Wendi Qian

A phase 3 trial of bevacizumab in ovarian cancer.

BACKGROUND Angiogenesis plays a role in the biology of ovarian cancer. We examined the effect of bevacizumab, the vascular endothelial growth factor inhibitor, on survival in women with this disease. METHODS We randomly assigned women with ovarian cancer to carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body-surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease. Outcome measures included progression-free survival, first analyzed per protocol and then updated, and interim overall survival. RESULTS A total of 1528 women from 11 countries were randomly assigned to one of the two treatment regimens. Their median age was 57 years; 90% had epithelial ovarian cancer, 69% had a serous histologic type, 9% had high-risk early-stage disease, 30% were at high risk for progression, and 70% had stage IIIC or IV ovarian cancer. Progression-free survival (restricted mean) at 36 months was 20.3 months with standard therapy, as compared with 21.8 months with standard therapy plus bevacizumab (hazard ratio for progression or death with bevacizumab added, 0.81; 95% confidence interval, 0.70 to 0.94; P=0.004 by the log-rank test). Nonproportional hazards were detected (i.e., the treatment effect was not consistent over time on the hazard function scale) (P<0.001), with a maximum effect at 12 months, coinciding with the end of planned bevacizumab treatment and diminishing by 24 months. Bevacizumab was associated with more toxic effects (most often hypertension of grade 2 or higher) (18%, vs. 2% with chemotherapy alone). In the updated analyses, progression-free survival (restricted mean) at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab (P=0.04 by log-rank test); in patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression-free survival (restricted mean) at 42 months of 14.5 months with standard therapy alone and 18.1 months with bevacizumab added, with respective median overall survival of 28.8 and 36.6 months. CONCLUSIONS Bevacizumab improved progression-free survival in women with ovarian cancer. The benefits with respect to both progression-free and overall survival were greater among those at high risk for disease progression. (Funded by Roche and others; ICON7 Controlled-Trials.com number, ISRCTN91273375.).

High-Dose Therapy Improves Progression-Free Survival and Survival in Relapsed Follicular Non-Hodgkin's Lymphoma: Results From the Randomized European CUP Trial

PURPOSE To determine, in a randomized clinical trial, whether high-dose therapy (HDT) followed by autologous stem-cell transplantation is more effective than standard treatment with regard to progression-free survival (PFS) and overall survival (OS) in patients with relapsed follicular non-Hodgkins lymphoma; and to assess the additional value of B-cell purging of the stem-cell graft with regards to PFS and OS. PATIENTS AND METHODS Patients received three cycles of chemotherapy. Responding patients with limited bone marrow infiltration were eligible for random assignment to three further cycles of chemotherapy (C), unpurged HDT (U), or purged HDT (P). RESULTS Between August 1993 and April 1997, 140 patients were registered from 36 centers internationally, and 89 were randomly assigned. Reasons for not randomizing included patient refusal, early progression, or death on induction therapy. With a 69-month median follow-up, the log-rank P value for PFS and OS were.0037 and.079, respectively. For PFS, the hazard ratios (95% CIs) for U versus C, P versus C, and P versus U were 0.33 (0.16 to 0.70), 0.38 (0.19 to 0.79), and 1.02 (0.51 to 2.05), respectively. The hazard ratio (95% CI) for C versus U + P was 0.30 (0.15 to 0.61). Hazard ratios (95% CIs) for OS were 0.43 (0.18 to 1.06), 0.43 (0.18 to 1.02), and 0.72 (0.32 to 1.63). For C versus U + P, the hazard ratio (95% CI) was 0.40 (0.18 to 0.89). Kaplan-Meier estimates (95% CIs) of 2-year PFS for C, U, and P were 26% (8% to 44%), 58% (37% to 79%), and 55% (34% to 75%), respectively. OS at 4 years for C, U, and P are 46% (25% to 67%), 71% (52% to 91%), and 77% (60% to 95%) respectively. CONCLUSION HDT significantly improves PFS and OS. There is no clear evidence of benefit through purging.

Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial

BACKGROUND Previously, we have shown that the combination of cyclophosphamide, doxorubicin, and cisplatin (CAP) and single-agent carboplatin produce similar survival and progression-free survival rates in women with ovarian cancer. Subsequently, paclitaxel combined with platinum has become a widely accepted treatment for the disease. We aimed to compare the safety and efficacy of paclitaxel plus carboplatin with a control of either CAP or carboplatin alone. METHODS Between February, 1995, and October, 1998, we enrolled 2074 patients from 130 centres in eight countries. Women were randomly assigned paclitaxel plus carboplatin or control, the control (CAP or single-agent carboplatin) being chosen by the patient and clinician before randomisation. The primary outcome measure was overall survival. Secondary outcomes were progression-free survival and toxicity. Analysis was by intention to treat. FINDINGS With a median follow-up of 51 months, 1265 patients had died, and survival curves showed no evidence of a difference in overall survival between paclitaxel plus carboplatin and control (hazard ratio 0.98, 95% CI 0.87-1.10, p=0.74). The median overall survival was 36.1 months on paclitaxel plus carboplatin and 35.4 months on control (difference 0.7 months, 95% CI -3.6 to 4.7). 1538 patients had progressive disease or died, and again, Kaplan-Meier curves showed no evidence of a difference between the groups (hazard ratio 0.93, 95% CI 0.84-1.03, p=0.16). Median progression-free survival was 17.3 months on paclitaxel plus carboplatin and 16.1 months on control (difference 1.2 months, 95% CI -0.5 to 2.8). Paclitaxel plus carboplatin caused more alopecia, fever, and sensory neuropathy than carboplatin alone, and more sensory neuropathy than CAP. CAP was associated with more fever than paclitaxel plus carboplatin. INTERPRETATION Single-agent carboplatin and CAP are as effective as paclitaxel plus carboplatin as first-line treatment for women requiring chemotherapy for ovarian cancer. The favourable toxicity profile of single-agent carboplatin suggests that this drug is a reasonable option as first-line chemo therapy for ovarian cancer.Background Previously, we have shown that the combination of cyclophosphamide, doxorubicin, and cisplatin (CAP) and single-agent carboplatin produce similar survival and progression-free survival rates in women with ovarian cancer. Subsequently, paclitaxel combined with platinum has become a widely accepted treatment for the disease. We aimed to compare the safety and efficacy of paclitaxel plus carboplatin with a control of either CAP or carboplatin alone. Methods Between February, 1995, and October, 1998, we enrolled 2074 patients from 130 centres in eight countries. Women were randomly assigned paclitaxel plus carboplatin or control, the control (CAP or single-agent carboplatin) being chosen by the patient and clinician before randomisation. The primary outcome measure was overall survival. Secondary outcomes were progression-free survival and toxicity. Analysis was by intention to treat. Findings With a median follow-up of 51 months, 1265 patients had died, and survival curves showed no evidence of a difference in overall survival between paclitaxel plus carboplatin and control (hazard ratio 0.98, 95% Cl 0.87-1.10, p=0.74). The median overall survival was 36.1 months on paclitaxel plus carboplatin and 35.4 months on control (difference 0.7 months, 95% Cl -3.6 to 4.7). 1538 patients had progressive disease or died, and again, Kaplan-Meier curves showed no evidence of a difference between the groups (hazard ratio 0.93, 95% Cl 0.84-1.03, p=0.16). Median progression-free survival was 17.3 months on paclitaxel plus carboplatin and 16.1 months on control (difference 1.2 months, 95% Cl -0.5 to 2.8). Paclitaxel plus carboplatin caused more alopecia, fever, and sensory neuropathy than carboplatin alone, and more sensory neuropathy than CAP. CAP was associated with more fever than paclitaxel plus carboplatin. Interpretation Single-agent carboplatin and CAP are as effective as paclitaxel plus carboplatin as first-line treatment for women requiring chemotherapy for ovarian cancer. The favourable toxicity profile of single-agent carboplatin suggests that this drug is a reasonable option as first-line chemotherapy for ovarian cancer.

Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis

Summary Background Early endometrial cancer with low-risk pathological features can be successfully treated by surgery alone. External beam radiotherapy added to surgery has been investigated in several small trials, which have mainly included women at intermediate risk of recurrence. In these trials, postoperative radiotherapy has been shown to reduce the risk of isolated local recurrence but there is no evidence that it improves recurrence-free or overall survival. We report the findings from the ASTEC and EN.5 trials, which investigated adjuvant external beam radiotherapy in women with early-stage disease and pathological features suggestive of intermediate or high risk of recurrence and death from endometrial cancer. Methods Between July, 1996, and March, 2005, 905 (789 ASTEC, 116 EN.5) women with intermediate-risk or high-risk early-stage disease from 112 centres in seven countries (UK, Canada, Poland, Norway, New Zealand, Australia, USA) were randomly assigned after surgery to observation (453) or to external beam radiotherapy (452). A target dose of 40–46 Gy in 20–25 daily fractions to the pelvis, treating five times a week, was specified. Primary outcome measure was overall survival, and all analyses were by intention to treat. These trials were registered ISRCTN 16571884 (ASTEC) and NCT 00002807 (EN.5). Findings After a median follow-up of 58 months, 135 women (68 observation, 67 external beam radiotherapy) had died. There was no evidence that overall survival with external beam radiotherapy was better than observation, hazard ratio 1·05 (95% CI 0·75–1·48; p=0·77). 5-year overall survival was 84% in both groups. Combining data from ASTEC and EN.5 in a meta-analysis of trials confirmed that there was no benefit in terms of overall survival (hazard ratio 1·04; 95% CI 0·84–1·29) and can reliably exclude an absolute benefit of external beam radiotherapy at 5 years of more than 3%. With brachytherapy used in 53% of women in ASTEC/EN.5, the local recurrence rate in the observation group at 5 years was 6·1%. Interpretation Adjuvant external beam radiotherapy cannot be recommended as part of routine treatment for women with intermediate-risk or high-risk early-stage endometrial cancer with the aim of improving survival. The absolute benefit of external beam radiotherapy in preventing isolated local recurrence is small and is not without toxicity. Funding Medical Research Council, National Cancer Research Network, National Cancer Institute of Canada, with funds from the Canadian Cancer Society.

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.

Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles

BACKGROUND Dose intensification with a combination of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) every 2 weeks improves outcomes in patients older than 60 years with diffuse large B-cell lymphoma compared with CHOP every 3 weeks. We investigated whether this survival benefit from dose intensification persists in the presence of rituximab (R-CHOP) in all age groups. METHODS Patients (aged ≥18 years) with previously untreated bulky stage IA to stage IV diffuse large B-cell lymphoma in 119 centres in the UK were randomly assigned centrally in a one-to-one ratio, using minimisation, to receive six cycles of R-CHOP every 14 days plus two cycles of rituximab (R-CHOP-14) or eight cycles of R-CHOP every 21 days (R-CHOP-21). R-CHOP-21 was intravenous cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), vincristine 1·4 mg/m(2) (maximum dose 2 mg), and rituximab 375 mg/m(2) on day 1, and oral prednisolone 40 mg/m(2) on days 1-5, administered every 21 days for a total of eight cycles. R-CHOP-14 was intravenous cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), vincristine 2 mg, rituximab 375 mg/m(2) on day 1, and oral prednisolone 100 mg on days 1-5, administered every 14 days for six cycles, followed by two further infusions of rituximab 375 mg/m(2) on day 1 every 14 days. The trial was not masked. The primary outcome was overall survival (OS). This study is registered, number ISRCTN 16017947. FINDINGS 1080 patients were assigned to R-CHOP-21 (n=540) and R-CHOP-14 (n=540). With a median follow-up of 46 months (IQR 35-57), 2-year OS was 82·7% (79·5-85·9) in the R-CHOP-14 group and 80·8% (77·5-84·2) in the R-CHOP-21 (standard) group (hazard ratio 0·90, 95% CI 0·70-1·15; p=0·3763). No significant improvement was noted in 2-year progression-free survival (R-CHOP-14 75·4%, 71·8-79·1, and R-CHOP-21 74·8%, 71·0-78·4; 0·94, 0·76-1·17; p=0·5907). High international prognostic index, poor-prognosis molecular characteristics, and cell of origin were not predictive for benefit from either schedule. Grade 3 or 4 neutropenia was higher in the R-CHOP-21 group (318 [60%] of 534 vs 167 [31%] of 534), with no prophylactic use of recombinant human granulocyte-colony stimulating factor mandated in this group, whereas grade 3 or 4 thrombocytopenia was higher with R-CHOP-14 (50 [9%] vs 28 [5%]); other frequent grade 3 or 4 adverse events were febrile neutropenia (58 [11%] vs 28 [5%]) and infection (125 [23%] vs 96 [18%]). Frequencies of non-haematological adverse events were similar in the R-CHOP-21 and R-CHOP-14 groups. INTERPRETATION R-CHOP-14 is not superior to R-CHOP-21 chemotherapy for previously untreated diffuse large B-cell lymphoma; therefore, R-CHOP-21 remains the standard first-line treatment in patients with this haematological malignancy. No molecular or clinical subgroup benefited from dose intensification in this study. FUNDING Chugai Pharmaceutical, Cancer Research UK, National Institute for Health Research Biomedical Research Centres scheme at both University College London and the Royal Marsden NHS Foundation Trust, and Institute of Cancer Research.

