Management of advanced metastatic germ cell tumours

Forty patients with poor prognosis germ cell tumours were treated with a combination of cisplatin 40 mg/m2 and VP-16 200 mg/m2, both given days 1-5 every 3 weeks, and bleomycin 15 mg/m2 every week. Of thirty-three previously untreated patients twenty-eight (85%) patients obtained complete remission (CR) and four (12%) patients partial remission (PR). One patient was not evaluable for response. Twenty-four patients are alive 2-32 months after completion of therapy without evidence of disease (median observation 18.5 months). Of seven patients previously treated with cisplatin, five obtained CR (71%), one PR (14%) and one patient had progressive disease. Five patients are still alive, four without evidence of disease after a median follow-up of 22 months (range 16-25 months).     

Retroperitoneal lymph node dissection for metastatic germ cell tumours

INTRODUCTION

In the North Trent Cancer Network (NTCN) patients requiring retroperitoneal lymphadenectomy for metastatic testicular cancer have been treated by vascular service since 1990. This paper reviews our experience and considers the case for involvement of vascular surgeons in the management of these tumours.

PATIENTS AND METHODS

Patients referred by the NTCN to the vascular service for retroperitoneal lymphadenectomy between 1990 and 2009 were identified through a germ cell database. Data were supplemented by a review of case notes to record histology, intraoperative and postoperative details.

RESULTS

A total of 64 patients were referred to the vascular service for retroperitoneal lymph node dissection, with a median age of 29 years (16–63 years) and a median follow-up of 4.9 years. Ten patients died: eight from tumour recurrence, one from septicaemia during chemotherapy and one by suicide. Of the 54 who survived, 7 were alive with residual masses and 47 patients were disease-free at the last follow-up. Sixteen patients required vascular procedures: four had aortic repair (fascia), three had aortic replacement (spiral graft), four had inferior vena cava resection, two had iliac artery replacement and two had iliac vein resection.

CONCLUSIONS

Retroperitoneal lymph node dissection often involves mobilisation and/or the resection/replacement of major vessels. We recommend that a vascular surgeon should be a part of testicular germ cell multidisciplinary team.     

Pituitary and testicular hormonal function after treatment for germ cell tumours

The endocrine effects of cisplatin based chemotherapy in patients with germ cell tumours were studied in twenty-two patients 9+ to 24+ months after completing treatment. The mean basal FSH and stimulated LH and FSH levels were found to be elevated in treated patients when compared to untreated controls. Serum testosterone levels in treated patients were similar to those in untreated controls. Mean basal LH and FSH levels tended to return toward normal in those patients treated more than 18 months prior to study, and were lower in patients less than 25 years of age at the time of treatment when compared to those aged over 25. These data demonstrate that compensated hypogonadism is common after treatment for metastatic germ cell tumours, that young patients appear to be more resistant to the effects of cisplatin based chemotherapy, and that these effects tend to recover with time.     

Vascular toxicity following vinblastine, bleomycin, and cisplatin therapy for germ cell tumours

Vascular toxicity following the use of vinblastine, bleomycin, and cisplatin (VBP) combination chemotherapy has been described. This report gives details of five patients who suffered acute life-threatening vascular events following such a chemotherapy regimen for germ cell tumours. In three of the cases no evidence of tumour was found at autopsy. Both acute and long-term vascular toxicity were seen. Large artery vascular disease may result from synergistic toxicity of the drugs comprising the regimen. These cases, with an additional sixteen collected from the literature, suggest that major vascular disease is a significant side-effect of the VBP regimen.     

