J. T. Hartmann

Nilotinib in the treatment of advanced gastrointestinal stromal tumours resistant to both imatinib and sunitinib

Patients diagnosed with advanced gastrointestinal stromal tumours (GISTs) who are resistant or intolerant to both imatinib and second-line sunitinib have a poor prognosis and few therapeutic options. We evaluated the efficacy of nilotinib, a novel tyrosine kinase inhibitor (TKI) in patients pretreated with imatinib and sunitinib. Fifty-two consecutive patients treated with oral nilotinib, 400mg twice daily, within the nilotinib compassionate use programme in 12 European cancer centres, were included in this retrospective analysis. Median age was 59 years (range 24-80), and all patients had WHO performance score better than 3. All patients had failed both imatinib and sunitinib pretreatment, either due to progressing GIST (96%) or intolerance (4%). Five patients (10%; 95% confidence interval (CI) 2-18) responded to nilotinib and 19 patients (37%; 95% CI 24-50) achieved a disease stabilisation. Nilotinib was generally well tolerated, but six patients (12%) discontinued treatment due to intolerance. Median progression-free survival of nilotinib treatment was 12 weeks (95% CI 9-15; range 0-104) and median overall survival was 34 weeks (95% CI 3-65; range 2-135). Nilotinib is active in GIST resistant to both imatinib and sunitinib. These results warrant further investigation of nilotinib in GIST.

Comparison of histological results from the resection of residual masses at different sites after chemotherapy for metastatic non-seminomatous germ cell tumours

Cisplatin-based combination chemotherapy is considered standard treatment for patients with metastatic testicular cancer. However, despite the normalisation of serum tumour markers, 25-50% of patients will demonstrate residual neoplastic masses on radiological examination after completion of chemotherapy. The management of patients presenting with multiple residual masses at different localisations remains particularly difficult. This report summarises the histological findings and the clinical outcome of 27 patients with metastatic non-seminomatous germ cell tumours who underwent multiple resections for residual masses at different localisations after first-line cisplatin-based chemotherapy at Hannover University Medical School between 1980 and 1995. Fifty-six resections were performed (27 retroperitoneal interventions, 21 thoracotomies, 4 resections of hepatic lesions, 3 neck dissections, 1 craniotomy). No surgery-related mortality was observed. 8 patients (30%) showed dissimilar histological findings at sequential or one-stage resections. 5 of these demonstrated less favourable pathological features (mature teratoma or undifferentiated tumour) at the second operation, while only necrosis (n = 3) or teratoma (n = 2) had been found following the first operation. Tumour necrosis was documented more frequently at thoracotomy (n = 15/21) compared to retroperitoneal lymph node excision (n = 17/27). By univariate analysis, completeness of surgery (R0 resection) and the histological finding of necrosis or differentiated teratoma were associated with improved relapse-free and overall survival. After a median follow-up period of 33 months (range 1-167), 19 of 26 (73%) evaluable patients are alive; 18 of 27 (67%) patients have continuous no evidence of disease (1 patient with recurrent disease was lost to follow-up). Since the histological findings in postchemotherapy residuals may vary between different anatomical sites and no prediction seems possible, patients are best managed by excision of all present tumour masses if technically feasible. Necrosis identified at thoractomy should not lead to omission of retroperitoneal lymph node resection since there was, in accordance to other authors, a trend that the retroperitoneum harbours unfavourable histological findings more frequently.

The role of paclitaxel in chemosensitive urological malignancies: current strategies in bladder cancer and testicular germ-cell tumors