Concordance between four European centres of PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma

PurposeTo determine if PET reporting criteria for the Response Adapted Treatment in Hodgkin Lymphoma (RATHL) trial could enable satisfactory agreement to be reached between ‘core’ laboratories operating in different countries.MethodsFour centres reported scans from 50 patients with stage II–IV HL, acquired before and after two cycles of Adriamycin/bleomycin/vinblastine/dacarbazine. A five-point scale was used to score response scans using ‘normal’ mediastinum and liver as reference levels. Centres read scans independently of each other. The level of agreement between centres was determined assuming (1) that uptake in sites involved at diagnosis that was higher than liver uptake represented disease (conservative reading), and (2) that uptake in sites involved at diagnosis that was higher than mediastinal uptake represented disease (sensitive reading).ResultsThere was agreement that the response scan was ‘positive’ or ‘negative’ for lymphoma in 44 patients with a conservative reading and in 41 patients with a sensitive reading. Kappa was 0.85 (95% CI 0.74–0.96) for conservative reading and 0.79 (95% CI 0.67–0.90) for sensitive reading. Agreement was reached in 46 and 44 patients after discussion for the conservative and sensitive readings, respectively.ConclusionThe criteria developed for reporting in the RATHL trial are sufficiently robust to be used in a multicentre setting.

Improving Survival Without Reducing Quality of Life in Small-Cell Lung Cancer Patients by Increasing the Dose-Intensity of Chemotherapy With Granulocyte Colony-Stimulating Factor Support: Results of a British Medical Research Council Multicenter Randomized Trial

PURPOSE The treatment of small-cell lung cancer patients with good performance status aims to improve survival. Dose-intensification could be a way to achieve improved survival but can be limited by neutropenia and thrombocytopenia. Preliminary, nonrandomized feasibility studies showed that doxorubicin, cyclophosphamide, and etoposide (ACE) could be given every 2 (instead of the usual 3) weeks with granulocyte colony-stimulating factor (G-CSF) (lenograstim; Chugai-Rh¿one-Poulenc, Tokyo, Japan) support. The present multicenter randomized trial was designed to examine whether such dose-intensification improves survival while maintaining acceptable toxicity levels. PATIENTS AND METHODS All patients were randomized to receive six cycles of ACE either every 3 weeks (control [C] group) or every 2 weeks with G-CSF (G group). The standard dose-intensity of ACE was increased by 50% in group G. RESULTS Four hundred and three patients (G group: n = 201; C group: n = 202) were randomized. The received dose-intensity was 34% higher in the G group than in the C group. Complete response rates were 40% for the G group and 28% for the C group (P =.02), and overall rates were 78% for the G group and 79% for the C group. Survival was longer in the G group (hazard ratio = 0.80; 95% confidence interval, 0.65 to 0.99; P =.04), survival rates for the G and C groups being 47% and 39% at 12 months and 13% and 8% at 24 months, respectively. Metastasis-free survival, nonhematologic toxicity, and quality of life were similar in the two groups. In the G group, there was less neutropenia but more thrombocytopenia and more frequent blood and platelet transfusions. CONCLUSION Increasing the dose-intensity of ACE with G-CSF support improved survival while maintaining acceptable toxicity.

Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: A randomised phase III trial

PURPOSE This multicentre, prospective, randomised-controlled trial compared efficacy and toxicity of differing radiotherapy doses in non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS Patients with any histological subtype of NHL, requiring radiotherapy for local disease control, whether radical, consolidative or palliative, were included. Three hundred and sixty one sites of indolent NHL (predominantly follicular NHL and marginal zone lymphoma) were randomised to receive 40-45Gy in 20-23 fractions or 24Gy in 12 fractions. Six hundred and forty sites of aggressive NHL (predominantly diffuse large B cell lymphoma as part of combined-modality therapy) were randomised to receive 40-45Gy in 20-23 fractions or 30Gy in 15 fractions. Patients with all stages of disease, having first-line and subsequent therapies were included; first presentations of early-stage disease predominated. RESULTS There was no difference in overall response rate (ORR) between standard and lower-dose arms. In the indolent group, ORR was 93% and 92%, respectively, (p=0.72); in the aggressive group, ORR was 91% in both arms (p=0.87). With a median follow-up of 5.6years, there was no significant difference detected in the rate of within-radiation field progression (HR=1.09, 95%CI=0.76-1.56, p=0.64 in the indolent group; HR=0.98, 95%CI=0.68-1.4, p=0.89 in the aggressive group). There was also no significant difference detected in the progression free or overall survival. There was a trend for reduced toxicities in the low-dose arms; only the reduction in reported erythema reached significance. CONCLUSION In a large, randomised trial, there was no loss of efficacy associated with radiotherapy doses of 24Gy in indolent NHL and 30Gy in aggressive NHL, compared with previous standard doses of 40-45Gy.

Rituximab versus a watch-and-wait approach in patients with advanced- stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial

BACKGROUND Patients with advanced-stage, low-tumour-burden follicular lymphoma have conventionally undergone watchful waiting until disease progression. We assessed whether rituximab use could delay the need for chemotherapy or radiotherapy compared with watchful waiting and the effect of this strategy on quality of life (QoL). METHODS Asymptomatic patients (aged ≥18 years) with low-tumour-burden follicular lymphoma (grades 1, 2, and 3a) were randomly assigned centrally (1:1:1), by the minimisation approach stratified by institution, grade, stage, and age, to watchful waiting, rituximab 375 mg/m(2) weekly for 4 weeks (rituximab induction), or rituximab induction followed by a maintenance schedule of 12 further infusions given at 2-monthly intervals for 2 years (maintenance rituximab). On Sept 30, 2007, recruitment into the rituximab induction group was closed and the study was amended to a two-arm study. The primary endpoints were time to start of new treatment and QoL at month 7 (ie, 6 months after completion of rituximab induction). All randomly assigned patients were included in the analysis of time to start of new treatment on an intention-to-treat basis. The main study is now completed and is in long-term follow-up. The study is registered with ClinicalTrials.gov, NCT00112931. FINDINGS Between Oct 15, 2004, and March 25, 2009, 379 patients from 118 centres in the UK, Australia, New Zealand, Turkey, and Poland were randomly assigned to watchful waiting or maintenance rituximab. 84 patients were recruited to the rituximab induction group before it was closed early. There was a significant difference in the time to start of new treatment, with 46% (95% CI 39-53) of patients in the watchful waiting group not needing treatment at 3 years compared with 88% (83-92) in the maintenance rituximab group (hazard ratio [HR] 0·21, 95% CI 0·14-0·31; p<0·0001). 78% (95% CI 69-87) of patients in the rituximab induction group did not need treatment at 3 years, which was significantly more than in the watchful waiting group (HR 0·35, 95% CI 0·22-0·56; p<0·0001), but no different compared with the maintenance rituximab group (0·75, 0·41-1·34; p=0·33). Compared with the watchful waiting group, patients in the maintenance rituximab group had significant improvements in the Mental Adjustment to Cancer scale score (p=0·0004), and Illness Coping Style score (p=0·0012) between baseline and month 7. Patients in the rituximab induction group did not show improvements in their QoL compared with the watchful waiting group. There were 18 serious adverse events reported in the rituximab groups (four in the rituximab induction group and 14 in the maintenance rituximab group), 12 of which were grade 3 or 4 (five infections, three allergic reactions, and four cases of neutropenia), all of which fully resolved. INTERPRETATION Rituximab monotherapy should be considered as a treatment option for patients with asymptomatic, advanced-stage, low-tumour-burden follicular lymphoma. FUNDING Cancer Research UK, Lymphoma Research Trust, Lymphoma Association, and Roche.