Use of strategies to improve retention in primary care randomised trials: a qualitative study with in-depth interviews.

OBJECTIVE: To explore the strategies used to improve retention in primary care randomised trials. DESIGN: Qualitative in-depth interviews and thematic analysis. PARTICIPANTS: 29 UK primary care chief and principal investigators, trial managers and research nurses. METHODS: In-depth face-to-face interviews. RESULTS: Primary care researchers use incentive and communication strategies to improve retention in trials, but were unsure of their effect. Small monetary incentives were used to increase response to postal questionnaires. Non-monetary incentives were used although there was scepticism about the impact of these on retention. Nurses routinely used telephone communication to encourage participants to return for trial follow-up. Trial managers used first class post, shorter questionnaires and improved questionnaire designs with the aim of improving questionnaire response. Interviewees thought an open trial design could lead to biased results and were negative about using behavioural strategies to improve retention. There was consensus among the interviewees that effective communication and rapport with participants, participant altruism, respect for participant's time, flexibility of trial personnel and appointment schedules and trial information improve retention. Interviewees noted particular challenges with retention in mental health trials and those involving teenagers. CONCLUSIONS: The findings of this qualitative study have allowed us to reflect on research practice around retention and highlight a gap between such practice and current evidence. Interviewees describe acting from experience without evidence from the literature, which supports the use of small monetary incentives to improve the questionnaire response. No such evidence exists for non-monetary incentives or first class post, use of which may need reconsideration. An exploration of barriers and facilitators to retention in other research contexts may be justified.

Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials.

BACKGROUND: REAL3 (Randomised ECF for Advanced or Locally advanced oesophagogastric cancer 3) was a phase II/III trial designed to evaluate the addition of panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in untreated advanced oesophagogastric adenocarcinoma, or undifferentiated carcinoma. MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) was a phase III study which demonstrated that peri-operative epirubicin, cisplatin and infused 5-fluorouracil (ECF) improved survival in early oesophagogastric adenocarcinoma. PATIENTS AND METHODS: Analysis of response rate (RR; the primary end-point of phase II) and biomarkers in the first 200 patients randomised to EOC or modified dose (m) EOC+P in REAL3 was pre-planned to determine if molecular selection for the on-going study was indicated. KRAS, BRAF and PIK3CA mutations and PTEN expression were assessed in pre-treatment biopsies and results correlated with response to mEOC+P. Association between these biomarkers and overall survival (OS) was assessed in MAGIC patients to determine any prognostic effect. RESULTS: RR was 52% to mEOC+P, 48% to EOC. Results from 175 assessable biopsies: mutations in KRAS (5.7%), BRAF (0%), PIK3CA (2.5%) and loss of PTEN expression (15.0%). None of the biomarkers evaluated predicted resistance to mEOC+P. In MAGIC, mutations in KRAS, BRAF and PIK3CA and loss of PTEN (phosphatase and tensin homolog) were found in 6.3%, 1.0%, 5.0% and 10.9%, respectively, and were not associated with survival. CONCLUSIONS: The RR of 52% in REAL3 with mEOC+P met pre-defined criteria to continue accrual to phase III. The frequency of the mutations was too low to exclude any prognostic or predictive effect.

Bevacizumab with peri-operative epirubicin, cisplatin and capecitabine (ECX) in localised gastro-oesophageal adenocarcinoma: a safety report.

BACKGROUND: Peri-operative chemotherapy and surgery is a standard treatment of localised oesophagogastric adenocarcinoma; however, the outcomes remain poor. PATIENTS AND METHODS: ST03 is a multicentre, randomised, phase II/III study comparing peri-operative ECX with or without bevacizumab (ECX-B). The primary outcome measure of phase II (n = 200) was safety, specifically gastrointestinal (GI) perforation rates and cardiotoxicity. RESULTS: Two hundred patients were randomised between October 2007 and April 2010. Ninety-one/101 (90%) ECX and 86/99 (87%) ECX-B patients completed pre-operative chemotherapy; 7 ECX and 9 ECX-B patients stopped due to toxicity. Gastrointestinal perforations (3 ECX, 1 ECX-B), cardiac events (1 ECX, 4 ECX-B) and venous thromboembolic events (VTEs, 8 ECX, 7 ECX-B) were uncommon. Arterial thromboembolic events (ATEs, myocardial infarction (MI) or cerebrovascular accident) were more frequent with ECX-B (5 versus 1 with ECX). Delayed wound healing, anastomotic leaks and GI bleeding rates were similar. More asymptomatic left ventricular ejection fraction (LVEF) falls (≥15% and/or to <50%) occurred with ECX-B (21.2% versus 11.1% with ECX). Clinically significant falls (≥10% to below lower limit of normal, LLN) occurred in (15.3%) and (8.9%) respectively, with no associated cardiac failure (median 22 months follow-up). CONCLUSIONS: Addition of bevacizumab to peri-operative ECX chemotherapy is feasible with acceptable toxicity and no negative impact on surgical outcomes.

