Phase I, pharmacokinetic and pharmacodynamic evaluation of CYT997, an orally-bioavailable cytotoxic and vascular-disrupting agent.

PURPOSE: CYT997 is a novel microtubule inhibitor and vascular disrupting agent. This phase I trial examined the safety, tolerability, pharmacokinetics and vascular-disrupting effects of orally-administered CYT997. EXPERIMENTAL DESIGN: We performed a phase I accelerated dose-escalation study of CYT997 given orally once every 2 to 3 weeks in patients with advanced solid tumours. Vascular disruption was assessed by measurement of plasma von Willebrand factor (vWF) levels and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS: A total of 56 doses were administered to 21 patients over 8 dose levels (15-164 mg/m(2)). Grade 3 fatigue and grade 3 hypoxia were dose limiting. Oral bioavailability was observed with approximate linear pharmacokinetics over the 11-fold dose range. At doses of 84 mg/m(2) and above, plasma vWF levels increased above baseline and DCE-MRI scans showed reductions in tumour K(trans) in some patients. CONCLUSIONS: CYT997 is orally bioavailable. The 118 mg/m(2) dose level should be used to guide dosing in future studies.

Pegylated liposomal Doxorubicin and Carboplatin compared with Paclitaxel and Carboplatin for patients with platinum-sensitive ovarian cancer in late relapse.

PURPOSE: This randomized, multicenter, phase III noninferiority trial was designed to test the efficacy and safety of the combination of pegylated liposomal doxorubicin (PLD) with carboplatin (CD) compared with standard carboplatin and paclitaxel (CP) in patients with platinum-sensitive relapsed/recurrent ovarian cancer (ROC). PATIENTS AND METHODS: Patients with histologically proven ovarian cancer with recurrence more than 6 months after first- or second-line platinum and taxane-based therapies were randomly assigned by stratified blocks to CD (carboplatin area under the curve [AUC] 5 plus PLD 30 mg/m(2)) every 4 weeks or CP (carboplatin AUC 5 plus paclitaxel 175 mg/m(2)) every 3 weeks for at least 6 cycles. Primary end point was progression-free survival (PFS); secondary end points were toxicity, quality of life, and overall survival. RESULTS: Overall 976 patients were recruited. With median follow-up of 22 months, PFS for the CD arm was statistically superior to the CP arm (hazard ratio, 0.821; 95% CI, 0.72 to 0.94; P = .005); median PFS was 11.3 versus 9.4 months, respectively. Although overall survival data are immature for final analysis, we report here a total of 334 deaths. Overall severe nonhematologic toxicity (36.8% v 28.4%; P < .01) leading to early discontinuation (15% v 6%; P < .001) occurred more frequently in the CP arm. More frequent grade 2 or greater alopecia (83.6% v 7%), hypersensitivity reactions (18.8% v 5.6%), and sensory neuropathy (26.9% v 4.9%) were observed in the CP arm; more hand-foot syndrome (grade 2 to 3, 12.0% v 2.2%), nausea (35.2% v 24.2%), and mucositis (grade 2-3, 13.9% v 7%) in the CD arm. CONCLUSION: To our knowledge, this trial is the largest in recurrent ovarian cancer and has demonstrated superiority in PFS and better therapeutic index of CD over standard CP.

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.

Does aggressive surgery only benefit patients with less advanced ovarian cancer? Results from an international comparison within the SCOTROC-1 Trial.