SummaryRecent results demonstrate an emerging role for paclitaxel in patients with urothelial-tract cancer and in patients with testicular cancer. Yielding response rates in the range of 40–50% as a single agent, paclitaxel is one of the most active drugs in metastatic bladder cancer. Ongoing trials of paclitaxel combination chemotherapy with cisplatin or cisplatin and ifosfamide demonstrate substantial objective remission rates above 70% and, in addition, a high range of complete responses. Thus, paclitaxel appears to be an important drug when used as part of first-line combination chemotherapy for metastatic bladder cancer. Ongoing clinical trials focus on the combination of paclitaxel with cisplatin, ifosfamide, gemcytabine, and carboplatin. Furthermore, paclitaxel administration has been demonstrated to be easily applicable to patients with reduced renal function, requiring no dose reduction and producing no increase in toxicity. Future strategies will have to compare the most active paclitaxel combination regimen with first-line MVAC (methotrexate, vinblastine, adriamycin, cisplatin) chemotherapy. Finally, the role of paclitaxel combination regimens needs to be explored in the adjuvant and neoadjuvant setting in patients with bladder cancer. In testicular cancer, paclitaxel has initially been tested in patients with cisplatin-refractory disease. Among 4 consecutive trials involving a total of 83 patients a response rate of 26% has been observed using dose schedules varying from 3-h to 24-h infusions and doses ranging from 175 to 250 mg/m2. The major toxicities of paclitaxel include neutropenia, neurotoxicity, and fatigue syndrome. Currently, combinations of paclitaxel with cisplatin ± ifosfamide are used as first- or second-line salvage therapy in patients with relapsed metastatic testicular cancer. The German Testicular Cancer Study Group uses a paclitaxel (Taxol, ifosfamide, cisplatin; TIP) combination regimen as salvage treatment. Following the TIP regimen and the application of granulocyte colony-stimulating factor (GCSF), peripheral blood stem cells (PBSC) are harvested and the patients subsequently receive high-dose chemotherapy with PBSC rescue. Since only a few drugs have demonstrated substantial activity in cisplatin-refractory disease, paclitaxel will be used in early salvage strategies and, possibly, as first-line chemotherapy as a part of platinum-based combination regimens in patients with testicular cancer. Further trials confirming the important role of paclitaxel in this highly curable malignancy and a thorough investigation of its acute and long-term toxicity will be the future tasks.

Recent strategies for the use of paclitaxel in the treatment of urological malignancies

Abstract Paclitaxel, a natural anticancer drug, has gained widespread acceptance as an active broad-spectrum antitumor agent, including its use in urological malignancies, particularly urothelial tract cancer and testicular cancer. The mechanism of action, based on the premature stabilization of the microtubule assembly with disruption of the cytoskeletal framework, is completely different from those of DNA-damaging agents, e.g., cisplatin and ifosfamide. As a single agent, paclitaxel is one of the most active drugs in metastatic bladder cancer, with an overall response rate of 40–50% being obtained in previously untreated patients. These promising single-agent results have prompted the use of combination regimens including, in particular, cisplatin and paclitaxel. A high degree of activity for the cisplatin-paclitaxel combination as reflected by responses in 50–80% of patients, including a substantial number of complete responses (>30%), has been identified. The role of other agents such as vinorelbine, methotrexate, 5-fluorouracil, or ifosfamide as additions to this two-drug combination currently remains open. The combination of paclitaxel plus ifosfamide or vinorelbine in the absence of a platinum derivative has yielded rather disappointing results. Of particular interest may be the combination of paclitaxel and carboplatin. Both drugs can be given to patients with impaired renal function. Overall response rates of 45–60% have been reported in phase II studies. The so-called platelet-sparing effect of paclitaxel given in combination with carboplatin has resulted in a surprisingly low frequency of myelotoxicity, particularly thrombocytopenia. The combination of paclitaxel with carboplatin is being compared in an ongoing trial against the current standard MVAC regimen (methotrexate/vinblastine/Adriamycin/cisplatin) in patients with metastatic disease. Furthermore, the activity of paclitaxel-based combinations is currently being explored in the neoadjuvant setting in phase II studies, and the potential for the combination with the other new promising agent – gemcitabine – will be evalutated in a phase I setting. In prostate cancer, estramustine phosphate is widely used as palliative treatment for patients with hormone-refractory disease. In vitro synergistic activity has been observed between estramustine and paclitaxel in prostate-cancer cell lines, although paclitaxel has not demonstrated single-agent activity in patients with hormone-refractory prostate cancer. In clinical trials the combination of the two agents was associated with increased gastrointestinal toxicity. The addition of etoposide as a third drug has yielded prostate-specific antigen (PSA)-response rates of >50%, but data on quality of life and survival time have not been reported for these combinations. A true clinical role for paclitaxel in prostate cancer has therefore not been established. Paclitaxel has finally demonstrated single-agent activity in relapsed and/or cisplatin-refractory testicular cancer in recent phase II trials, indicating different mechanisms of resistance to cisplatin and paclitaxel. These results have formed the rationale for the introduction of paclitaxel as part of combination chemotherapy regimens in patients with relapsed but chemosensitive testicular cancer. Preliminary results demonstrate that paclitaxel can be safely included into these conventional-dose combination regimens. When it is used prior to high-dose chemotherapy, sufficient numbers of peripheral blood stem cells (PBSCs) for high-dose therapy can be collected. The final role of paclitaxel in risk-adapted chemotherapeutic strategies in testicular cancer is not defined, but it appears that paclitaxel-based combinations can achieve a substantial response rate in patients with relapsed disease.

