Imaging Modality and Frequency in Surveillance of Stage I Seminoma Testicular Cancer: Results From a Randomized, Phase III, Noninferiority Trial (TRISST).

PURPOSE: Survival in stage I seminoma is almost 100%. Computed tomography (CT) surveillance is an international standard of care, avoiding adjuvant therapy. In this young population, minimizing irradiation is vital. The Trial of Imaging and Surveillance in Seminoma Testis (TRISST) assessed whether magnetic resonance images (MRIs) or a reduced scan schedule could be used without an unacceptable increase in advanced relapses. METHODS: A phase III, noninferiority, factorial trial. Eligible participants had undergone orchiectomy for stage I seminoma with no adjuvant therapy planned. Random assignment was to seven CTs (6, 12, 18, 24, 36, 48, and 60 months); seven MRIs (same schedule); three CTs (6, 18, and 36 months); or three MRIs. The primary outcome was 6-year incidence of Royal Marsden Hospital stage ≥ IIC relapse (> 5 cm), aiming to exclude increases ≥ 5.7% (from 5.7% to 11.4%) with MRI (v CT) or three scans (v 7); target N = 660, all contributing to both comparisons. Secondary outcomes include relapse ≥ 3 cm, disease-free survival, and overall survival. Intention-to-treat and per-protocol analyses were performed. RESULTS: Six hundred sixty-nine patients enrolled (35 UK centers, 2008-2014); mean tumor size was 2.9 cm, and 358 (54%) were low risk (< 4 cm, no rete testis invasion). With a median follow-up of 72 months, 82 (12%) relapsed. Stage ≥ IIC relapse was rare (10 events). Although statistically noninferior, more events occurred with three scans (nine, 2.8%) versus seven scans (one, 0.3%): 2.5% absolute increase, 90% CI (1.0 to 4.1). Only 4/9 could have potentially been detected earlier with seven scans. Noninferiority of MRI versus CT was also shown; fewer events occurred with MRI (two [0.6%] v eight [2.6%]), 1.9% decrease (-3.5 to -0.3). Per-protocol analyses confirmed noninferiority. Five-year survival was 99%, with no tumor-related deaths. CONCLUSION: Surveillance is a safe management approach-advanced relapse is rare, salvage treatment successful, and outcomes excellent, regardless of imaging frequency or modality. MRI can be recommended to reduce irradiation; and no adverse impact on long-term outcomes was seen with a reduced schedule.

Pazopanib and Fosbretabulin in recurrent ovarian cancer (PAZOFOS): A multi-centre, phase 1b and open-label, randomised phase 2 trial.

OBJECTIVE: Vascular co-option is a resistance mechanism to anti-angiogenic agents, but combinations of anti-vascular agents may overcome this resistance. We report a phase 1b and randomised phase 2 trial to determine the safety and efficacy of pazopanib with fosbretabulin. METHODS: Eligible patients had recurrent, epithelial ovarian cancer with a platinum-free interval (PFI) of 3 to 12 months. Patients were stratified according to PFI (>6 versus ≤6 months) and prior bevacizumab use. RESULTS: Twelve patients were treated in the phase 1b. Commonest grade ≥ 2 adverse events (AEs) were hypertension (100%), neutropenia (50%), fatigue (50%), vomiting (50%). There was one DLT (grade 3 fatigue). The recommended phase 2 dose level was fosbretabulin 54 mg/m2 on days 1, 8 and 15 and pazopanib 600 mg once daily (od), every 28 days, which was then compared to pazopanib 800 mg od in a randomised phase 2 trial. Twenty-one patients were randomised (1:1) in the phase 2 trial. In phase 1b and phase 2, four patients treated with pazopanib and fosbretabulin developed reversible, treatment-related cardiac AEs, leading to premature discontinuation of the study. In the phase 2 trial, the median PFS was 7.6 months (95% CI 4.1-not estimated) versus 3.7 months (95% CI 1.0-8.1) in favour of the experimental arm (HR 0.30, 95% CI 0.09-1.03, P = .06). CONCLUSIONS: It remains unclear whether pazopanib with with fosbretabulin is an efficacious regimen to treat epithelial ovarian cancer. Effective cardiac risk mitigation is needed to increase the tolerability and maximize patient safety in future trials.

Wanna Get Away? Maintenance Treatments and Chemotherapy Holidays in Gynecologic Cancers.

