Update on chemotherapy for advanced bladder cancer

PURPOSE: Recent years have seen several advances in the treatment of locally advanced and metastatic bladder cancer. We summarize the current state of the art for advanced bladder cancer treatment. MATERIALS AND METHODS: A comprehensive review of published, prospective phase II/III clinical trials and retrospective analyses of patients with advanced bladder cancer was performed. RESULTS: Adjuvant and neoadjuvant chemotherapeutic strategies around the time of radical cystectomy have been used to decrease the risk of subsequent metastatic disease. Although the benefit of adjuvant chemotherapy remains unproven, neoadjuvant chemotherapy is associated with a modest 5% to 6% absolute survival benefit in 2 meta-analyses of the available data. Chemoradiation is feasible and effective in some patients, allowing bladder preservation with an acceptable risk of progression. Randomized, phase III data comparing methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy to gemcitabine/cisplatin showed similar response proportions and overall survival with less toxicity in the gemcitabine/cisplatin arm. This has led to the widespread use of gemcitabine/cisplatin as first line chemotherapy for metastatic bladder cancer. The optimal agents and regimens for second line chemotherapy remain undefined. Similarly biological and targeted therapies for advanced bladder cancer remain investigational. CONCLUSIONS: Combination cisplatin based neoadjuvant chemotherapy may benefit patients with locally advanced bladder cancer. Gemcitabine/cisplatin has replaced methotrexate, vinblastine, doxorubicin and cisplatin as the regimen of choice in patients with good renal function. The optimal regimens for the medically unfit patient and second line chemotherapy remain undefined. The development of targeted therapies, less toxic regimens and improved cytotoxic agents are necessary to improve outcomes.     

Adjuvant and neoadjuvant chemotherapy for bladder cancer: management and controversies

Radical cystectomy remains the gold standard treatment for muscle-invasive bladder cancer. Although surgery achieves excellent local control, within 5 years almost 50% of patients relapse and subsequently progress to develop systemic disease. Transitional cell carcinoma of the bladder is sensitive to chemotherapy. Although platinum-based chemotherapy can produce relatively high overall response rates, the impact on the survival of patients with advanced disease has, at best, been limited. Randomized trials of cisplatin-based chemotherapy regimens in the neoadjuvant setting have demonstrated the potential to improve survival. By comparison, adjuvant studies have been plagued by suboptimal trial design, limited patient numbers, and lack of standardization of the chemotherapy regimens used. With the introduction of new cytotoxic drugs and novel small molecules, there is a need for well-designed studies to address the optimal utility of perioperative therapy in high-risk patients with bladder cancer.     

Recent advances in conventional-dose salvage chemotherapy in patients with cisplatin-resistant or refractory testicular germ cell tumors

Testicular germ cell tumors represent the most frequent malignancy in young males aged 20-35 years. Despite the considerably high cure rates provided by platinum-based chemotherapy, 20-30% of cases with advanced disease do not achieve a long-term disease-free survival with first-line chemotherapy. These patients are candidates for conventional-dose or high-dose salvage chemotherapy. The current conventional-dose salvage regimens of reference are the vinblastine-ifosfamide-cisplatin or etoposide-ifosfamide-cisplatin combinations, which are expected to cure approximately 25% of non-seminomatous germ-cell tumour patients. Paclitaxel has also been proved effective both as monotherapy in heavily-pretreated cases and as part of first-line salvage regimens; the combination of paclitaxel-ifosfamide-cisplatin, followed or not by high-dose chemotherapy, induced a favorable long-term disease-free survival rate, especially in patients with good prognosis. Newer cytotoxic drugs, such as gemcitabine and oxaliplatin have also been proved effective, while other agents, such as temozolamide, or targeted therapies, such as trastuzumab in cases over-expressing HER2/neu (20% of relapsing germ-cell tumors) are currently under evaluation. Seminomas have generally a better prognosis than non-seminomatous tumors and salvage therapy is expected to cure about 50% of all cases.     