PURPOSE: Studies indicate that ovarian cancer patients who have been optimally debulked survive longer. Although chemotherapy has been variable, they have defined standards of care. Additionally, it is suggested that patients from the United Kingdom (UK) have inferior survival compared with some other countries. We explored this within the context of a large, international, prospective, randomized trial of first-line chemotherapy in advanced ovarian cancer (docetaxel-carboplatin v paclitaxel-carboplatin; SCOTROC-1). The Scottish Randomised Trial in Ovarian Cancer surgical study is a prospective observational study examining the impact on progression-free survival (PFS) of cytoreductive surgery and international variations in surgical practice. PATIENTS AND METHODS: One thousand seventy-seven patients were recruited (UK, n = 689; Europe, United States, and Australasia, n = 388). Surgical data were available for 889 patients. These data were analyzed within a Cox model. RESULTS: There were three main observations. First, more extensive surgery was performed in non-UK patients, who were more likely to be optimally debulked (< or = 2 cm residual disease) than UK patients [corrected] (71.3% v 58.4%, respectively; P < .001). Second, optimal debulking was associated with increased PFS mainly for patients with less extensive disease at the outset (test for interaction, P = .003). Third, UK patients with no visible residual disease had a less favorable PFS compared with patients recruited from non-UK centers who were similarly debulked (hazard ratio = 1.85; 95% CI, 1.16 to 2.97; P = .010). This observation seems to be related to surgical practice, primarily lymphadenectomy. CONCLUSION: Increased PFS associated with optimal surgery is limited to patients with less advanced disease, arguing for case selection rather than aggressive debulking in all patients irrespective of disease extent. Lymphadenectomy may have beneficial effects on PFS in optimally debulked patients.

Management of recurrent epithelial ovarian carcinoma.

Despite the standardisation of surgical techniques and significant progress in chemotherapeutics over the last 30 years, advanced epithelial ovarian cancer remains the most lethal gynaecological malignancy in the western world. Although the majority of women achieve a remission following primary therapy, most patients with advanced stage disease will eventually relapse and become candidates for 'salvage' therapy. The chances of a further remission depend on factors such as the 'treatment-free interval', and there are now a large number of chemotherapy agents with activity in ovarian cancer available to the oncologist. Recent randomised studies have reported on survival benefits for chemotherapy in recurrent disease, and therefore careful and appropriate selection of treatments has assumed a greater importance. This article reviews the most current data, and discusses the factors involved in making individualised treatment decisions.

Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma.

BACKGROUND: Chemotherapy with a platinum agent and a taxane (paclitaxel) is considered the standard of care for treatment of ovarian carcinoma. We compared the combination of docetaxel-carboplatin with the combination of paclitaxel-carboplatin as first-line chemotherapy for stage Ic-IV epithelial ovarian or primary peritoneal cancer. METHODS: We randomly assigned 1077 patients to receive docetaxel at 75 mg/m2 of body surface area (1-hour intravenous infusion) or paclitaxel at 175 mg/m2 (3-hour intravenous infusion). Both treatments then were followed by carboplatin to an area under the plasma concentration-time curve of 5. The treatments were repeated every 3 weeks for six cycles; in responding patients, an additional three cycles of single-agent carboplatin was permitted. Survival curves were calculated by the Kaplan-Meier method, and hazard ratios were estimated with the Cox proportional hazards model. All statistical tests were two-sided. RESULTS: After a median follow-up of 23 months, both groups had similar progression-free survival (medians of 15.0 months for docetaxel-carboplatin and 14.8 months for paclitaxel-carboplatin; hazard ratio [HR] docetaxel-paclitaxel = 0.97, 95% confidence interval [CI] = 0.83 to 1.13; P = .707), overall survival rates at 2 years (64.2% and 68.9%, respectively; HR = 1.13, 95% CI = 0.92 to 1.39; P = .238), and objective tumor (58.7% and 59.5%, respectively; difference between docetaxel and paclitaxel = -0.8%, 95% CI = -8.6% to 7.1%; P = .868) and CA-125 (75.8% and 76.8%, respectively; difference docetaxel-paclitaxel = -1.0%, 95% CI = -7.2% to 5.1%; P = .794) response rates. However, docetaxel-carboplatin was associated with substantially less overall and grade 2 or higher neurotoxicity than paclitaxel-carboplatin (grade > or =2 neurosensory toxicity in 11% versus 30%, difference = 19%, 95% CI = 15% to 24%; P<.001; grade > or =2 neuromotor toxicity in 3% versus 7%, difference = 4%, 95% CI = 1% to 7%; P<.001). Treatment with docetaxel-carboplatin was associated with statistically significantly more grade 3-4 neutropenia (94% versus 84%, difference = 11%, 95% CI = 7% to 14%; P<.001) and neutropenic complications than treatment with paclitaxel-carboplatin, although myelosuppression did not influence dose delivery or patient safety. Global quality of life was similar in both arms, but substantive differences in many symptom scores favored docetaxel. CONCLUSIONS: Docetaxel-carboplatin appears to be similar to paclitaxel-carboplatin in terms of progression-free survival and response, although longer follow-up is required for a definitive statement on survival. Thus, docetaxel-carboplatin represents an alternative first-line chemotherapy regimen for patients with newly diagnosed ovarian cancer.