Epithelial ovarian cancer has a very high rate of relapse after primary therapy; historically approximately 70% of patients with a complete clinical response to surgery and adjuvant chemotherapy will relapse and die of the disease. Although this number has slowly improved, cure rates remain less than 50%. As such, maintenance therapy with the aim of preventing or delaying disease relapse and the goal of improving overall survival has been the subject of intense study. Numerous earlier studies with agents ranging from radioactive phosphorus to extended frontline therapy or to monthly taxol administration demonstrated encouraging improvements in progression-free survival (PFS) only to find, disappointingly, no benefit in overall survival. In addition, the PFS advantage of maintenance therapy was associated with disconcerting side effects such that maintenance therapy was not adapted as standard of care. Studies with bevacizumab and PARP inhibitors have demonstrated a PFS advantage with a manageable side-effect profile. However, an overall survival advantage remains unclear, and the use of these approaches thus remains controversial. Furthermore, in recurrent disease, the length of chemotherapy and benefits of extended chemotherapy is unclear. Thus, additional trials assessing maintenance strategies in ovarian and other gynecologic malignancies are needed.

A phase II study of carboplatin AUC-10 guided by positron emission tomography-defined metabolic response in metastatic seminoma.

INTRODUCTION: Carboplatin monotherapy for metastatic seminoma at a dose of AUC-10 has shown promising activity. Three or four cycles have been given with most haematological side-effects seen with the 4th cycle. An early response might allow de-escalation of therapy. METHODS: Forty-eight patients with metastatic seminoma (International Germ Cell Cancer Collaborative Group good prognosis) were recruited. Positron emission tomography (PET) scanning was performed before and after one cycle of carboplatin. Those with a Deauville score of 3 or less were given a total of three cycles of carboplatin, the rest received four. RESULTS: PET scanning allowed 44% to receive three cycles of carboplatin. With a median follow-up of 31.2 months, 95.6% (95% confidence interval: 83.5%-98.9%) were progression free. The overall survival at 2-years was 100%. Lower stage (2A and 2B) disease was significantly (P = 0.001) associated with the better metabolic response, but the association was not strong (correlation coefficient = -0.48). Over a third of the blood products given were used to support the 4th cycle. The regimen was well tolerated with a low incidence of grade III neutropenic sepsis or nausea and vomiting (<3% cycles). CONCLUSION: Carboplatin AUC-10 monotherapy is effective with low toxicity. Early changes during PET scanning may allow de-escalation of therapy in high volume disease-comparison against combination therapy is warranted. CLINICALTRIALS. GOV IDENTIFIER: NCT02272816. EUDRACT NUMBER: 2009-009882-33.

Salvage Chemotherapy With Gemcitabine, Paclitaxel, Ifosfamide, and Cisplatin for Relapsed Germ Cell Cancer.

BACKGROUND: Metastatic germ cell tumors remain potentially curable when treated with salvage chemotherapy at first relapse. In the present phase I/II study, we sought to improve on the response rate and duration of the TIP (paclitaxel, ifosfamide, cisplatin) regimen by adding gemcitabine (Gem-TIP). MATERIALS AND METHODS: Twenty patients were recruited after failure of first-line cisplatin-containing chemotherapy. The primary objectives were to determine the maximum tolerated dose of gemcitabine when combined with TIP and to establish the dose intensity of the TIP drugs in this combination. The secondary objectives were the response rates, failure-free survival, and overall survival. RESULTS: The maximum tolerated dose of gemcitabine was 1200 mg/m2. The mean relative dose intensity was 95% (95% confidence interval [CI], 90.2%-99.2%) for gemcitabine, 96% (95% CI, 92.9%-98.7%) for paclitaxel, 92% (95% CI, 84.5%-98.8%) for ifosfamide, and 94% (95% CI, 89.3%-99.0%) for cisplatin. The overall complete response rate was 50%; another 30% of the patients achieved a partial response. The 1-year failure-free survival and overall survival rates were 68% (95% CI, 43%-84%) and 89.5% (95% CI, 64%-97%), respectively. CONCLUSION: Gemcitabine can be added to TIP chemotherapy at the full dose, with manageable toxicity and no detrimental effect on the dose intensity of the TIP drugs. The response rate and duration were improved compared with those reported from the Medical Research Council TIP trial; further evaluation is warranted.

Audit of CA125 Follow-Up After First-Line Therapy for Ovarian Cancer.

