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.

Long-term sexual functioning in germ-cell tumor survivors.

BACKGROUND: Survivors of germ-cell tumors (GCT) may suffer from long-term adverse consequences. Our study was conducted to assess a long-term sexual functioning in GCT survivors. METHODS: GCT survivors (N = 170) from the National Cancer Institute in Slovakia completed a Sexual Function Questionnaire that was modified from PROMIS Sexual Function and Satisfaction Questionnaire 9-year median follow up (range 5-32) as a primary exploratory aim. Study groups consisted of 17 survivors (10%) who had active surveillance (AS, controls), and 153 (90%) survivors who received treatment beyond orchiectomy (Tx), including cisplatin-based chemotherapy (CT, N = 132; 78%), radiotherapy to the retroperitoneal lymph nodes (RT, N = 12; 7%) or both (CTRT, N = 9; 5%). RESULTS: In univariate analysis, treatment of any type resulted in difficulty to maintain erection during sexual intercourse compared to patients treated with AS (P = 0.04). Survivors who received CTRT had lower ability to achieve orgasm during sexual activities (P = 0.04) and they reported disappointment with their overall quality of sex life (P = 0.002). The number of attempts to initiate sexual intercourse did not differ. Sexual relationships caused none or mild anxiety and the desire to be sexually active was higher after CTRT (P = 0.05). Multivariable analysis confirmed that orgasmic dysfunction after ≥400 mg/m2 of cisplatin and issues in maintaining erection after Tx were independent of retroperitoneal lymph-node dissection (P = 0.03 and P = 0.04, respectively). Survivors were disappointed with the quality of sex life and had stronger desire to be sexually active independent of age, (P = 0.01 and P = 0.05, respectively). CONCLUSIONS: This study identified an impairment in sexual function may represent an issue for long-term GCT survivors. Treatment with chemotherapy plus radiotherapy were associated with disappointment and stronger sexual desire, while a higher cumulative dose of cisplatin may be responsible for orgasmic dysfunction.

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.

The first Slovak experience with second-line vinflunine in advanced urothelial carcinomas.

BACKGROUND: Based on the results of phase III trial, vinflunine was approved by European Medicines Agency in 2010 as second line treatment of advanced urothelial cancer in patients with good performance status (ECOG 0- 1). The objective of this prospective observational study was to assess vinflunine treatment of advanced urothelial cancer patients in terms of progression free survival and overall survival, and to evaluate vinflunine toxicity. PATIENTS AND METHODS: From April 2011 to June 2014 a total of 16 patients (100%) with advanced urothelial cancer were treated with vinflunine. The median age was 62 years (range 43- 80) and the median Karnofsky index was 90% (range 80- 100%). Thirteen patients (81.25%) had urothelial bladder cancers, two patients (12.50%) suffered from urothelial cancers of ureter, and one patient (6.25%) had urothelial cancer of unknown origin (histology was obtained from liver metastasis). Histologically, all the lesions were grade 3 tumors (100%). The number of metastatic sites ranged from 1- 4 (median 3). RESULTS: The effect of treatment was evaluated in accord with RECIST: two patients (12.50%) obtained partial remission, three (18.75%) stabilization, eight patients (50.00%) progressed, and treatment was suspended in one case at patients request. Vinflunine toxicity grade 3- 4 included neutropenia in six patients (37.50%), leukopenia in four patients (25.00%), anemia in one patient (6.25%), constipation in three patients (18.75%), and febrile neutropenia in one patient (6.25%). Median overall survival was 5.2 months (95% CI 3.4- 8.8) and median progression-free survival was 2.3 months (95% CI 2.1- 3.2). CONCLUSION: This study summarizes the first Slovak experience with vinflunine therapy. Our data confirmed the efficacy of vinflunine and its acceptable toxicity in the treatment of patients with advanced urothelial cancer previously treated with a platinum-based regimen.Key words: advanced urothelial cancer -  vinflunine -  progression-free survival -  overall survival -  side effects.

Adenocarcinoma of the rete testis - a rare case of testicular malignancy.

BACKGROUND: Adenocarcinoma of rete testis is an extremely rare dia-gnosis described in around 70 patients worldwide. The prognosis of the disease in metastatic stage is very poor and there is no standard systemic treatment available. CASE: Herein we present a unique case report of a 47-year- old man with metastatic adenocarcinoma of rete testis who achieved substantial disease response after four cycles of paclitaxel, ifosfamide and cisplatin. The chemotherapy was administered in five -day regimen, which comprised 250 mg/ m2 of paclitaxel on day one, 20 mg/ m2 of cisplatin on day one to five and 1,2 g/ m2 of ifosfamide on day one to five, in a three-week interval. The patient received prophylactic pegfilgrastim after each cycle of TIP. The treatment was well tolerated -  without any significant toxicity. RESULT: Patient achieved a partial 14- month remission. CONCLUSION: On basis of this experience we suggest that paclitaxel, ifosfamide and cisplatin might be adopted as novel agents in treatment of rete testis adenocarcinoma.

[Is the same tyrosine kinase inhibitor still effective after development of brain metastases? A Case report]. / Je ten istý tyrozín- kinázový inhibítor efektívny aj po vzniku mozgových metastáz? Kazuistika.