Novel targets and approaches in advanced prostate cancer

PURPOSE OF REVIEW: The development of therapeutic resistance is the underlying cause for most cancer deaths. By understanding the molecular basis of resistance to androgen withdrawal and chemotherapy in prostate cancer, the rational design of targeted therapeutics is possible. We review new treatment options for men with advanced prostate cancer. RECENT FINDINGS: Although the taxanes currently represent the most active chemotherapeutic agents and standard of care for first-line treatment of metastatic hormone-refractory prostate cancer, most patients eventually progress because of intrinsic or acquired drug resistance. In recent years, increased knowledge of cancer progression and therapeutic resistance has identified many gene targets that regulate apoptosis, proliferation, and cell signalling. To date, numerous novel compounds have entered clinical trials as either single agents or in combination with cytotoxic chemotherapy. SUMMARY: Even though hormone-refractory prostate cancer is still incurable, it is not untreatable. As cancer cells are proficient at adapting to therapeutic stressors, a combination regimen with drugs that target crucial cellular networks like the apoptotic rheostat may be more promising than treatment with highly selective single-target agents. Recent findings are very hopeful, but challenges remain to demonstrate effective antitumour activity in phase III trials with survival as the principal endpoint.     

Carboplatin in the treatment of oesophageal cancer

Cisplatin has modest activity in squamous cancer of the oesophagus but substantial toxicity limits its usefulness. Carboplatin (Paraplatin; BM Group), a second-generation platinum analogue, was developed to maintain the antitumour activity of cisplatin and reduce toxicity. Eleven patients with advanced oesophageal cancer were treated with carboplatin. A partial response was seen in 1 patient (9%) and minor responses in 2 cases. The median survival was 12 months in responding patients and 3 months in non-responders. One patient suffered reversible myelosuppression but nephrotoxicity and vomiting were not observed. Carboplatin is well tolerated and may have a role as a less toxic substitute for cisplatin in combination chemotherapy regimens for oesophageal cancer.     

State-of-the-art management of metastatic disease at initial presentation or recurrence

Carcinoma of the bladder is the second most prevalent genitourinay malignancy and the fifth most common solid tumor in the USA. On the basis of favorable response rates and survival data, cisplatin-based regimens can be considered the standard treatment for fit patients with metastatic urothelial cancer. Since cisplatin-containing regimens are contraindicated for patients with impaired renal function, gemcitabine plus either paclitaxel or docetaxel may be an effective and well-tolerated treatment option for these patients. Randomized trials are needed to determine the future role of these combinations in the management of advanced transitional cell carcinoma. The optimal regimens for the medically unfit patients and second-line chemotherapy remain undefined. Postchemotherapy surgical resection of residual cancer may result in a disease-free survival in highly selected patients who would otherwise die of the disease. Progresses in the understanding of the molecular biology of bladder cancer and identification of new targeted therapies will undoubtedly provide new opportunities but whether or not this approach to therapy will lead to better results must still be determined.     

Bendamustine in Metastatic Breast Cancer: An Old Drug in New Design

The goal of treatment for patients with advanced breast cancer is to prolong survival, control symptoms, and reduce disease-related complications. Despite the introduction of many cytotoxic agents during the past decade, only modest improvement in survival in metastatic breast cancer has been achieved. In order to improve this situation, new cytotoxic drugs as well as molecule-targeted agents are now under investigation. Bendamustine is a bifunctional alkylating agent with cytotoxic activity against several types of solid tumors. In the search for new anthracycline-free combinations, taxanes and alkylating agents might be worth investigating, in order to reduce cardiac toxicity. In this article, we reviewed the latest information regarding antitumor activity, toxicity, pharmacokinetics, and clinical application of bendamustine as a cytotoxic agent in metastatic breast cancer.Key Words: Bendamustine, First-line chemotherapy, Metastatic breast cancer     

Chemotherapy of soft tissue tumors

The use of chemotherapy in the treatment of patients with advanced soft tissue sarcoma and as adjuvant and neoadjuvant therapy is reviewed. In advanced disease a response rate of up to 35% can be achieved with combination chemotherapy, but these are mainly partial remissions; few complete remissions are attained. The median survival for patients in partial remission is 2 years. The most active cytotoxic drug is adriamycin, with a remission rate of 30%. The addition of dacarbazine can increase the remission rate; however, this has no significant impact on survival and the toxicity is more pronounced. The activity of neoadjuvant or adjuvant chemotherapy is still controversial. Some studies indicate a positive effect on disease-free or overall survival with adriamycin-containing regimens. Other studies have not confirmed these results. More controlled trials with adequate numbers of patients stratified for tumor subtype, tumor localization and grading are needed to define the value of adjuvant or neoadjuvant chemotherapy in soft tissue sarcomas. Optimal interdisciplinary treatment can only be realized at specialized centers.     