AIMS: The Medical Research Council OVO5/EORTC 55955 trial showed that patients in remission after first-line therapy for ovarian cancer did not benefit from routine measurement of CA125 during follow-up. Since the presentation of these results, we have counseled patients about the options for follow-up and provided them with an information leaflet about the trial results and the symptoms that should prompt an early appointment and CA125 measurement. We present an audit of practice after the presentation of those results. METHODS: The medical records of 143 consecutive patients completing first-line therapy for epithelial ovarian, fallopian tube, or primary peritoneal cancer in our unit between July 2009 and December 2013 were analyzed. RESULTS: An agreed plan of CA125 follow-up was recorded in 69 (79%) of 87 eligible patients on completion of first-line therapy. No routine CA125 follow-up was selected by 55 (80%) patients, and routine CA125 follow-up was selected by 14 (20%), of whom 3 wished not to be informed of the results. CA125 levels were checked in 28 (51%) patients in the no routine CA125 follow-up group, in 26 cases because of the development of symptoms. Relapse was confirmed in 22. Median follow-up was 360 days (range, 100-836). CA125 levels were checked in all 14 patients who had requested routine CA125 follow-up. Relapse has been confirmed in 2 patients. Median follow-up was 560 days (range, 500-620). CONCLUSIONS: If patients are given sufficient information about the role of routine CA125 measurements during follow-up, the majority decide against CA125 monitoring and hence, avoid these blood tests.

Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Angiogenesis is a validated clinical target in advanced epithelial ovarian cancer. Cediranib is an oral antiangiogenic vascular endothelial growth factor receptor 1-3 inhibitor that has shown antitumour activity in recurrent ovarian cancer. We assessed efficacy and safety of cediranib in combination with platinum-based chemotherapy and as continued maintenance treatment in patients with first relapse of platinum-sensitive ovarian cancer. METHODS: In this randomised, three-arm, double-blind, placebo-controlled phase 3 trial, we randomly assigned patients aged 18 years or older with relapsed platinum-sensitive ovarian cancer at 63 centres in Australia, Canada, New Zealand, Spain, and the UK. Participants received up to six cycles of platinum-based chemotherapy (once every 3 weeks) then entered a maintenance phase. Participants were randomly allocated (2:3:3), with five stratification factors and in alternating blocks, to receive placebo alongside chemotherapy and then placebo only maintenance (arm A; reference), cediranib 20 mg once-daily alongside chemotherapy then placebo only maintenance (arm B; concurrent), or cediranib 20 mg once-daily alongside chemotherapy then cediranib 20 mg once-daily maintenance (arm C; maintenance). Patients continued treatment to progression or excessive toxic effects. The primary efficacy endpoint was progression-free survival between arms A and C. Efficacy analysis was by intention to treat. Safety was assessed in all patients who received the allocated study drug. This trial is registered with ClinicalTrials.gov, number NCT00532194; the ISRCTN registry, number ISRCTN68510403; and ANZ Clinical Trials Registry, number ACTRN1261000016003. FINDINGS: We randomly assigned 486 [corrected] women between Nov 13, 2007, and Dec 23, 2011; results presented are for 456 patients randomly assigned subsequent to the 30mg safety phase. During a median of 19·5 months (IQR 14-26) follow-up, 113 (96%) of 118 women assigned to arm A and 141 (86%) of 164 assigned to arm C had disease progression. Median progression-free survival was 11·0 months (95% CI 10·4-11·7) in arm C and 8·7 months (7·7-9·4) in arm A (hazard ratio 0·56, 0·44-0·72, p<0·0001). 156 (90%) of 174 patients in arm B had disease progression, and median progression-free survival was 9·9 months (95% CI 9·4-10·5). Diarrhoea, neutropenia, hypertension, and voice changes were significantly more common, during chemotherapy with cediranib, and diarrhoea, hypothyroidism and voice changes were more common during maintenance. Poor compliance with cediranib was noted during maintenance treatment with toxic effects being the most common cause for discontinuation. INTERPRETATION: Cediranib, when given orally with chemotherapy and continued as maintenance, yielded a meaningful improvement [corrected] in progression-free survival in women with recurrent platinum-sensitive ovarian cancer, albeit with added toxic effects. The positive results in ICON6 could provide women with a new therapeutic option for recurrent ovarian cancer. Assessment of the secondary endpoint of overall survival will need longer follow-up. FUNDING: Medical Research Council, Cancer Research UK, Canadian Cancer Society Research Institute, Cancer Australia, National Gynecological Cancer Centre, and AstraZeneca.