Initial dose intensity has limited impact on the outcome of ABVD chemotherapy for advanced Hodgkin lymphoma (HL): data from UKLG LY09 (ISRCTN97144519).

BACKGROUND: This analysis was undertaken to assess the relationship between the dose intensity (DI) of initial chemotherapy and outcome in a large cohort of patients with advanced Hodgkin lymphoma treated in a randomised controlled trial, in which detailed dose data were collected prospectively. PATIENTS AND METHODS: Three-hundred and eighty patients randomly assigned to receive standard doxorubicin, bleomycin, vinblastine and dacarbazine who underwent at least two cycles of treatment were studied. With a median follow-up of 6.9 years, progression-free survival (PFS) from the end of cycle 2 was analysed according to DI during those cycles. RESULTS: During the first two cycles, 25% of patients received >97% of planned DI, 37% received between 86% and 97% and 38% received <86%. DI during the first two cycles was correlated with DI during the remainder of the course, but there was no evidence that early DI influenced PFS (hazard ratio 0.87, 95% confidence interval 0.67-1.11; P = 0.265). Multivariate analysis also failed to confirm the influence of early DI on PFS or overall survival. CONCLUSIONS: At the range of DI delivered in a multicentre trial using conventional therapy, there is no clear evidence that early DI influences outcome. This should be tested in a prospective study.

Mathematical modelling of survival of glioblastoma patients suggests a role for radiotherapy dose escalation and predicts poorer outcome after delay to start treatment.

AIMS: The outcome of patients with glioblastoma (GBM) remains extremely poor. We have developed a mathematical model, using pathological and radiation biology concepts, to assess the detrimental effect of delay to start radiotherapy, the possible benefit from dose escalation, and to extract biological data from clinical data. MATERIALS AND METHODS: Survival data were available for 154 adult patients with GBM treated in our centre with curative intent to a dose of 60 Gy in 30 fractions between 1996 and 2002. Survival data for 129 patients from the 60 Gy arm of the MRC BR02 randomised trial of radiotherapy dose were obtained for comparison. The model generates the equivalent of individual patients with a brain tumour, and produces an explicit outcome, either death or survival. The tumour, assumed to be growing exponentially, causes normal cell damage in the brain, and death occurs when the number of normal brain cells falls below a critical level. The outcome for an individual patient is determined by values of the variables assigned by the model. Parameters for the single patient include tumour doubling time, surviving fraction of tumour cells after each fraction of radiotherapy, and a waiting time from presentation to the start of radiotherapy. A surrogate for performance status is implemented, using a rule that rejects patients whose tumours are too advanced at presentation to be suitable for radical radiotherapy. Values for the parameters that determine individual patient outcome are randomly assigned from a set of probability distributions, using Monte Carlo simulation. The simulation constructs survival results for a population, typically 2000 individuals. The descriptors of the probability distributions that are used to determine the parameters that define the patient characteristics are adjusted to optimise the fit of the modelled population to real clinical data, using a combination of folding polygon and simulated annealing techniques. RESULTS: The model fits the clinical data well. The results suggest that the surviving fraction of tumour cells after a radiation dose of 2 Gy (SF2) does influence patient outcome. The mean in vivo SF2 for the Addenbrooke's data is 0.80, implying that hypoxia is a serious problem in radiotherapy for GBM. The Addenbrooke's data suggest a mean tumour doubling time of 24 days, so that a delay to start radiotherapy would be expected to have an adverse effect. Considering patients by treatment intent, median survival plummets as delay increases, and almost no patients survive long term after a 70-day delay. Radiotherapy dose escalation has an important predicted effect on survival. Assuming that the treatment could be delivered safely, a dose of 74 Gy, given at 2 Gy/fraction, would extend the survival of all patients. The proportion of long-term survivors would increase, from 2.4% with 60 Gy, to 6.4% with 74 Gy. The model can be used to derive gamma50, which has a value of 0.42, lower than the typical value of 1-2. CONCLUSION: Using the model, we have extracted biological information from clinical data. The model could be used to assess the potential benefit, or lack of benefit, from a proposed radiotherapy trial, and to estimate the necessary size. It shows that a single modality is unlikely to achieve a major improvement in long-term survival, although radiotherapy dose escalation should have a role, provided it can be given safely. The model could be extended to include chemotherapy, bio-reductive drugs, or gene therapy.

Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial.

BACKGROUND: Adjuvant radiotherapy is effective treatment for stage I seminoma, but is associated with a risk of late non-germ-cell cancer and cardiovascular events. After good results in initial studies with one injection of carboplatin, we undertook a large randomised trial to compare the approaches of radiotherapy with chemotherapy in seminoma treatment. METHODS: Between 1996 and 2001, 1477 patients from 70 hospitals in 14 countries were randomly assigned to receive radiotherapy (para-aortic strip or dog-leg field; n=904) or one injection of carboplatin (n=573; dose based on the formula 7x[glomerular filtration rate+25] mg), at two trial centres in the UK and Belgium. The primary outcome measure was the relapse-free rate, with the trial powered to exclude absolute differences in 2-year rates of more than 3%. Analysis was by intention to treat and per protocol. This trial has been assigned the International Standard Randomised Controlled Trial Number ISRCTN27163214. FINDINGS: 885 and 560 patients received radiotherapy and carboplatin, respectively. With a median follow-up of 4 years (IQR 3.0-4.9), relapse-free survival rates for radiotherapy and carboplatin were similar (96.7% [95% CI 95.3-97.7] vs 97.7% [96.0-98.6] at 2 years; 95.9% [94.4-97.1] vs 94.8% [92.5-96.4] at 3 years, respectively; hazard ratio 1.28 [90% CI 0.85-1.93], p=0.32). At 2 years' follow-up, the absolute differences in relapse-free rates (radiotherapy-chemotherapy) were -1.0% (90% CI -2.5 to 0.5) by direct comparison of proportions, and 0.9% (-0.5 to 3.0) by a hazard-ratio-based approach. Patients given carboplatin were less lethargic and less likely to take time off work than those given radiotherapy. New, second primary testicular germ-cell tumours were reported in ten patients allocated irradiation (all after para-aortic strip field) and two allocated carboplatin (5-year event rate 1.96% [95% CI 1.0-3.8] vs 0.54% [0.1-2.1], p=0.04). One seminoma-related death occurred after radiotherapy and none after carboplatin. INTERPRETATION: This trial has shown the non-inferiority of carboplatin to radiotherapy in the treatment of stage I seminoma. Although the absence of disease-related deaths and preliminary data indicating fewer second primary testicular germ-cell tumours favour carboplatin use, these findings need to be confirmed beyond 4 years' follow-up.

A phase II trial of TIP (paclitaxel, ifosfamide and cisplatin) given as second-line (post-BEP) salvage chemotherapy for patients with metastatic germ cell cancer: a medical research council trial.

This phase II trial describes the use of TIP chemotherapy (paclitaxel, ifosfamide and cisplatin) as salvage for patients with metastatic germ cell cancer (GCC) who have failed initial BEP (bleomycin, etoposide and cisplatin) chemotherapy. Patients with first relapse following BEP for metastatic GCC, confirmed by biopsy or sequentially rising markers, received four courses of TIP (paclitaxel 175 mg m(-2) day 1, followed on days 1-5 by ifosfamide 1 g m(-2) intravenously (i.v.) and cisplatin 20 mg2 i.v.) at 3-weekly intervals. The primary outcome measure was response to TIP. In all, 51 patients were registered, of whom 43 were eligible for response assessment. Eight achieved complete remission (CR) and 18 a partial remission with negative markers (PR(-ve)); favourable response rate (FRR = CR + PR(-ve)) 60%, 95% CI (44-75%); survival at 1 year was 70% (56-84%) and failure-free survival 36% (22-50%). In the group of 26 patients meeting the 'good-risk' criteria described by the Memorial Hospital, the FRR was 73% (52-88%) compared with 41% (18-67%) for the 17 'poor-risk' patients. These results are inferior to those previously reported for TIP in a single-centre study when it was given more intensively, at higher dose and with growth factor support. Nonetheless, TIP as described here can cure a substantial proportion of patients.