Multi-modality treatment of advanced malignant germ cell tumours in males. I. Experience with cis-platinum-based combination chemotherapy

Three-weekly cis-platinum-based combination chemotherapy with or without subsequent surgery and/or radiotherapy resulted in a 58% 3-year-survival in 79 patients with advanced malignant germ cell tumours. Poor risk factors were relapse after previous chemotherapy, retroperitoneal bulky disease, liver metastases and extremely high serum levels of AFP, beta-HCG, and LDH. Patients with pure seminoma had a high curation rate. The overall toxicity was acceptable. Cis-platinum-based chemotherapy is at present the most effective cytotoxic treatment for patients with advanced malignant germ cell tumours. The relatively low survival rate in poor-risk patients necessitates more aggressive primary chemotherapy in this subgroup of patients.     

The current and future application of adjuvant systemic chemotherapy in patients with bladder cancer following cystectomy

Urothelial transitional cell cancer has a high rate of response to combination cytotoxic therapy. Approximately 50% of patients with high-grade bladder cancer and deep muscle invasion ultimately die of disseminated disease. Translating the high response seen in locally advanced disease into long-term survival in the metastatic setting and to improved survival in the advanced setting has proved difficult. This article reviews the use of adjuvant chemotherapy in localized or locally advanced transitional cell cancer. The chemotherapy of urological malignancies, including bladder cancer, has recently been reviewed in detail; this article does not contain an extensive review of the drugs used.     

Reappraising antiangiogenic therapy for breast cancer

Phase III trials of antiangiogenic drugs for metastatic breast cancer have either had only limited success, e.g. the monoclonal anti-VEGF antibody bevacizumab when used with various conventional chemotherapy regimens, or have failed altogether, e.g. the small molecule oral tyrosine kinase inhibitor (TKI) sunitinib. No phase III trial has yet demonstrated an overall survival benefit and the progression free survival (PFS) benefits, when attained with bevacizumab are short, with perhaps one exception. Together, these results call for a reappraisal of using antiangiogenic drugs for breast cancer and possible strategies to improve their efficacy. Among the reasons to help explain the limited benefits observed thus far include the possibility that angiogenesis may not be a major driver of breast cancer growth, compared to some other types of cancer; that acquired resistance may develop rapidly to VEGF-pathway targeting antiangiogenic drugs, in part due to angiogenic growth factor redundancy; that optimal chemotherapy regimens have not been used in conjunction with an antiangiogenic drug; and that antiangiogenic drugs may secondarily aggravate biologic aggressiveness of the tumors, thereby reducing their overall efficacy after inducing an initial benefit. Several possible strategies are discussed for improving the efficacy of antiangiogenic drugs, including combination with different chemotherapy regimens, e.g. long term and less toxic metronomic chemotherapy protocols; validation of predictive biomarkers to individualize patient therapy; development of improved preclinical therapy models, e.g. involving advanced metastatic breast cancer, and combination with other types of anti-cancer agents especially biologies such as trastuzumab for Her2-positive breast cancer. Reasons for the current concern regarding use of antiangiogenic drug treatments for early stage cancers, including breast cancer, are also discussed.     

Changing perspectives of the role of chemotherapy in advanced prostate cancer

The use of cytotoxic chemotherapy in advanced prostate adenocarcinoma has been validated by the recent demonstration of survival benefit in two large randomized phase III trials. Before publication of these landmark trials, SWOG 9916 and TAX 327, no chemotherapeutic regimen had shown survival benefit in the treatment of androgen independent prostate cancer (AIPC). These trials provide new encouragement for the use of chemotherapy in all stages of disease. Improved communication between medical and urologic oncologists and early patient referral for clinical trial participation remains essential for identifying new chemotherapeutic regimens with improved activity in AIPC and for defining the role of chemotherapy in earlier-stage disease. This article discusses the role of chemotherapy as the current standard of care for the treatment of AIPC and provides a historical perspective of the trials that preceded the development of current docetaxel-based regimens.     