Phase I study of nintedanib incorporating dynamic contrast-enhanced magnetic resonance imaging in patients with advanced solid tumors.

BACKGROUND: This open-label phase I dose-escalation study investigated the safety, efficacy, pharmacokinetics (PK), and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) effects of the oral angiokinase inhibitor nintedanib in patients with advanced solid tumors. METHODS: Nintedanib was administered once daily continuously, starting at 100 mg and later amended to allow evaluation of 250 mg b.i.d. The primary endpoint was maximum tolerated dose (MTD). DCE-MRI studies were performed at baseline and on days 2 and 28. RESULTS: Fifty-one patients received nintedanib 100-450 mg once daily (n = 40) or 250 mg b.i.d. (n = 11). Asymptomatic reversible liver enzyme elevations (grade 3) were dose limiting in 2 of 5 patients at 450 mg once daily. At 250 mg b.i.d., 2 of 11 patients experienced dose-limiting toxicity (grade 3 liver enzyme elevation and gastrointestinal symptoms). Common toxicities included fatigue, diarrhea, nausea, vomiting, and abdominal pain (mainly grade ≤2). Among 45 patients, 22 (49%) achieved stable disease; 7 remained on treatment for >6 months. DCE-MRI of target lesions revealed effects in some patients at 200 and ≥400 mg once daily. CONCLUSION: Nintedanib is well tolerated by patients with advanced solid malignancies, with MTD defined as 250 mg b.i.d., and can induce changes in DCE-MRI. Disease stabilization >6 months was observed in 7 of 51 patients.

Using serum CA125 to assess the activity of potential cytostatic agents in ovarian cancer.

OBJECTIVE: New strategies are required to rapidly identify novel cytostatic agents before embarking on large randomized trials. This study investigates whether a change in rate of rise (slope) of serum CA125 from before to after starting a novel agent could be used to identify cytostatic agents. Tamoxifen was used to validate this hypothesis. METHODS: Asymptomatic patients with relapsed ovarian cancer who had responded to chemotherapy were enrolled and had CA125 measurements taken every 4 weeks, then more frequently when rising. Once levels reached 4 times the upper limit of normal or nadir, they started continuous tamoxifen 20 mg daily, as well as fortnightly CA125 measurements until symptomatic progression. Because of the potentially nonlinear relationship of CA125 over time, it was felt that to enable normal approximations to be utilized a natural logarithmic standard transformation [ln(CA125)] was the most suitable to improve linearity above the common logarithmic transformation to base 10. RESULTS: From 235 recruited patients, 81 started tamoxifen and had at least 4 CA125 measurements taken before and 4 CA125 measurements taken after starting tamoxifen, respectively. The mean regression slopes from using at least 4 1n(CA125) measurements immediately before and after starting tamoxifen were 0·0149 and 0·0093 [ln(CA125)/d], respectively. This difference is statistically significant, P = 0·001. Therefore, in a future trial with a novel agent, at least as effective as tamoxifen, using this effect size, the number of evaluable patients needed, at significance level of 5% and power of 80%, is 56. CONCLUSIONS: Further validation of this methodology is required, but there is potential to use comparison of mean regression slopes of ln(CA125) as an interim analysis measure of efficacy for novel cytostatic agents in relapsed ovarian cancer.

Current controversies in the management of germ cell ovarian tumours.

PURPOSE OF REVIEW: Fewer than 70 new cases of malignant ovarian germ cell tumours (MOGCTs) are seen each year in the UK. Because of their rarity, no randomized trials have been reported and many of the advances in management have arisen from adopting practices developed for managing male germ cell tumours (GCTs). Not surprisingly, there have been few important publications related to ovarian germ cell tumuors over the past 2 years. We have therefore included some relevant male germ cell publications. The area in which there is greatest variability in practice globally is in the proportion of patients with stage 1a disease who go on surveillance rather than receiving adjuvant chemotherapy. Although there is increasing agreement about the best management of ovarian GCTs amongst those who treat more than five per year, many patients are still treated by doctors who usually manage epithelial ovarian cancer but rarely see these patients. RECENT FINDINGS: Novel biomarkers including microRNA profiles and DICER1 mutations, identify potential diagnostic and therapeutic targets in this group of tumours. The role of KIT mutation and amplification in the development of ovarian dysgerminoma and the use of Sunitinib, a receptor tyrosine kinase inhibitor with an effect on vascular endothelial growth factor, platelet-derived growth factor and KIT receptors in patients with platinum-resistant GCT, are novel promising approaches. SUMMARY: We will therefore highlight some key differences in management of epithelial and germ cell ovarian tumours.