The acquisition of hMLH1 methylation in plasma DNA after chemotherapy predicts poor survival for ovarian cancer patients.

Aberrant epigenetic regulation, such as CpG island methylation and associated transcriptional silencing of genes, has been implicated in a variety of human diseases, including cancer. Methylation of genes involved in apoptosis, including the DNA mismatch repair (MMR) gene hMLH1, can occur in tumor models of resistance to chemotherapeutic drugs. However, the relevance for acquired resistance to chemotherapy of patients' tumors remains unsubstantiated. Plasma DNA from cancer patients, including those with ovarian cancer, often contains identical DNA changes as the tumor and provides a means to monitor CpG island methylation changes. We have examined plasma DNA of patients with epithelial ovarian cancer enrolled in the SCOTROC1 Phase III clinical trial for methylation of the hMLH1 CpG island before carboplatin/taxoid chemotherapy and at relapse. Methylation of hMLH1 is increased at relapse, and 25% (34 of 138) of relapse samples have hMLH1 methylation that is not detected in matched prechemotherapy plasma samples. Furthermore, hMLH1 methylation is significantly associated with increased microsatellite instability in plasma DNA at relapse, providing an independent measure of function of the MMR pathway. Acquisition of hMLH1 methylation in plasma DNA at relapse predicts poor overall survival of patients, independent from time to progression and age (hazard ratio, 1.99; 95% confidence interval, 1.20-3.30; P = 0.007). These data support the clinical relevance of acquired hMLH1 methylation and concomitant loss of DNA MMR after chemotherapy of ovarian cancer patients. DNA methylation changes in plasma provide the potential to define patterns of methylation during therapy and identify those patient populations who would be suitable for novel epigenetic therapies.

Part I: testicular cancer--management of early disease.

For patients diagnosed with early-stage testicular cancer radical orchidectomy is the primary therapeutic intervention. The major pathological types of testicular cancer are seminoma and non-seminomatous germ-cell cancer. After orchidectomy, most patients with seminoma receive adjuvant radiotherapy as standard of care, although surveillance and adjuvant chemotherapy protocols are being developed. For patients with non-seminomatous tumours there are three therapeutic options; surveillance, adjuvant chemotherapy, or retroperitoneal lymph-node dissection. These patients are classified into groups with high-risk or low-risk of recurrence by presence of vascular invasion in the surgical specimen. After orchidectomy, about 50% of patients with high-risk disease will relapse but this risk is reduced to less than 5% with adjuvant therapy. Surveillance of patients with low-risk disease is acceptable because testicular cancer is still curable if metastatic recurrence occurs. There is no consensus about the management of early non-seminomatous testicular cancer because survival is almost 100% irrespective of the initial treatment decision.

Part II: testicular cancer--management of advanced disease.

