The efficacy of irinotecan, paclitaxel, and oxaliplatin (IPO) in relapsed germ cell tumours with high-dose chemotherapy as consolidation: a non-cisplatin-based induction approach.

OBJECTIVES: To determine the outcome of an expanded cohort of patients with relapsed germ cell tumours (GCTs) treated with a salvage chemotherapy regimen consisting of irinotecan, paclitaxel and oxaliplatin (IPO) and assess the role of IPO as an alternative to standard cisplatin-based chemotherapy regimens in this setting. PATIENTS AND METHODS: The results of 72 consecutive patients were reviewed retrospectively. IPO was used either as a second-line treatment (29 patients), of which 20 patients subsequently received high-dose chemotherapy (HDCT), or third-line (43), of which 32 patients proceeded to HDCT. RESULTS: The 2-year progression-free survival (PFS) and 3-year overall survival (OS) rates for the whole cohort were 30.2% (95% confidence interval [CI] 17.3-40.5%) and 33.4% (95% CI 20.1-43.8%), respectively. Complete remission was achieved in 3%, marker-negative partial response (PR) in 41%, marker-positive PR in 18%, stable disease in 17% and progressive disease in 20%. In the second-line setting, the 2-year PFS rate was 43.5% (95% CI 21.7-60.8%) and 3-year OS 49.1% (95% CI 24.2-65.1%). In the third-line setting, the 2-year PFS rate was 21.0% (95% CI 9.5-35.4%) and the 3-year OS rate was 23.9% (95% CI 11.7-38.2). According to the current international prognostic factor study group criteria for first relapse for the high- and very high-risk group the 2-year PFS rates were 50% and 30%, respectively. There were two treatment-related deaths from IPO, and four from HDCT. Grade 3 or 4 toxicities included neutropenia (35%), thrombocytopaenia (18%), infection (15%), diarrhoea (11%) and lethargy (8%). CONCLUSIONS: IPO offers an effective, well-tolerated, non-nephrotoxic alternative to cisplatin-based salvage regimens for patients with relapsed GCTs. It appears particularly useful in high-risk patients and for those in whom cisplatin is ineffective or contra-indicated.

Electromotive drug administration with mitomycin C for intravesical treatment of non-muscle invasive transitional cell carcinoma.

This article reviews the use and application of electromotive drug administration for the intravesical treatment of bladder cancer. Strong evidence supports the use of passive intravesical chemotherapy in the management of non-muscle invasive bladder cancer. More recently, two published randomised trials have shown therapeutic advantage with protocols that use electromotive drug administration to enhance urothelial penetration of intravesical mitomycin C. The results suggest that the passive intravesical administration of chemotherapeutic drugs may be suboptimal. Further studies are required to demonstrate the feasibility and advantage of electromotive intravesical mitomycin C in the wider uro-oncological community.

18fluorodeoxyglucose positron emission tomography in the prediction of relapse in patients with high-risk, clinical stage I nonseminomatous germ cell tumors: preliminary report of MRC Trial TE22--the NCRI Testis Tumour Clinical Study Group.

PURPOSE: There are several management options for patients with clinical stage I (CS1) nonseminomatous germ cell tumors (NSGCT); this study examined whether an 18fluorodeoxyglucose positron emission tomography (18FDG PET) scan could identify patients without occult metastatic disease for whom surveillance is an attractive option. METHODS: High-risk (lymphovascular invasion positive) patients with CS1 NSGCT underwent 18FDG PET scanning within 8 weeks of orchidectomy or marker normalization. PET-positive patients went off study; PET-negative patients were observed on a surveillance program. The primary outcome measure was the 2-year relapse-free rate (RFR) in patients with a negative PET scan (the negative predictive value). Assuming an RFR of 90% to exclude an RFR less than 80% with approximately 90% power, 100 PET-negative patients were required; 135 scanned patients were anticipated. RESULTS: Patients were registered between May 2002 and January 2005, when the trial was stopped by the independent data monitoring committee due to an unacceptably high relapse rate in the PET-negative patients. Of 116 registered patients, 111 underwent PET scans, and 88 (79%) were PET-negative (61% of preorchidectomy marker-negative patients v 88% of marker-positive patients; P = .002); 87 proceeded to surveillance, and one requested adjuvant chemotherapy. With a median follow-up of 12 months, 33 of 87 patients on surveillance relapsed (1-year RFR, 63%; 90% CI, 54% to 72%). CONCLUSION: Though PET identified some patients with disease not detected by computed tomography scan, the relapse rate among PET negative patients remains high. The results show that 18FDG PET scanning is not sufficiently sensitive to identify patients at low risk of relapse in this setting.

Randomized trial of two or five computed tomography scans in the surveillance of patients with stage I nonseminomatous germ cell tumors of the testis: Medical Research Council Trial TE08, ISRCTN56475197--the National Cancer Research Institute Testis Cancer Clinical Studies Group.

PURPOSE: Surveillance is a standard management approach for stage I nonseminomatous germ cell tumors (NSGCT). A randomized trial of two versus five computed tomography (CT) scans was performed to determine whether the number of scans influenced the proportion of patients relapsing with intermediate- or poor-prognosis disease at relapse. METHODS: Patients with clinical stage I NSGCT opting for surveillance were randomly assigned to chest and abdominal CT scans at either 3 and 12 or 3, 6, 9, 12, and 24 months, with all other investigations identical in the two arms. Three of five patients were allocated to the two-scan schedule. Four hundred patients were required. RESULTS: Two hundred forty-seven patients were allocated to a two-scan and 167 to five-scan policy. With a median follow-up of 40 months, 37 relapses (15%) have occurred in the two-scan arm and 33 (20%) in the five-scan arm. No patients had poor prognosis at relapse, but two (0.8%) of those relapsing in the two-scan arm had intermediate prognosis compared with 1 (0.6%) in the five-scan arm, a difference of 0.2% (90% CI, -1.2% to 1.6%). No deaths have been reported. CONCLUSION: This study can rule out with 95% probability an increase in the proportion of patients relapsing with intermediate- or poor-prognosis disease of more than 1.6% if they have two rather than five CT scans as part of their surveillance protocol. CT scans at 3 and 12 months after orchidectomy should be considered a reasonable option in low-risk patients.