Pathological findings after primary chemotherapy in patients undergoing simultaneous orchidectomy and retroperitoneal lymph node dissection for advanced germ cell tumours.

OBJECTIVE: To determine the differential response to systemic chemotherapy in patients undergoing simultaneous orchidectomy and retroperitoneal lymph node dissection (RPLND) after chemotherapy for metastatic testicular cancer. PATIENTS AND METHODS: Patients who underwent simultaneous RPLND and orchidectomy after chemotherapy were identified from our clinical databases. Postoperative pathological findings and patient characteristics were reviewed. RESULTS: In all, 42 patients were identified. After chemotherapy, necrosis, teratoma and cancer were identified in 25 (59.5%), 14 (33.3%) and three (7.1%) RPLN specimens and 15 (35.7%), 15 (35.7%) and 12 (28.6%) orchidectomy specimens respectively. Of the 25 patients with necrotic RPLN specimens 12 (48.0%) had active disease within the orchidectomy specimen (eight invasive cancer and four mature teratoma). The overall histological discordance rate was 38.1%. Findings in the orchidectomy specimens were more aggressive than those in the RPLN specimens (i.e. cancer worse than teratoma, which is worse than necrosis) in 33.3%. CONCLUSIONS: There is significant disparity between orchidectomy and RPLND findings with viable tumour appearing frequently in the testis despite tumour-free RPLNs. These findings support completion orchidectomy as part of advanced testicular germ cell treatment.

Phase I trial of combretastatin A4 phosphate (CA4P) in combination with bevacizumab in patients with advanced cancer.

PURPOSE: The vascular disrupting agent (VDA) combretastatin A4 phosphate (CA4P) induces significant tumor necrosis as a single agent. Preclinical models have shown that the addition of an anti-VEGF antibody to a VDA attenuates the revascularization of the surviving tumor rim and thus significantly increases antitumor activity. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies received CA4P at 45, 54, or 63 mg/m(2) on day 1, day 8, and then every 14 days. Bevacizumab 10 mg/kg was given on day 8 and at subsequent cycles four hours after CA4P. Functional imaging with dynamic contrast enhanced-MRI (DCE-MRI) was conducted at baseline, after CA4P alone, and after cycle 1 CA4P + bevacizumab. RESULTS: A total of 63 mg/m(2) CA4P + 10 mg/kg bevacizumab q14 is the recommended phase II dose. A total of 15 patients were enrolled. Dose-limiting toxicities were grade III asymptomatic atrial fibrillation and grade IV liver hemorrhage in a patient with a history of hemorrhage. Most common toxicities were hypertension, headache, lymphopenia, pruritus, and pyrexia. Asymptomatic electrocardiographic changes were seen in five patients. Nine of 14 patients experienced disease stabilization. A patient with ovarian cancer had a CA125 response lasting for more than a year. DCE-MRI showed statistically significant reductions in tumor perfusion/vascular permeability, which reversed after CA4P alone but which were sustained following bevacizumab. Circulating CD34(+) and CD133(+) bone marrow progenitors increased following CA4P as did VEGF and granulocyte colony-stimulating factor levels. CONCLUSIONS: CA4P in combination with bevacizumab appears safe and well tolerated in this dosing schedule. CA4P induced profound vascular changes, which were maintained by the presence of bevacizumab.

Phase I clinical and pharmacokinetic evaluation of the vascular-disrupting agent OXi4503 in patients with advanced solid tumors.