Up to 80% of metastatic germ-cell tumours are curable with conventional chemotherapy. The combination of cisplatin, bleomycin, and etoposide has become the gold standard in this disease. Patients can be divided into good, intermediate, and poor prognosis groups. For those patients with good prognostic features, cure rates reach 90% and attempts have been made to reduce toxic effects of treatment while maintaining efficacy. Patients that relapse require salvage treatment. This can involve the incorporation of drugs such as ifosfamide and taxol into conventional protocols or the use of high-dose chemotherapy with stem-cell transplants. Patients with poor prognosis disease are much more likely to fail conventional chemotherapy and are candidates for dose-intensive protocols or transplants as first-line treatment. Although the results obtained in treating metastatic germ-cell tumours are superior to those with other solid tumour types, there are still many areas that require further improvement.

Role of docetaxel in the treatment of newly diagnosed advanced ovarian cancer.

Docetaxel is currently licensed for use in a variety of malignancies, including breast cancer and lung cancer, and is the preferred taxane in breast cancer treatment. In ovarian cancer, the taxane of choice has historically been paclitaxel; however, there is now substantial evidence that docetaxel also may be the preferred taxane in this disease. Docetaxel has many preclinical advantages over paclitaxel and has been shown to be effective in both platinum- and paclitaxel-resistant disease. Phase I and II studies have shown docetaxel plus carboplatin to be feasible, and the combination is associated with a tolerable adverse-effect profile. The Scottish Randomized Trial in Ovarian Cancer (SCOTROC) trial randomly assigned 1,077 patients with International Federation of Gynecology and Obstetrics stage Ic to IV disease to six cycles of docetaxel plus carboplatin (DC) or paclitaxel plus carboplatin (PC) as primary chemotherapy. Progression-free survival is not statistically different, and to date, no differences are apparent in overall survival. Toxicity differences were evident. There was more myelosuppression with DC but no additional mortality. More neuropathy was present with PC, with more patients stopping paclitaxel because of this toxicity during chemotherapy. Quality-of-life analyses highlighted important differences, all favoring the DC treatment arm. Additional SCOTROC studies using docetaxel are ongoing. These data indicate that docetaxel and carboplatin represent a reasonable first-line option for patients with newly diagnosed epithelial ovarian cancer.

Docetaxel in ovarian cancer: phase III perspectives and future development.

In the mid 1990s, the incorporation of paclitaxel into platinum-based therapy for ovarian cancer marked a significant advance in treatment. Future progress will probably involve reductions in toxicity, which may be achieved by combining the less neurotoxic agent docetaxel with carboplatin. In an international phase III study, 1,077 chemotherapy-naive patients with stage Ic-IV ovarian cancer were randomized to receive carboplatin targeted to an AUC of 5 plus either docetaxel 75 mg/m(2) or paclitaxel 75 mg/m(2) for six cycles. Patients treated with paclitaxel plus carboplatin experienced significantly greater neurotoxicity than those treated with docetaxel plus carboplatin. Docetaxel/carboplatin and paclitaxel/carboplatin produced similar rates of objective response (66% and 62%, respectively), and initial data on progression-free survival indicate that the two treatments appear very similar in efficacy. Thus, docetaxel may prove to be a valid alternative to paclitaxel as part of first-line therapy in ovarian cancer. Nevertheless, there remains considerable scope for improvements in treatment. There is the possibility of using existing drugs more effectively, perhaps by the use of sequential rather than concurrent regimens. This would allow the most active drugs to be used at full dose, increase tolerability, and avoid the possibility of negative drug interaction. The integration of molecularly targeted agents, such as those directed at epidermal growth factor receptors, into existing regimens is highly promising but will need to be explored in randomized trials of first-line therapy. Because the prime obstacle to successful treatment is the acquisition of drug resistance, understanding the underlying mechanisms is an important future priority. One candidate is mismatch repair deficiency; the interest here is that experimental resistance reversal is achievable with hypomethylating agents, raising the possibility of future clinical trials if the clinical relevance of this mechanism can be confirmed.