Gemcitabin in der Behandlung des fortgeschrittenen Urothelkarzinoms

MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) has been the standard treatment for patients with advanced urothelial cancer for more than 15 years. Combination chemotherapy including gemcitabine/cisplatin showed similar tumor response and survival rates with a more tolerable toxicity profile in a recent multinational phase III study when compared to MVAC. Effectiveness of gemcitabine as a single agent or in combination with other cytotoxic agents had been investigated before in several phase II studies treating patients with advanced urothelial cancers. The tumor response rate for single agent gemcitabine in advanced urothelial cancers is between 11% and 28%. Tumor response rates rise to 50% when combining gemcitabine with cisplatin, and median survival times between 12 and 15 months can be expected. Triplet therapy schedules including gemcitabine may yield response rates in up to 80% of patients, particularly when used sequentially with other regimens. Further improvement of tolerability during systemic gemcitabine/cisplatin combination therapy without compromising effectiveness was recently demonstrated by a German phase II study when the 4-week schedule was reduced to a 3-week schedule with gemcitabine given on days 1 and 8.     

Ⅳ期胃癌转化治疗的研究进展

胃癌是我国最常见的恶性肿瘤之一,临床收治的胃癌患者以进展期为主。近年来,随着药物治疗的进步,对于无法手术的Ⅳ期胃癌采取以药物治疗为主的综合治疗后,可以使部分病例肿瘤降期,从而获得根治手术的机会,部分接受手术治疗的患者从而获得了长期生存的机会。REGATTA研究结果证实,姑息手术+化疗不能改善Ⅳ期胃癌患者的远期生存。新辅...     

Long-term follow-up in 54 surgically treated patients with gastrointestinal stromal tumours

Background  Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the alimentary tract. Since these tumours are rather resistant to radiation and conventional chemotherapy, prognosis may be poor. Imatinib, a KIT tyrosine kinase inhibitor, has been shown to have dramatic antitumour effects on GISTs; however, surgical en bloc resection of the tumour with free resection margins remains still the first option for cure. Materials and methods  Here, we present a retrospective study with 54 consecutive GIST patients who were treated surgically at our University Hospital between 1993 and 2005 and were followed up at 5 and 10 years. Results  The disease-specific survival rate was 94% at 1 year, 91% at 3 years, 76% at 5 years, and 72% at 10 years. In univariate analysis, tumour size, mitotic rate, morphology, and necrosis predicted survival in patients with negative margins. Age, sex, and symptoms did not influence outcome. Conclusion  GISTs have a high incidence of associated secondary malignancies which may have a significant influence on prognosis and outcome. Patients with R0 resections had a significantly better survival rate of 86% at 5 years and of 81% at 10 years than those with R1 and R2 resections (21% and 0%).     

Systemic chemotherapy

The main use of systemic chemotherapy in metastatic melanoma remains palliative. Dacarbazine (dimethyl-1-triazeno imidazole-4-carboxamide [DTIC]) is the standard chemotherapy agent for advanced disease. The combination chemotherapy and biochemotherapy regimens have achieved higher response rates, but have not led to durable remission or improved survival. The field of systemic therapy remains in need of a more effective and less toxic treatment strategy.     

The Role of Preoperative Chemotherapy in Patients with Resectable Colorectal Liver Metastases

Background  Liver metastases develop in 40–50% of patients with colorectal cancer and represent the major cause of death in this disease. Surgical resection remains the only treatment procedure that can ensure long-term survival and provide cure when liver metastases can be totally resected with clear margins, when the primary cancer is controlled, and when there is no nonresectable extrahepatic disease. Five-year survival rate after surgical resection of colorectal metastases varies from 25% to 55%, but cancer relapse is observed in most patients. Aim  To review the potential benefits and disadvantages of neoadjuvant chemotherapy administered before surgery to patients with initially resectable metastases. Results  European Organization for Research and Treatment of Cancer (EORTC) study 40983 has shown that neoadjuvant chemotherapy could reduce the risk of relapse by one-quarter, and allows to test the chemosensitivity of the cancer, to help to determine the appropriateness of further treatments, and to observe progressive disease, which contraindicates immediate surgery. Neoadjuvant chemotherapy can induce damage to the remnant liver. Oxaliplatin-based combination regimen is associated with increased risk of vascular lesions, whereas irinotecan-containing regimens have been associated with increased risks of steatosis and steatohepatitis. Analysis of EORTC study 40983 showed that administration of six cycles of neoadjuvant systemic chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) was associated with moderate increase of the risk of reversible complications after surgery, but mortality rate was below 1% and not increased. If patients are not overtreated, chemotherapy before surgery is well tolerated. The integration of novel targeted agents in combination with cytotoxic drugs is a promising way to improve outcome in patients with advanced colorectal cancer. Preliminary trials have shown that targeted agents combined with cytotoxic regimens can increase tumor response rates. Another impact of preoperative chemotherapy is that metastases that respond to treatment may no longer be visible on computed tomography (CT) scan or at surgery. Patients should be carefully monitored and receive surgery before metastases disappear. Conclusion  Treatment of most patients with liver metastases—those with resectable metastases as well as those with initially unresectable metastases—should start with chemotherapy. If drugs are well chosen and the duration of treatment is monitored with care during multidisciplinary meetings, benefits largely outweigh potential disadvantages.     