PURPOSE: Preclinical studies show that OXi4503 (combretastatin A1 diphosphate, CA1P) is more potent than other clinically evaluated vascular-disrupting agents. EXPERIMENTAL DESIGN: Escalating doses of OXi4503 were given intravenously over 10 minutes on days 1, 8, and 15 every 28 days to patients with advanced solid tumors. RESULTS: Doses were escalated in single-patient cohorts from 0.06 to 1.92 mg/m(2), then expanded cohorts to 15.4 mg/m(2) in 43 patients. Common adverse drug reactions were hypertension, tumor pain, anemia, lymphopenia, and easily controllable nausea/vomiting and fatigue. Five patients experienced different drug-related dose-limiting toxicities, atrial fibrillation, increased troponin, blurred vision, diplopia, and tumor lysis. Prophylactic amlodipine failed to prevent adverse events. Pharmacokinetics showed dose-dependent linear increases in peak plasma concentrations and area under the curve value of OXi4503. One partial response was seen in a heavily pretreated patient with ovarian cancer. Dynamic contrast-enhanced MRI confirmed a dose effect and showed significant antivascular effects in 10 of 13 patients treated at doses of 11 mg/m(2) or higher. CONCLUSIONS: The maximum tolerated dose was 8.5 mg/m(2) but escalation to 14 mg/m(2) was possible with only temporary reversible cerebrovascular toxicity by excluding hypertensive patients. As a tumor response was seen at 14 mg/m(2) and maximum tumor perfusion reductions were seen at doses of 11 mg/m(2) or higher, the recommended phase II dose is from 11 to 14 mg/m(2).

Biologicals in the upfront treatment of ovarian cancer: focus on bevacizumab and poly (adp-ribose) polymerase inhibitors.

Biologicals have made a major impact in the management of several cancers, but have hitherto had a negligible impact in ovarian cancer. Fortunately, ovarian cancer has been much more sensitive to cytotoxic chemotherapy than many cancers, so treatments were still available. However, improvements are required as more than 80% of patients who present with advanced ovarian cancer eventually will die as a result of their disease. The antiangiogenic antibody bevacizumab and the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib have recently been shown to improve progression-free survival of patients with ovarian cancer with better hazard ratios in certain groups than have been seen previously.

Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC 30982 study (ISRCTN27163214).

PURPOSE: Initial results of a randomized trial comparing carboplatin with radiotherapy (RT) as adjuvant treatment for stage I seminoma found carboplatin had a noninferior relapse-free rate (RFR) and had reduced contralateral germ cell tumors (GCTs) in the short-term. Updated results with a median follow-up of 6.5 years are now reported. PATIENTS AND METHODS: Random assignment was between RT and one infusion of carboplatin dosed at 7 × (glomerular filtration rate + 25) on the basis of EDTA (n = 357) and 90% of this dose if determined on the basis of creatinine clearance (n = 202). The trial was powered to exclude a doubling in RFRs assuming a 96-97% 2-year RFR after radiotherapy (hazard ratio [HR], approximately 2.0). RESULTS: Overall, 1,447 patients were randomly assigned in a 3-to-5 ratio (carboplatin, n = 573; RT, n = 904). RFRs at 5 years were 94.7% for carboplatin and 96.0% for RT (RT-C 90% CI, 0.7% to 3.5%; HR, 1.25; 90% CI, 0.83 to 1.89). One death as a result of seminoma (in RT arm) occurred. Patients receiving at least 99% of the 7 × AUC dose had a 5-year RFR of 96.1% (95% CI, 93.4% to 97.7%) compared with 92.6% (95% CI, 88.0% to 95.5%) in those who received lower doses (HR, 0.51; 95% CI, 0.24 to 1.07; P = .08). There was a clear reduction in the rate of contralateral GCTs (carboplatin, n = 2; RT, n = 15; HR, 0.22; 95% CI, 0.05 to 0.95; P = .03), and elevated pretreatment follicle-stimulating hormone (FSH) levels (> 12 IU/L) was a strong predictor (HR, 8.57; 95% CI, 1.82 to 40.38). CONCLUSION: These updated results confirm the noninferiority of single dose carboplatin (at 7 × AUC dose) versus RT in terms of RFR and establish a statistically significant reduction in the medium term of risk of second GCT produced by this treatment.

What surveillance plan should be advised for patients in remission after completion of first-line therapy for advanced ovarian cancer?

Based on the results of the Medical Research Council OVO5/European Organisation for Research and Treatment of Cancer 55955 trial, the follow-up plan I recommend for patients in remission after completion of first-line therapy for advanced ovarian cancer is appointments: every 3 months for 2 years, every 4 months on the third year, then every 6 months thereafter, and discharge if no relapse by 10 years. History and examination (not internal) should be performed at each appointment. CA-125 should only be measured if there is a suspicion of relapse or at patient's request. No scans should be performed unless clinical indication or rising CA-125.

Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial.