Adjuvant bleomycin, vincristine and cisplatin (BOP) for high-risk stage I non-seminomatous germ cell tumours: a prospective trial (MRC TE17).

Adjuvant BEP (bleomycin, etoposide, cisplatin) is effective treatment for high-risk clinical stage I (HRCS1) non-seminomatous germ cell tumours (NSGCT), but the known toxicities of etoposide, and the expansion of the HR group to any patient with vascular invasion (50% of patients), led the Medical Research Council to pilot the BOP regimen. Patients received two courses of BOP 14 days apart: cisplatin 50 mg m(-2) days 1 and 2, vincristine 1.4 mg m(-2) (max. 2 mg) days 2 and 8, bleomycin 30,000 IU days 2 and 8. Primary outcome was relapse rate; quality of life, fertility, hearing and lung function were assessed pre- and post-treatment. In all, 100 patients were required. A total of 115 eligible patients were registered, all received two courses of chemotherapy. Median follow-up is 70 months; two relapses have occurred and the 5-year relapse-free rate is 98.3% (95% confidence interval (CI) 95.5%, 99.9%). As assessed by clinicians during treatment, complete (reversible) alopecia was present in 20% of patients; World Health Organization (WHO) grade 1/2 neurotoxicity was present in 41%/5% of patients during treatment and 22%/1% at 6 months. However, 12% of patients reported 'quite a bit' or 'very much' pain/numbness/tingling in hands/feet 2 years after chemotherapy. Mature follow-up confirms high efficacy for two courses of cisplatin-based adjuvant chemotherapy in HRCS1 NSGCT. Substituting vincristine for etoposide decreases alopecia, but gives a low incidence of significant neuropathy. There are no clearcut advantages to 2 x BOP over 2 x BEP, except for patients who wish to maximise the chance of avoiding significant alopecia.

Identifying subgroups among poor prognosis patients with nonseminomatous germ cell cancer by tree modelling: a validation study.

BACKGROUND: In order to target intensive treatment strategies for poor prognosis patients with non-seminomatous germ cell cancer, those with the poorest prognosis should be identified. These patients might profit most from more intensive treatment strategies. For this purpose, a regression tree was previously developed on 332 patients. We aimed to evaluate the performance and structure of this tree. PATIENTS AND METHODS: The previously developed tree was applied to 456 patients with a poor prognosis as defined by the International Germ Cell Cancer Collaborative Group (IGCCCG). Next, we developed a new tree to evaluate whether a similar structure to the previous tree was found. We assessed the internal validity of the new tree, and compared the 2-year survival estimates of each subgroup together with the discriminative ability for both the previously developed and the new tree. Discriminative ability was measured by a concordance (c) statistic, which varies between 0.5 (no discrimination) and 1.0 (perfect discrimination). RESULTS: The 2-year survival estimates in the IGCCCG data ranged from 33% to 63%. The ordering of the subgroups was different and discriminative ability was lower than originally found (c = 0.56 in the IGCCCG data versus 0.63 originally). The new tree differed considerably from the original tree, and identified poor prognosis subgroups with 2-year survival estimates from 38% to 73%. Internal validation showed similar discriminative ability for the new tree and the original tree (c = 0.59 versus 0.56). CONCLUSIONS: The previously developed tree showed poor validity with respect to discriminative ability and the stability of its structure. The performance of the new tree was also unsatisfactory. Given the low proportion of patients categorised as poor prognosis, it seems that the potential to identify further subgroups with the currently available patient characteristics is limited.

Survival of patients with nonseminomatous germ cell cancer: a review of the IGCC classification by Cox regression and recursive partitioning.