Late relapse after treatment for nonseminomatous testicular germ cell tumors according to a single center-based experience

The introduction of cisplatin-based systemic chemotherapy into the clinical routine has resulted in a substantial improvement of the recurrence-free and long-term survival of patients with metastatic testicular germ cell tumors. Late relapses after the completion of first-line therapy, comprising systemic chemotherapeutic treatment in combination with a complete resection of residual tumor masses visible in about 25–50% of patients, have been reported to occur in 1–5% of patients later than 2xa0years following the initial treatment. It has been reported that the risk for the development of late recurrence is correlated to the tumor burden at first diagnosis and/or the presence of teratomatous components within the primary testicular cancer. Second-line chemotherapy in combination with surgery, although not very well standardized, has been recommended as the most effective therapeutic regimen during the treatment of patients suffering from late recurrent germ cell tumors. Herein, we report our single-center experience with 14 patients in different clinical stages who developed late relapse after successful first-line therapy. In the present series, the risk for late relapse was not correlated to the clinical stage at first diagnosis or the presence of teratomatous elements within the primary tumor. It became evident that in selected cases chemotherapy alone can be considered a curative treatment option.

Surgical bladder preserving strategies in the treatment of muscle-invasive bladder cancer

Abstract. Single modality bladder-sparing therapy for muscle-invasive bladder cancer, including transurethral resection (TUR), partial cystectomy, systemic chemotherapy or radiotherapy, have been demonstrated to result in insufficient local control of the primary tumour, as well as decreased long-term survival in the patients when compared to radical cystectomy. Therefore, multimodality treatment protocols that aim at bladder preservation and involve all of the aforementioned approaches have been established. Arguments for combining systemic chemotherapy with radiation are to sensitise tumour tissue to radiotherapy and to eradicate occult metastases that have already developed in as many as 50% of patients at the time of first diagnosis. It has been shown that the clinical outcome observed with this approach approximates that after radical cystectomy. Additionally, a substantial number of patients survive with an intact bladder. However, bladder-sparing approaches are costly, and require close co-operation between different clinical specialists as well as careful follow-up. The good long-term results that are observed after cystectomy and the creation of an orthotopic neobladder make the substantial advantage of a bladder preservation strategy questionable when the patients quality of life is addressed. Additionally, bladder-sparing therapy-related side effects might result in an increased morbidity and mortality in those patients who need to undergo surgery due to recurrent or progressive disease. Multimodality bladder-sparing treatment is a therapeutic option that can be offered to the patient at centres that have a dedicated multidisciplinary team at their disposal. However, radical cystectomy remains the standard of care for muscle-invasive bladder cancer.

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.

Future prospects in the chemotherapy of metastatic nonseminomatous testicular germ-cell cancer

Abstract The current aims of chemotherapy in metastatic testicular cancer are to reduce treatment-related toxicity in patients with “good-prognosis” metastatic disease without compromising the efficacy and to improve treatment results in “poor-prognosis” patients according to the IGCCCG classification by the use of more dose-intensive regimens. Three cycles of PEB chemotherapy, consisting of cisplatin, etoposide, and bleomycin, remain the standard treatment for good-prognosis patients despite a number of randomized studies trying to avoid the toxicity of bleomycin or to abandon cisplatin-associated side effects by substitution with the less toxic analogue carboplatin. In patients with intermediate- and poor-prognosis criteria, four cycles of PEB given at 3-weekly intervals are considered routine treatment. The role of high-dose chemotherapy with peripheral blood stem-cell (PBSC) transplantation (HDCT) is currently being investigated for patients who initially present with poor-prognosis metastatic disease and for patients with relapse after previous chemotherapy. Favorable results with long-term survival rates of approximately 75% have been achieved with up-front sequential HDCT in a phase I–II trial of the German Testicular Cancer Study Group (GTCSG) in such patients. A randomized phase III trial comparing conventional dose chemotherapy (4×u2009PEB) with HDCT (2×u2009PEBu2009+u20092×u2009HD-CEC) was initiated as a United States intergroup trial in 1996. In patients with relapsed disease, conventional salvage chemotherapy results in only an approximately 20% long-term survival rate. Particularly, primary mediastinal disease and chemotherapy refractoriness represent variables associated with a very poor outcome. HDCT is also employed in relapsed patients to improve the long-term outcome. Long-term toxicity of treatment has become an important issue due to the large group of patients with metastatic disease now being cured with modern treatment strategies. The cumulative dose of cisplatin applied has been identified as a major risk factor for the development of many types of late toxicity. Despite the major advances made in the last 20 years, evaluation of the role of HDCT in both first-line and salvage treatment, investi- gation of new cytotoxic agents in refractory patients, and assessment of the long-term toxicities are major tasks that remain to be addressed in controlled clinical trials.