BACKGROUND: Serum CA125 concentration often rises several months before clinical or symptomatic relapse in women with ovarian cancer. In the MRC OV05/EORTC 55955 collaborative trial, we aimed to establish the benefits of early treatment on the basis of increased CA125 concentrations compared with delayed treatment on the basis of clinical recurrence. METHODS: Women with ovarian cancer in complete remission after first-line platinum-based chemotherapy and a normal CA125 concentration were registered for this randomised controlled trial. Clinical examination and CA125 measurement were done every 3 months. Patients and investigators were masked to CA125 results, which were monitored by coordinating centres. If CA125 concentration exceeded twice the upper limit of normal, patients were randomly assigned (1:1) by minimisation to early or delayed chemotherapy. Patients and clinical sites were informed of allocation to early treatment, and treatment was started as soon as possible within 28 days of the increased CA125 measurement. Patients assigned to delayed treatment continued masked CA125 measurements, with treatment commencing at clinical or symptomatic relapse. All patients were treated according to standard local practice. The primary outcome was overall survival. Analysis was by intention to treat. This study is registered, ISRCTN87786644. FINDINGS: 1442 patients were registered for the trial, of whom 529 were randomly assigned to treatment groups and were included in our analysis (265 early, 264 delayed). With a median follow-up of 56·9 months (IQR 37·4-81·8) from randomisation and 370 deaths (186 early, 184 delayed), there was no evidence of a difference in overall survival between early and delayed treatment (HR 0·98, 95% CI 0·80-1·20, p=0·85). Median survival from randomisation was 25·7 months (95% CI 23·0-27·9) for patients on early treatment and 27·1 months (22·8-30·9) for those on delayed treatment. INTERPRETATION: Our findings showed no evidence of a survival benefit with early treatment of relapse on the basis of a raised CA125 concentration alone, and therefore the value of routine measurement of CA125 in the follow-up of patients with ovarian cancer who attain a complete response after first-line treatment is not proven. FUNDING: UK Medical Research Council and the European Organisation for Research and Treatment of Cancer.

Inhibition of carboplatin-induced DNA interstrand cross-link repair by gemcitabine in patients receiving these drugs for platinum-resistant ovarian cancer.

BACKGROUND: The potential of gemcitabine to interact with carboplatin was explored in a phase II trial in platinum-resistant ovarian cancer. Peripheral blood lymphocytes were sampled after drug administration to measure DNA interstrand cross-link formation and repair. PATIENTS AND METHODS: Forty patients received carboplatin target area under concentration-time curve (AUC 4) followed by gemcitabine 1,000 mg/m(2) with a second dose of gemcitabine on day 8. Peripheral blood lymphocytes were obtained in 12 patients before and at intervals during the first cycle of chemotherapy. DNA cross-link formation and repair (unhooking) were measured by the single-cell gel electrophoresis (comet) assay following ex vivo incubation. RESULTS: The global response rate was 47% (Response Evaluation Criteria in Solid Tumors rate, 29%; CA125 rate, 63%). Delays in treatment were seen in 24% of cycles largely due to myelosuppression; 15% of day 8 administration was omitted. Peak carboplatin-induced DNA cross-linking was seen by 24 hours. Significant reduction was seen in the repair of in vivo carboplatin-induced DNA cross-links following administration of gemcitabine. CONCLUSION: An enhanced activity of carboplatin in platinum-resistant ovarian cancer may be due to synergy with gemcitabine through inhibition of repair of DNA cross-links. Future studies should explore coadministration of these drugs, as this may be a more effective schedule.

How to follow-up patients with epithelial ovarian cancer.

PURPOSE OF REVIEW: Despite optimal primary treatment most patients with advanced epithelial ovarian cancer will relapse. This review discusses the controversy regarding surveillance and the timing of treatment for recurrent disease. RECENT FINDINGS: Routine physical examination has a limited role in the detection of recurrent ovarian cancer. PET/computed tomography (CT) has been shown to be useful in detecting small volume disease not apparent on traditional imaging in patients with suspected recurrence based on symptoms and/or rising CA125. The results of PET/CT can alter treatment plans and have particular use in guiding site-directed therapy. The benefits of early detection and systemic treatment of recurrence are now in doubt following the presentation of the MRC/EORTC CA125 surveillance trial. The impact on survival of secondary cytoreductive surgery requires more investigation. SUMMARY: Uncertainties remain in the surveillance and timing of treatment for relapsed disease. Patients should be informed of these uncertainties and become involved in decisions regarding their follow-up.