Treating stage I nonseminomatous germ cell tumours with a single cycle of chemotherapy

OBJECTIVE: To estimate the rate of relapse in men with stage I nonseminomatous germ cell tumours (NSGCT) of the testis treated with one cycle of chemotherapy instead of the usual two cycles. PATIENTS AND METHODS: Between 1992 and 1996, 22 men with stage I NSGCT who had normalized tumour markers after orchidectomy and negative findings on computed tomography, and who were at moderate risk of relapse, were treated with one cycle of platinum-containing chemotherapy (bleomycin and etoposide with either cisplatin or carboplatin). RESULTS: At a median follow-up of 10.2 years, none of the patients have relapsed with malignant GCTs. CONCLUSION: The results after one cycle of chemotherapy are no worse than after two cycles. The present study needs to be replicated in a larger cohort of patients to define the relapse risk more accurately. This approach is soon to be tested in a large multicentre trial randomizing patients between one and two cycles.     

Oncogenes and germ cell tumours

The central problem in cancer therapy is the poor selectivity of current systemic agents against the common solid tumours. The demonstration that unique segments of DNA, constant in location and conserved in evolution are involved in growth control opens new avenues for basic and clinical research. The function of the products of these genes needs to be elucidated. Examples of growth control functions include homology to growth factors, surface receptors, protein kinases and cell cycle control proteins. From DNA sequence data peptides predicted to be exposed within intact molecules can be constructed and used to produce monoclonal antibodies to oncogene products. Such antibodies have now been successfully used to demonstrate the intracellular localization of gene products as well as the cell cycle regulatory role of the c-myc protein. By having a battery of antibodies against the different gene products their direct clinical application for diagnosis and prognosis has become a reality. Immunohistology and flow cytometry permit the geographical and quantitative analysis of function in normal and neoplastic tissues. Furthermore, by purification and biochemical analysis the molecular basis for their action can be elucidated. It is likely that by the end of the decade new drugs that inhibit oncoprotein function will be available for clinical trial.     

Adjuvant treatment in the management of testis-confined germ cell tumours after orchidectomy

Germ cell tumours are highly curable, especially when still at the localized stage, which is the case for most testicular tumours. Various options are available for organ-confined disease; depending on the histological review, patients with clinical stage I seminomas can be offered radiotherapy, surveillance or chemotherapy, whereas those with clinical stage I nonseminomas can be offered retroperitoneal lymph node dissection, surveillance or chemotherapy. As it is unlikely that any of these approaches will have a clear survival advantage, the most appropriate variables to be considered are acute and late side-effects, acceptability and quality of life. In recent years adjuvant chemotherapy has been extensively evaluated in patients with seminoma or nonseminoma. In this review we discuss the advantages and disadvantages of the different strategies for treating seminomas and nonseminomas, and their associated prognostic factors, and then consider future developments.     

Pathology of tumours of the male genital tract

Tumours of the male genital tract are diverse. Prostatic adenocarcinoma is important because of its high incidence and mortality, the increased frequency of detection following a drive towards early diagnosis and the need to identify those early cancers requiring immediate intervention and those suitable for an active surveillance programme. Testicular germ cell tumours are relatively uncommon but are important because they involve a young patient group and, although potentially highly aggressive, have been a remarkable success story of modern chemotherapy with current cure rates of approximately 97–98%. Penile cancer largely overlaps with the more common cutaneous cancer types.     

Pathology of tumours of the male genital tract

Tumours of the male genital tract are diverse. Prostatic adenocarcinoma is important because of its high incidence and mortality, the increased frequency of detection following a drive towards early diagnosis and the need to identify those early cancers requiring immediate intervention and those suitable for an active surveillance programme. Testicular germ cell tumours are relatively uncommon but are important because they involve a young patient group and, although potentially highly aggressive, have been a remarkable success story of modern chemotherapy with current cure rates of approximately 98%. Penile cancer largely overlaps with the more common cutaneous cancer types.     

