypsies) constitute one of the largest ethnic minorities in Slovakia. Some reports have supported a higher prevalence of communicable diseases in Roma but data on cancer prevalence in Roma is absent. The aim of this study was to compare differences in the incidence and pathological characteristics of breast cancer between Roma and non-Roma in Slovakia. PATIENTS AND METHODS: Roma and non-Roma breast cancer patients were identified using the Slovak HER2 Registry. The database from the last Census of Slovakia in 2011 was matched by gender, date of birth, and residency with the HER2 Registry from 2011 to 2013. Based on the match, Roma and non-Roma breast cancer patients were identified. RESULTS: Thirty-two and 5,775 women with breast cancer were identified as Roma and non-Roma, resp. The age-standardized breast cancer incidence rate was 2.12 times higher for non-Roma than for Roma patients (36 vs. 17 per 100,000 people). Roma patients were younger than non-Roma patients (median 49 vs. 61 years; p = 0.00001). Roma patients had more hormone receptor negative (34.4% vs. 18.1%; p = 0.03) and triple negative tumors (28.1% vs. 12.3%; p = 0.01) than non-Roma, and these differences remained statistically significant in multivariate analysis. CONCLUSION: For the first time, this study has revealed that the incidence and biological characteristics of breast cancer are different between Roma and non-Roma. Our data suggests that Roma patients are younger at diagnosis, have a lower age-standardized breast cancer incidence rate, and have more aggressive tumors than non-Roma.

Differences in Age-distribution, Oncological Diagnoses and Stage in Roma and Non-Roma Cancer Patients Registered at the Outpatient Oncology Department Poprad in 2014 and 2015 - a Retrospective Study.

BACKGROUND: Roma (Gypsies) constitute the largest ethnic minority in Slovakia. Although some studies have reported a higher prevalence of communicable diseases in Roma, there have been no studies on cancer prevalence in Roma. The aim of this study was to compare differences in age at diagnosis, oncological diagnoses, and stage between Roma and non-Roma patients registered at a single oncology outpatient department in Eastern Slovakia where substantial numbers of Roma patients are treated. PATIENTS AND METHODS: Roma and non-Roma cancer patients were identified based on the judgement of both the treating physician and nurse. Age at diagnosis, oncology diagnoses, and disease stage were compared between Roma and non-Roma patients. RESULTS: Thirty Roma and 702 non-Roma cancer patients were identified. The age distribution at diagnosis was not statistically different between Roma and non-Roma for both male and female patients. A statistically significant difference was detected in the number of Roma men having lung cancer (risk ratio - RR 0.19; 95% CI 0.13-0.35; p < 0.01), and more Roma women had kidney cancer (RR 0.16; 95% CI 0.05-0.69; p = 0.01). There were numerically more Roma patients diagnosed with TNM stage IV disease. Significantly more Roma men were diagnosed with stage IV disease than with stage I-III disease. CONCLUSION: The data suggest that differences in cancer type exist between Roma and non-Roma patients. Larger population--based studies directed at analyzing for differences between Roma and non-Roma cancer patients are warranted.Key words: Roma - neoplasms - histology - stage.

Small-cell carcinoma of the ovary with breast metastases: a case report.

BACKGROUNDS: Small cell carcinoma (SCC) is characterised by high metastatic potential and the possibility to metastasize to practically any tissue. Small cell carcinoma of the ovary (SCCO) has a very poor prognosis and patients usually die within one year of the initial diagnosis. Breast metastases from SCCO are extremely rare. CASE: We present a 67-year-old female patient with SCCO who initially presented with bone and bilateral breast metastases. Considering the clinical presentation, the patient's age, the absence of hypercalcemia and histological characteristics, a diagnosis of pulmonary type SCCO was made. There was no tumour present in the lungs at the time of the initial diagnosis and thus we ruled out pulmonary SCC. RESULTS: Initially, the patient was treated with radiotherapy of the bone lesion and systemic chemotherapy (etoposide with carboplatin) with the result of partial remission. Then, radical abdominal surgery was performed. Six months later she was diagnosed with progressive disease in the bone, soft tissue including the breast as well as new lesions in the right kidney, pelvis and lungs. She was treated with 2nd line chemotherapy (topotecan with cisplatin) with the result of progressive disease. Because of mediastinal lymphadenopathy, which was causing tracheobronchial compression, radiotherapy was administered with a good palliative outcome. Nine months later, multiple brain metastases were diagnosed and she was treated with whole brain radiotherapy. Shortly after brain irradiation, her status deteriorated rapidly and she died two years after her initial SCCO diagnosis. CONCLUSION: Extrapulmonary small cell carcinoma is a clinicopathological entity distinct from pulmonary small cell carcinoma. It is very rare and therefore there is very little information available regarding treatment of this disease. In contrast to experience in the treatment of pulmonary small cell cancers, prolonged survival is not common.

Kinetics of tumor marker decline as an independent prognostic factor in patients with relapsed metastatic germ-cell tumors.