Detection of the multidrug resistance marker P-glycoprotein by immunohistochemistry in malignant lung tumours.

BACKGROUND: The multidrug resistance marker P-glycoprotein (P-gp) was studied immunohistochemically in 78 primary malignant lung tumours. P-gp is a 170 kD transmembrane ATP dependent drug efflux pump which has been shown to be important in the resistance of some tumours to chemotherapy. Certain normal tissues express P-gp and tumours derived from these tissues are often insensitive to cytotoxic agents, showing raised P-gp levels innately or following chemotherapy or radiotherapy. METHODS: Samples from 78 patients undergoing surgery for primary malignant lung tumours were snap frozen and stained immunohistochemically using the monoclonal antibody C219 which reacts with a P-gp epitope. None of the study group had received chemotherapy or radiotherapy before surgery was performed. RESULTS: Twenty seven of the 78 lung tumours (34.6%) showed immunohistochemically detectable levels of P-gp which varied with tumour type; 17 of 54 squamous cell carcinomas (31.5%), seven of 15 adenocarcinomas (46.7%), and neither of two small cell carcinomas showing positive staining. In six of seven cases normal respiratory epithelium present showed the presence of P-gp. CONCLUSIONS: P-gp is immunohistochemically detectable in frozen tissue from a proportion of malignant lung tumours before exposure to radiotherapy or drugs associated with multidrug resistance. It may have a role in tumour resistance to cytotoxic drugs, but further clinical studies will be required to evaluate any correlation between P-gp levels and response to treatment.     

Diagnosis and management of adrenal cortical carcinoma

Adrenal cortical carcinoma is a relatively uncommon malignancy that represents a significant clinical challenge for the development of optimal treatment strategies. Historically, successful treatment has relied upon rapid identification of the lesion, accurate staging with diagnostic imaging, and complete surgical extirpation. Although the framework of a successful treatment paradigm still relies on these steps, advances in diagnostic imaging have led to increased accuracy in diagnosis, and advances in laparoscopic surgical technique have served to reduce morbidity for patients facing treatment. This review focuses on a discussion of advances in modalities for the diagnosis and treatment of adrenal cortical carcinoma amenable to curative therapy. Patients that present with metastatic or locally advanced disease generally are treated with mitotane-based chemotherapy with or without the addition of cytotoxic drugs. Contemporary results of this treatment approach are presented in this review as well as a discussion of further directions for the treatment of patients with advanced disease.     

Preoperative induction therapy in non-small cell lung cancer

The clinical significance of preoperative induction therapy for non-small cell lung cancer (NSCLC) is reviewed. As the survival rate in locally advanced NSCLC patients remains poor, preoperative therapy has been attempted in order to improve survival. Whereas some prospective phase II and phase III studies have demonstrated that preoperative cisplatin-based chemotherapy with or without concurrent radiation may improve the prognosis, the efficacy has not been established. Recently, some new chemotherapeutic agents such as paclitaxel and gemcitabine have been introduced, and it has been suggested that preoperative therapy using these new drugs may be more effective. To establish effective preoperative therapy regimens, more sophisticated, prospective, randomized studies in sufficient numbers of homogenous populations such as mediastinoscopy-proven stage IIIA, T1-2N2 patients should be conducted.