High-dose chemotherapy for male germ cell tumor

Today, 20-30% of male patients with advanced germ cell tumor (GCT) do not have durable, complete remission in spite of cis-platinum (CDDP)-based chemotherapy. High-dose chemotherapy (HDCT) has been tried in CDDP refractory GCT patients. Initially HDCT was performed with autologous bone marrow transplantation in heavily treated patients. However, the clinical outcome was not good and the treatment-related death rate was not ignorable. Therefore, earlier introduction of HDCT with peripheral blood stem cell transplantation was preferable as it renders HDCT more effective and less toxic, and multicycle HDCT is feasible. The durable free rate of recent HDCT for refractory GCT patients is 32-65%. HDCT is also performed as first line chemotherapy for poor prognosis GCT patients. Induction chemotherapy followed by multicycles of HDCT was tried. The durable free rate of recent HDCT as first line chemotherapy is 43-73%. Although previous reports suggest the superiority of HDCT, one recent randomized controlled trial (RCT) failed to show an improvement with one cycle of HDCT followed by three cycles of standard-dose chemotherapy (SDCT) compared with four cycles of SDCT. Ongoing RCT comparing multicycles of HDCT with SDCT for poor prognostic GCT patients will clarify the role of HDCT. Recently, new regimens of HDCT containing paclitaxel have been devised. In this review, the history, current status and future of HDCT for advanced or refractory GCT will be discussed.     

Prognosis of intracranial germ cell tumours: Effectiveness of chemotherapy with cisplatin and etoposide (CDDP and VP-16)

Summary A co-operative study for patients with intracranial germ cell tumours was performed to analyze their prognosis and the effectiveness of Cisplatin/Etoposide (CDDP/VP-16) chemotherapy.A total of 46 patients; 30 primary and 16 recurrent cases were registered from 15 participating neurosurgical institutions in Japan. Based on histological criteria and tumour markers, they were classified into three groups; germinoma, germinoma with syncytiotro-phoblastic giant cell (STGC), and non-germinomatous malignant tumour.Sixteen patients were treated with CDDP/VP-16 chemotherapy alone and the other 30 patients were treated by a combination of surgery and/or radiation in addition to chemotherapy. Eleven out of 13 patients (85%) with germinoma showed a complete (n=10) or partial (n=1) response to CDDP/VP-16 chemotherapy even if their tumours were recurrent and there was evidence of CSF dissemination. For the germinoma with STGC and non-germinomatous malignant tumour, a high response rate; 100% for the former and 78% for the latter, could also be achieved in both the primary and the recurrent cases except in those cases of immature teratoma. Their survival times were still different between them. Two-year survival was 50% in germinoma with STGC and 48% in non-germinoma, while it was 88% in germinoma cases.     

An analysis of poor risk assignment in patients with germ cell tumours

Four methods for assigning patients with germ cell tumours to poor risk programmes were compared using 118 consecutive patients treated on 'good' and 'poor' risk studies. The median survival of patients deemed poor risk by Memorial Sloan-Kettering Cancer Center was 11 months, by Indiana University 15 months, by the National Cancer Institute 15 months, and by the European Organization for Research on the Treatment of Cancer 23.5 months. The major differences between these criteria were in the use of pretreatment tumour marker values, and the use of specific sites of metastases as independent prognostic variables. These data imply that a variable number of good prognosis patients enter some poor risk trials, the number being dependent upon the criteria used. Poor risk criteria should be as restrictive as possible in order to avoid over treating good risk patients, and to avoid artificially inflated response rates resulting from the successful treatment of such poor risk patients.     

甲氧滴滴涕对雄性大鼠生精细胞的细胞周期影响

目的探讨甲氧滴滴涕(MXC)对雄性大鼠生精细胞的细胞周期影响。方法实验动物分为对照组,溶剂组,5 d、10 d和15 d MXC实验组。用流式细胞仪检测染毒雄性大鼠生精细胞周期变化。结果随着MXC染毒时间延长与对照组比较,实验组G0/G1期与S期细胞数减少,G2/M期细胞数增多(P<0.05),单倍体细胞减少,二倍体与四倍体细胞增多(P<0.05);除5 d实验组二倍体与四倍体细胞荧光强度强外,其余各实验组的单倍体、二倍体和四倍体细胞荧光强度均减弱(P<0.05);溶剂组与对照组间的变化无显著性差异(P>0.05)。结论MXC可引起大鼠睾丸生精细胞S期抑制及G2期阻滞。     