There is a new era of treatment options since introduction of new biological targeted therapies (tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors) in renal cell cancer. However, in patients who developed brain metastases, there is still treatment dilemma about an optimal therapeutic scenario, particularly in the subgroup of patients with-out disease progression outside the central nervous system. The objective of this case report is to present that it is possible to continue the same targeted therapy after development of brain metastasis after application of local whole brain irradiation with meaningful overall survival.

Inflammatory skin metastasis as a first sign of progression of lung cancer--a case report.

BACKGROUND: Skin metastases are present in 1-9% of cancer patients. In rare cases, skin metastases can manifest as lesions with signs of inflammation and are diagnosed as inflammatory cutaneous metastases (ICM). ICM in lung cancer are extremely rare and often misdiagnosed. PATIENTS AND METHODS: We report on a 55-year-old man with metastatic lung adenocarcinoma and bone metastases in the axial skeleton and left humerus diagnosed in August 2008. He underwent 6 cycles of palliative chemotherapy with cisplatin and gemcitabine, obtaining a minor response. Five months later, he experienced increasing pain in his left arm, with erythematous oedematous lesion with poorly defined margins and an inflammatory appearance. A diagnosis of skin infection was made and he was treated by antibiotic therapy without improvement. RESULTS: Skin biopsy revealed skin infiltration by poorly differentiated carcinoma compatible with a primary lung tumour. He was started on second line therapy with docetaxel, however, the patient's status deteriorated rapidly and he died two months after the first appearance of ICM. CONCLUSION: Metastasis of lung carcinoma could be one of the causes of inflammatory skin lesions in cancer patients and these metastases should be considered in cancer patients with persisting cutaneous lesions with signs of inflammation and no response to antibiotic therapy.

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.

A rare case of malignant extragonadal germ cell tumor in the pineal region with an aggressive behaviour.

Though germ cell cancer is rare, it is the most common cancer in males between 20 and 40 years. The primary site for the development of germ cell tumor is testes, but it can be seen in extragonadal locations as well. Herein, we present a rare case of a 19-year-old patient with non/seminomatous extragonadal germ cell tumor in the pineal region with an aggressive behaviour, refractory to the combined therapy (surgery, radio- and chemotherapy). We suggest that early diagnosis and aggressive multimodal approaches along with surgery, radiotherapy and chemotherapy is necessary to improve the outcome of these patients (Ref. 5). Full Text (Free, PDF) www.bmj.sk.

Prognostic factors in patients with relapsed or primary refractory germ cell tumors.

The aim of the study was to define prognostic factors of overall and event- free survival in patients with germ cell tumors progressing after platinum-based induction chemotherapy with or without surgery. A total of 98 progressing patients were identified out of 700 patients with germ cell tumors treated with platinum-based induction chemotherapy in National Cancer Institute in Bratislava with or without surgery. 98 progressing patients received first salvage chemotherapy from October 1986 to November 2007 due to progression after a previous partial or complete response to induction chemotherapy as well as patients who failed to achieve favourable response to primary therapy. Prognostic factors of survival and event-free survival after first salvage chemotherapy were assessed by univariate analysis. For all 98 progressing patients the median time from the start of induction chemotherapy to progression was 10,2 months (range: 0-256,7 months). 24 (24 %) patients relapsed after 2 years. Median overall survival time following progression was 25,4 months. Estimated 2- and 5- year overall survival rate for all progressing patients was 46 % (95 % CI 41-61%) and 24 % (95% CI 31-51%) respectively. Survival after first salvage chemotherapy was significantly enhanced for patients with age more than 40 years at primary diagnosis, nonvisceral metastasis at the time of induction chemotherapy, prior CR to induction chemotherapy, progression-free interval > 2 years, serum human chorionic gonadotropin level at relapse above or bellow 100 IU/l, a normal serum lactate dehydrogenase level at relapse, one site of metastasis at relapse, treatment with cisplatin-based first salvage chemotherapy, first regimen VIP and favourable response to salvage chemotherapy. Estimated 2- and 5-year event-free survival rate for all patients was 30% (95% CI 24-43% ) and 16%(95% CI 19-37% ) respectively. As a significant favourable prognostic factors of event-free survival were identified: prior CR to induction chemotherapy, progression-free interval > 2 years, one site of metastasis at relapse, treatment with cisplatin-based first salvage chemotherapy, first line salvage regimen VIP and favourable response to salvage chemotherapy. Identification of prognostic features in patients with germ cell tumors progressing after platinum-based induction chemotherapy may direct salvage therapy and requires further investigation of new combination of salvage therapy for those with poor prognosis. Our study showed the indispensable revaluating of chemosenzitivity in patients with late relapses and therapeutic value of additive surgical approach after salvage chemotherapy in patients with reccurent germ cell tumors.

Paraneoplastic Cushing's syndrome as the first sign of progression of prostate cancer.

Cushing's syndrome accompanying the small cell de-differentiation of the prostatic adenocarcinoma is a relatively rare clinical entity, associated with poor overall prognosis. Despite several treatment options available, there is still no effective standard therapy for this clinical condition. Herein, we report two patients with prostate cancer presenting with clinical and laboratory features of Cushing's syndrome as the first sign of disease progression (Ref. 4). Full Text (Free, PDF) www.bmj.sk.

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.