A phase I pharmacokinetic study of matuzumab in combination with paclitaxel in patients with EGFR-expressing advanced non-small cell lung cancer.

SummaryMatuzumab is a humanized IgG1 EGFR monoclonal antibody. This phase I study investigated the tolerability, safety and pharmacokinetics (PK) of matuzumab in combination with paclitaxel in patients with EGFR-expressing advanced non-small cell lung cancer (NSCLC). Six dose levels/schedules of matuzumab were explored in combination with paclitaxel. Dose was escalated from 100xa0mg to 1,600xa0mg on a modified Fibonacci scheme according to the incidence of dose-limiting toxicity (DLT) over the first two cycles. DLT was assessed in patients who completed the first two treatment cycles or who stopped treatment because of a DLT during those cycles. Patients with non-progressive disease could then continue to receive study treatment for up to 6xa0months. The safety population comprised 44 patients, with DLT evaluable in 33. The maximum tolerated dose was not reached, with only one DLT reported at the 1,600xa0mg 3-weekly dose level. The most frequent grade 3/4 adverse events across all cycles were dyspnea (23xa0%) and neutropenia (11xa0%). Matuzumab exhibited non-linear PK, with accumulation after escalation and repeated dosing. Tumor growth control was seen in 15/44 (34xa0%) patients, including 5/9 (56xa0%) at the 800xa0mg weekly dose level. Matuzumab combined with paclitaxel was generally well tolerated in patients with advanced NSCLC. There was some evidence of anticancer activity in relation to the matuzumab 800xa0mg weekly dose.

Advances in our understanding of the biology, new diagnostic approaches and recent treatment strategies for testicular germ cell cancer

Testicular germ cell tumors represent a model for a curable disease in modern oncology. The interdisciplinary treatment approach consisting of surgery, chemotherapy and in some cases radiotherapy has yielded long-term survival rates of 90% for the total group of patients, and even 70–80% for patients with metastatic disease. Twenty five years after the introduction of cisplatin into combination chemotherapy for metastatic germ cell tumors, it appears that all problems involving the treatment of such tumors have been solved. However, an adequate diagnostic and treatment approach is still the ultimate key to optimal results. Therefore, spreading the knowledge on recent advances on the one hand, and training of urologists, medical oncologists and radio-oncologists on the other are essential. The aim of this issue of the World Journal of Urology is, thus, to summarize the most recent information on testicular germ cell tumors. There are in fact still several issues in which significant advances have been achieved in recent years, and important research is still ongoing. These aspects have formed the basis for the topics chosen for this issue. The epidemiology of germ cell tumors has shown that this entity has increased in incidence over the last decades and will thus remain an important malignancy in the younger male. New insights into the pathology and, particularly, into the molecular biology of germ cell tumors are discussed. Several aspects of this newly gained information will have implications for treatment strategies in the future. Chemotherapy for germ cell cancer is now based on clinical risk factors. Avoiding toxicity in the standard treatment situation appears to be as important as selecting those patients who will need more aggressive treatment approaches, such as high-dose chemotherapy for intermediate and poor risk patients as well as in refractory disease. Advances in surgical techniques have allowed the investigation of the role of laparoscopic approaches in stage I non-seminomatous germ cell tumors (NSGCT). Here, the role of primary lymphadenectomy within a risk-stratified therapeutic approach during the treatment of early stage NSGCT can be expected to be newly defined in the near future. Furthermore, post chemotherapy surgery is also an essential part of therapeutic management. Secondary surgery, including ‘‘salvage surgery’’, has significantly contributed to the success story in testicular cancer. Allowing the diagnosis of vital tumor residuals is another interesting aspect that is currently investigated by the use of positron emission tomography (PET). In patients with pure seminoma, PET seems to be very promising, allowing the avoidance of unnecessary operations after completion, due to systemic therapy. With the excellent overall survival rates in testicular cancer patients, the problem of late relapses has emerged over recent years. The approach to these patients may be different, since in many cases late relapses not only contain classical germ cell elements but also highly differentiated components of other tumor entities that will not be responsive to the chemotherapy protocols otherwise used in germ cell tumors. Based on the topics discussed in this issue, a close interaction between urologists, medical oncologists and radiotherapists, as well as an involvement of biologists, pathologists and radiologists will be necessary to further advance the results achieved for this tumor entity. In many cases, the best treatment for the patient will involve a multi-modality approach. Only close cooperation will enable us to explore new and promising treatment strategies. M. Kuczyk (&) Klinik für Urologie, Universitätsklinikum Tübingen, Hoppe Seiler Strasse 3, 72076 Tübingen, Germany