The changing presentation of germ cell tumours of the testis between 1983 and 2002

OBJECTIVE: To prospectively investigate the presentation of germ cell tumours (GCTs) of the testis in terms of stage or histology, as the incidence of this disease in increasing. PATIENTS AND METHODS: Patients diagnosed with GCT of the testis between 1983 and 2002 were categorised into three periods depending on the date of diagnosis of the GCT, and the presentational characteristics assessed. RESULTS There was a significant increase in the proportion of patients presenting with stage I disease (59% to 78%) and seminoma (43% to 58%) over this period. There was also a significant reduction in the size of the primary tumour (5 to 4 cm). CONCLUSION: A greater proportion of patients with GCT are presenting with stage I seminoma, the reasons for which are unclear, although earlier diagnosis through improved awareness of GCT may be important.     

Consolidative high-dose chemotherapy after conventional-dose chemotherapy as first salvage treatment for male patients with metastatic germ cell tumours

Introduction:

Some men with metastatic germ cell tumours that have progressed after response to initial cisplatin-based combination chemotherapy are cured with conventional dose first salvage chemotherapy (CDCT) – however, many are not. High-dose chemotherapy with autologous stem cell rescue (HDCT) may be of value in these patients. Prognosis has recently been better defined by International Prognostic Factor Study Group (IPFSG) prognostic factors. HDCT after response to CDCT has been offered at our institution over the past two decades. We retrospectively assessed the validity of the IPFSG prognostic factors in our patients and evaluated the value of HDCT.

Methods:

We identified eligible men with metastatic germ cell tumour progressed after at least 3 cycles of cisplatin-based chemotherapy and treated with cisplatin-based CDCT alone or with carboplatin-based HDCT. We also collected their clinical data. Patients were classified into risk groups using IPFSG factors, and progression-free and overall survival factors were analyzed and compared in patients treated with CDCT alone and with HDCT.

Results:

We identified 38 eligible first salvage patients who had received a median of 4 cycles (range, 1 to 7 cycles) of CDCT. Twenty patients received CDCT alone and 18 patients received CDCT plus HDCT. The overall median progression- free survival was 24.6 months (95%CI, 7.3 to 28.7 months) and overall median overall survival was 34.6 months (95%CI, 17.2 to 51.3 months). Distribution by IPFSG category and 2-year progression- free survival and 3-year overall survival rates within each risk category were very similar to the IPFSG results. There were two toxic deaths with CDCT and none with HDCT. Overall, patients treated with CDCT plus HDCT had improved progression- free survival and overall survival.

Conclusions:

The IPFSG prognostic risk factors appeared valid in our patient population. The safety of HDCT with etoposide and carboplatin was confirmed. HDCT was associated with improved progression- free survival and overall survival outcomes, consistent with observations of the IPFSG group. Ideally, the value of optimal HDCT should be determined in comparison to optimal CDCT as first salvage therapy in men with metastatic germ cell tumour with a randomized trial.     

The role of high-dose chemotherapy in relapsed germ cell tumors

Overall, patients with relapsed or progressive germ cell tumors after cisplatin-based chemotherapy have a low chance of cure. Using conventional-dose chemotherapy (CDCT) as salvage treatment, only 15–30% of the patients will become long-term survivors. It is well known that the majority of these patients will ultimately die of their disease. Therefore, improvement of the standard treatment is clearly desirable. In the last years, high-dose chemotherapy (HDCT) has been established as an effective salvage modality. A matched-pair analysis showed an advantage for HDCT compared with CDCT with an improvement in event-free and overall survival. Furthermore, due to increasing clinical experience in the management of side-effects, the use of peripheral blood progenitor cells and the availability of hematopoietic growth factors, HDCT has become relatively safe. Therefore, HDCT should be administered in patients with first relapse and unfavorable prognostic factors, and as second or subsequent salvage treatment followed by complete resections of tumor residuals. Patients with relapse or progressive disease after HDCT who do not qualify for desperation surgery could be salvaged with palliative chemotherapy combinations using gemcitabine, oxaliplatin and paclitaxel. This report reviews the current treatment strategies and recent developments with respect to HDCT given as salvage treatment and discusses the role of prognostic factors in the management of such situations.     