Chemotherapy for hormone-resistant prostate cancer: Where are we today?

Significant progress has been achieved in chemotherapy for hormone-resistant prostate cancer (HRPC) in the last five years. Although the disease was long considered to be chemoresistant, docetaxel-based regimens in particular have been shown to both palliate symptoms and prolong survival in HRPC patients. Docetaxel is now considered the best available chemotherapy for prostate cancer progressing on first-line hormonal treatment. Other cytotoxics including mitoxantrone, anthracyclines, vinorelbin and vinblastine can alleviate symptoms and improve progression-free survival in HRPC without affecting overall survival. The survival benefit from chemotherapy seen in randomized studies has been small or nonexistent. Results of a recent trial suggest that the survival benefit may have been underestimated as a result of crossover from the less active to the active arm.

Tumour markers for managing men who present with metastatic prostate cancer and serum prostate-specific antigen levels of <10 ng/mL.

OBJECTIVE: To define immunohistochemical features of the primary cancers that might help in the differential diagnosis and monitoring of treatment in men presenting with metastatic prostate cancer and low serum levels of prostate-specific antigen (PSA), who can be difficult to diagnose and manage. PATIENTS AND METHODS: Paraffin blocks of prostate biopsies were obtained for 33 patients presenting with untreated metastatic prostate cancer and serum PSA levels of <10 ng/mL. Sections were immunostained for PSA, prostatic acid phosphatase (PAP), prostate-specific membrane antigen (PSMA), androgen receptor (AR), chromogranin A and CD 56. RESULTS: The combined Gleason scores were 8-10 in 25 men (76%) and 6 or 7 in the other eight (24%). Morphologically, there were no neuroendocrine features. PSA immunostaining was equivocal in 12 (36%) cases and in a further 19 (58%) was strong but focal and could be missed on biopsy sampling. PSMA was expressed in 90% of cases, and staining was widely distributed in nine of the 12 in which PSA staining was equivocal. There was strong AR expression in 30 (91%) cases and it was present in areas where PSA was absent. CONCLUSION: In this patient group, immunohistochemical assessments of PSMA and AR are potentially useful as diagnostic markers.

Clinical features of patients who present with metastatic prostate carcinoma and serum prostate-specific antigen (PSA) levels < 10 ng/mL: the "PSA negative" patients.

BACKGROUND: Although < 1% of men present with prostate-specific antigen (PSA)-negative prostate carcinoma, in that they have serum PSA levels much lower than the tumor burden would suggest, such patients represent a management dilemma. To the authors' knowledge, little information exists in the literature regarding patterns of disease and response to treatment. The authors wished to define the clinical features of this patient group. METHODS: The British Association of Urological Surgeons Cancer Registry 2000 and 2001 data bases were used to identify the clinical features and outcome of 33 men with metastatic prostate carcinoma who presented with serum PSA levels < 10 ng/mL. Clinical notes and histopathology were reviewed for each patient. RESULTS: Seventeen patients (51%) presented with urinary symptoms and/or pelvic pain, 6% with cachexia and 21% with bone pain. Characteristic bone metastases were present in 81% of patients, similar to the presentation of men with high serum PSA levels. Hypercalcemia was a feature in 9% of patients. Visceral metastases were present in two patients. The median response duration to first-line hormone manipulation was 7 months. No responses were seen in 11 of 13 patients who received second-line hormones or to any third-line treatment. Three of 5 patients who received chemotherapy responded but developed recurrent disease within 8 weeks of treatment cessation. The median overall survival was 12 months. CONCLUSIONS: The presentation of patients with treatment-naïve PSA-negative metastatic prostate carcinoma is similar to that of patients with high serum PSA levels, but their median survival and response duration to first-line hormone therapy are of much shorter duration. Second-line hormone therapy is ineffective, but early chemotherapy may be beneficial. Hypercalcemia is a particular feature in this group of patients.

Broad clinical activity of zoledronic acid in osteolytic to osteoblastic bone lesions in patients with a broad range of solid tumors.

Bone metastases are a common feature of a variety of solid tumors and are associated with substantial skeletal morbidity, including severe bone pain and pathologic fractures. Treatment with bisphosphonates, primarily pamidronate, is the current standard of care for patients with breast cancer and multiple myeloma who have predominantly osteolytic lesions. However, until recently no bisphosphonate had demonstrated efficacy in patients with osteoblastic lesions, which are common during the progression of prostate cancer and other solid tumors. Zoledronic acid, a potent, new-generation, nitrogen-containing bisphosphonate, has demonstrated significant benefits for patients with bone metastases resulting from a broad range of primary tumors, including multiple myeloma and breast, lung, kidney, and prostate cancers, and other solid tumors. Benefits include a decreased incidence of pathologic fractures and longer time to the first skeletal complication. Zoledronic acid is the first and only bisphosphonate to be proved effective in patients with all types of bone lesions, from osteolytic to osteoblastic, and therefore represents an important therapeutic advancement in the treatment of bone metastases.