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.

Dia-gnostic Challenges and Extraordinary Treatment Response in Rare Malignant PEComa Tumor of the Kidney.

BACKGROUND: Epithelioid angiomyolipoma (EAML) of the kidney, in contrast to classic benign renal angiomyolipoma, is a rare mesenchymal neoplasm with malignant potential. Represent-ing a member of the perivascular epithelioid cells (PEComa) tumor family aris-ing from the perivascular epithelioid cells, its accurate dia-gnosis and therapeutic approach remains challenging. METHODS: We report a case of a patient with malignant EAML, initially treated as renal cell carcinoma (RCC) at our institution. In this paper, we briefly summarize current status of clinical and histopathological knowledge of renal PEComas with metastatic potential and reconsider the dia-gnostic and therapeutic approach in this particular case to highlight the risk of mis-dia-g----nosis, malignant potential of renal PEComas and to demonstrate an unexpected treatment response. RESULTS: The patient in our case was dia-gnosed with chromophobe RCC with sarcomatoid features. She underwent a radical nephrectomy and epinephrectomy with a satisfactory postoperative history. Local recurrence urged chemother-apy commencement with sunitinib in the first line, and shortly afterwards, the patient was enrolled in a clinical trial with everolimus, with an extraordinary favorable treatment response for 30 months. Follow-ing the extirpation of single abdominal nodularity after 36 months of treatment with mTOR inhibitor, and proceed-ing the everolimus administration, the dis-ease slowly progressed to the right liver lobe, result-ing in right hemihepatectomy in another 24 months. The immunoprofile of liver metastases with positive stain-ing of melanoma markers and smooth muscle markers induced the revaluation of the primary tumor and abdominal nodularity specimen to an invasive EAML of the kidney. Further dis-ease progression was unavoidable despite several chemother-apy regimens, and the patient died 104 months after primary dia-gnosis. CONCLUSIONS: Renal tumors with adverse radiographic and histopathological features should become candidates for immunohistochemical stain-ing as its omission frequently leads to a misdia-gnosis, as showed in our case report. Atypical treatment response might suggest a possibility of a diagnostic mistake and should lead to reevaluation of the diagnostic and treatment process in the particular patient. Key words: renal PEComa -  epithelioid angiomyolipoma -  dia-gnosis -  everolimus.

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.

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.

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.

Sequential intermediate high-dose therapy with etoposide, ifosfamide and cisplatin for patients with germ cell tumors.

Intermediate high dose VIP (etoposide, ifosfamide, cisplatin) achieved comparable efficacy and improved tolerance in comparison with high-dose chemotherapy plus PBSC in poor risk germ cell tumors. The aim of this study was to confirm the effectivity and tolerance of this regimen in clinical practice. Twenty-five consecutive patients, 9 previously untreated with poor prognosis and 16 relapsed, were treated with 1.6 VIP or 1.9 VIP+PBSC. A relative dose intensity of 1.6 VIP was used in 14 patients and 11 patients received the intensity of 1.9 VIP. Clinical response was achieved in 56% of patients. Fifty-eight percent of patients have survived more than 1 year and 44% more than 2 years. No significant difference was noted between previously treated and untreated patients, as well as between the patients on 1.6 VIP and 1.9 VIP, with the exception of improved 1-year survival of patients on 1.9 VIP. One of four cisplatin-refractory patients achieved durable partial remission with a normal level of tumor markers. Serious non-hematological toxicity was rare. Myelotoxicity of 1.9 VIP was less serious in comparison with 1.6 VIP regimen, but the difference was not significant. Sequential intermediate high-dose therapy is an effective and tolerable regimen for patients with poor risk germ cell tumor as well as for relapsed patients.

Carboplatin and cyclophosphamide in the treatment of metastatic seminoma.

Cisplatin-based chemotherapy is highly effective in advanced seminoma, but at the cost of a considerable toxicity. The response rate of carboplatin is comparable with cisplatin combinations but the relapse rate is higher. Our study assesses the efficacy and the toxicity of the combination of carboplatin and cyclophosphamide in patients with advanced seminoma. Nineteen consecutive patients received 6 cycles of intravenous cyclophosphamide 750 mg/m2 and carboplatin 350 mg/m2, repeated every 21 days. The overall objective response rate was 100%, 11 patients (58%) achieved a complete response and 8 patients (42%) showed a partial response. At median follow up of 4.2 years 3 patients (15%) relapsed. The 2-year disease-free survival and the overall survival are 72 and 94%, respectively. This outpatient treatment was well tolerated and the toxicity was mild. One patient had granulocytopenic fever and one patient had grade 3 cystitis. The combination therapy with carboplatin and cyclophosphamide is an effective and tolerable regimen in advanced seminoma.