Early serum tumor marker decline (STMD) during chemotherapy was shown to predict survival in patients with poor prognosis non-seminomatous germ cell tumors (GCT) in the first line. The aim of the study was to assess the prognostic value of STMD in relapsed GCT;s patients. From January 1995 to December 2007, all patients treated for GCT s with salvage therapy at the National Cancer Institute of Slovakia were identified from the tumor registry database and screened retrospectively for serum AFP and betaHCG level at the time of relapse. STMD rate was calculated for each patient and each tumor marker with an abnormal marker value at baseline and each tumor marker M (HCG or AFP) using only two values: the baseline value (M0) and the value obtained after one cycle of chemotherapy (day 21 value; M1). The decline rate was calculated using a logarithmic transformation, and it was expressed as a theoretical number of weeks necessary to normalization that was called predicted time to normalization. Decline rates were classified into "favorable" or "unfavorable". Totally, 75 patients were identified, 39 had favourable (group A) and 36 unfavorable (group B) STMD. The 2-year and 5-year PFS rates were 61% and 58% for group A and 17% and 7% group B (p<0.00001). Of all the baseline characteristics that were included in the Cox model, STMD was the most important predictor of PFS and OS. We suggest that STMD is strong independent prognostic factor in GCT patients treated with salvage chemotherapy. Prospective studies of different approaches in this patient's population based on STMD are warranted.

Paclitaxel, bleomycin, etoposide, and cisplatin (T-BEP) as initial treatment in patients with poor-prognosis germ cell tumors (GCT): a phase II study.

First line treatment of patients pts with poor-prognosis GCT, using BEP, is unsatisfactory. T-BEP (paclitaxel followed by BEP) demonstrated promising efficacy in the group of pts with intermediate and poor prognosis GCT. We present the results achieved with 1st line T-BEP in pts with poor-prognosis CGT. Twenty-four pts received T-BEP as initial therapy. Three pts (12.5%) had primary mediastinal GCT. Four cycles of T-BEP were given 21 days apart. Paclitaxel 175 mg/m2 was administered on day 1 before administration of BEP. The administration of G-CSF was not scheduled. Surgical resection of all radiographic residua was considered. All pts were assessable for response. Complete or partial response with negative tumor markers was achieved in 13 pts (54.2%; CI 95%: 34.3-74.1%). Median follow-up is 35.6 months. Median survival was not achieved and median time-to-progression is 9.5 months. Myelosuppression was the major toxicity with Gr3-4 granulocytopenia experienced in 52.1% of all courses. There were two treatment-related deaths due to sepsis. Patients treated with 1st line T-BEP didn't achieve higher response rate or time to progression. However, the overall survival observed in our study is surprisingly long. We do not recommend using this regimen without G-CSF support due to substantial toxicity.

Paclitaxel plus ifosfamide and cisplatin in second-line treatment of germ cell tumors: a phase II study.

The aim of this study was to determine efficacy and toxicity of TIP combination (paclitaxel, ifosfamid, cisplatin) as first salvage treatment in patients with relapsed germ cell tumours (GCTs). Excellent results were achieved from TIP combination with a dose 250 mg/m(2) of paclitaxel [5]. Our hypothesis was that comparable efficacy with less toxicity could be achieved even with a lower dose of 175 mg/m(2) paclitaxel in TIP. In 17 consecutive patients with failed standard 1st line treatment, we used four to six courses of paclitaxel 175 mg/m(2) on day 1 and ifosfamide 1,200 mg/m(2) plus cisplatin 20 mg/m(2), both on day 1 through 5, every 3 weeks. Eleven patients achieved favorable response (65%; 95% confidence interval, 42 to 87%) with 7 complete responses (41%). Estimated 2-year disease free survival is 47% (95% CI, 23-71%). Treatment combination was well tolerated and myelosupression was major toxicity. Granulocytopenia Gr3-4 was observed in 8% and febrile neutropenia in 7% of the courses. No case of severe neurotoxicity or treatment-related death was observed. In our study, TIP combination had good toxicity profile. The results however, did not show expected treatment efficacy and we raise the idea of paclitaxel dosage relevance in TIP.

Gemcitabine plus cisplatine and paclitaxel (GCP) in second-line treatment of germ cell tumors (GCT): a phase II study.

The aim of the study was to determine the efficacy and toxicity of gemcitabine, cisplatin and paclitaxel (GCP) combination as a first salvage treatment of patients with relapsed GCT. Four courses of paclitaxel 175 mg/m(2) and cisplatin 50 mg/m(2), both on day 1, and gemcitabine 1000 mg/m(2), on days 1 and 8, every 3 weeks, were given to 12 consecutive patients who had failed standard 1st line treatment. Six patients (50%; 95% CI 21-79%) achieved favourable response and two of them are maintained 38+ and 29+ months. Median survival time was 16 months (range, 0.77-38+). All, but two patients had hematological toxicity Gr3-4 with infectious complication seen only in 6 courses of therapy. GCP is an active second-line combination regimen for relapsed GCTs with acceptable toxicity profile. However the results of this study did not show expected treatment efficacy and we raise the idea of cisplatin dosage relevance in this combination.