High-risk clinical stage I nonseminomatous germ cell tumors: the case for chemotherapy

Testis cancer is the most frequent solid malignancy in young men. The majority of patients present with clinical stage I disease and about 50% of them are nonseminomatous germ cell tumors. In this initial stage of disease there is a subgroup of patients at high risk with a likelihood of more than 50% for relapse. Treatment options for these patients include: retroperitoneal lymph node dissection (RPLND), albeit 6–10% of patients will relapse outside the field of RPLND, active surveillance with even higher relapse rates and adjuvant chemotherapy. As most of these patients have the chance to become long-term survivors, avoidance of long-term side effects is of utmost importance. This review provides information on the potential of chemotherapy to achieve a higher chance of cure for patients with high-risk clinical stage I disease than its therapeutic alternatives and addresses toxicity and dose dependency.     

High-dose chemotherapy with haematopoietic stem-cell support in patients with poor prognosis, relapsed or refractory germ cell tumours

OBJECTIVE: To report our experience of high-dose chemotherapy (HDC) with haematopoietic stem-cell support (HSC) in patients with poor risk, relapsed or refractory germ cell tumours (GCTs), as this treatment might offer effective salvage for patients with disseminated GCTs. PATIENTS AND METHODS: We retrospectively reviewed the medical records and database for 33 patients with GCT who were treated with HDC with HSC in our centres. RESULTS: Thirty-three patients were treated with either one or two cycles of carboplatin and etoposide-based HDC with HSC support, between March 1990 and October 2003. Twenty-six patients (79%) had nonseminomatous GCT, six seminoma (18%), and one (3%) a combined seminoma and teratoma. Twenty patients (60%) had previously had a clinical complete response after previous chemotherapy +/- surgery for residual disease. Most patients were treated with HDC for relapsing (49%) or relative refractory disease (30%), but seven (21%) had HDC in the first partial remission. The complete response rate to HDC was 58%. There were two treatment-related deaths (6%). As of April 2005, 18 patients were alive and disease-free with a median (range) follow-up of 72 (0.5-174) months. The 5-year overall and progression-free survival probabilities were 57% and 56%, respectively. The median (range) times to absolute neutrophil count recovery (> or = 500/microL) were 13 (9-24) and 12 (10-15) days, and for platelet count recovery ( > or = 20,000/microL) were 16 (7-50) and 13 (11-17) days, in the first and second cycles, respectively. CONCLUSION: The role of HDC with HSC support in metastatic GCTs remains controversial, and data from randomized controlled trials are needed. Our experience suggests that, in selected patients, this approach might be a useful form of salvage therapy.     

HLA phenotype and clinicopathological behaviour of germ cell tumours: possible evidence for clonal evolution from seminomas to nonseminomas

Analysis of 101 patients with germ cell tumours of the testis who have been typed for HLA DR antigens has provided confirmatory evidence for an association of DR5 with the development of seminoma and demonstrated an association of DR7 with metastases. These observations taken with the suggestion of HLA linkage in the small numbers of familial cases reviewed, does suggest that there is an HLA linked gene involved in the clinicopathological behaviour of germ cell tumours. Though of only theoretical interest at present these observations may be of considerable importance in the future given the observation in mice that transfection of missing MHC genes into a malignant tumour can produce a vaccine that enables previously unexposed animals to resist the original malignant tumour (Hui et al., 1984).     

Extragonadal germ cell tumour

We report a rare case of extragonadal germ cell tumour in a 55-year-old man. He presented with a painless mass in right inguinal region, a few days after hernioplasty for right direct inguinal hernia, which caused diagnostic difficulties and treatment problems.