The International Germ Cell Consensus (IGCC) classification identifies good, intermediate and poor prognosis groups among patients with metastatic nonseminomatous germ cell tumours (NSGCT). It uses the risk factors primary site, presence of nonpulmonary visceral metastases and tumour markers alpha-fetoprotein (AFP), human chorionic gonadotrophin (HCG) and lactic dehydrogenase (LDH). The IGCC classification is easy to use and remember, but lacks flexibility. We aimed to examine the extent of any loss in discrimination within the IGCC classification in comparison with alternative modelling by formal weighing of the risk factors. We analysed survival of 3048 NSGCT patients with Cox regression and recursive partitioning for alternative classifications. Good, intermediate and poor prognosis groups were based on predicted 5-year survival. Classifications were further refined by subgrouping within the poor prognosis group. Performance was measured primarily by a bootstrap corrected c-statistic to indicate discriminative ability for future patients. The weights of the risk factors in the alternative classifications differed slightly from the implicit weights in the IGCC classification. Discriminative ability, however, did not increase clearly (IGCC classification, c=0.732; Cox classification, c=0.730; Recursive partitioning classification, c=0.709). Three subgroups could be identified within the poor prognosis groups, resulting in classifications with five prognostic groups and slightly better discriminative ability (c=0.740). In conclusion, the IGCC classification in three prognostic groups is largely supported by Cox regression and recursive partitioning. Cox regression was the most promising tool to define a more refined classification. British Journal of Cancer (2004) 90, 1176-1183. doi:10.1038/sj.bjc.6601665 www.bjcancer.com Published online 24 February 2004

Randomized clinical trial of adjuvant radiotherapy and 5-fluorouracil infusion in colorectal cancer (AXIS).

BACKGROUND: Postoperative portal vein infusion (PVI) of 5-fluorouracil (5-FU) is a well tolerated and widely applicable treatment for colorectal cancer that might have an enormous public health impact, even if it produced survival benefits of just a few per cent. Very large trials are required to detect such differences, and the Adjuvant X-ray and 5-FU Infusion Study (AXIS) is the largest such trial yet reported. METHODS: Consenting patients with presumed colorectal cancer were randomized to surgery with or without 7 days of PVI (1 g 5-FU plus 5000 units heparin in 1 litre 5 per cent dextrose infused over each 24-h period). In addition, patients with rectal cancer could be randomized to radiotherapy or no radiotherapy to be given either before or after surgery. RESULTS: Between November 1989 and December 1997, 3583 patients were randomized with respect to PVI. The survival hazard ratios (95 per cent confidence interval (c.i.)) in all patients randomized and in the curatively resected subgroup (71.2 per cent of patients) were 1.00 (0.92 to 1.11) and 0.94 (0.83 to 1.06) respectively. Tests for heterogeneity suggested a greater treatment benefit for patients with colonic cancer than for patients with rectal cancer with respect to disease-free survival (hazard ratio 0.79 versus 1.03; P = 0.07), and there was a non-significant trend with respect to overall survival (hazard ratio 0.87 versus 1.03; P = 0.17). No survival benefit was seen in the 761 patients randomized with respect to radiotherapy; although not statistically significant, the impact on local recurrence rates was similar to that reported in the literature. CONCLUSION: No overall benefit of PVI was established in AXIS when colonic and rectal cancers were considered together, but the evidence suggesting a differential treatment effect according to site of cancer in AXIS was strongly supported by a meta-analysis incorporating the previous trials. Combining the data gave hazard ratios of 0.82 and 1.00 for colonic and rectal tumours respectively (test for interaction, P = 0.024), equating to an absolute survival benefit for patients with colonic cancer of 5.8 (95 per cent c.i. 2.8 to 8.5) per cent, a level close to that seen for prolonged systemic therapy.

Hypofractionated radiotherapy for poor prognosis malignant glioma: matched pair survival analysis with MRC controls.

PURPOSE: To assess the survival benefit of palliative hypofractionated radiotherapy in patients with poor prognosis high grade glioma by a matched comparison to conventionally treated controls. METHOD: Ninety-two elderly and/or disabled patients with high grade glioma with poor prognostic features received palliative partial brain radiotherapy to a dose of 30Gy in six fractions over 2 weeks. Patients were matched for WHO histological grade, performance status and age from a cohort of patients treated with conventionally fractionated radiotherapy to a dose of 60Gy in 30 fractions in an Medical Research Council (MRC) BR05 trial. RESULTS: Patients treated with hypofractionated radiotherapy had a median survival of 5 months with a 1-year survival rate of 12% from diagnosis. The median survival of case-matched controls was estimated to be 2.5-4.5 months longer. Following hypofractionated radiotherapy, Barthel score was improved or remained stable in 68% of patients. CONCLUSION: Hypofractionated partial brain radiotherapy is a well-tolerated regimen with palliative benefit. Comparison with matched controls suggests lesser survival benefit than would be obtained with radical radiotherapy. However, this is compensated by lower intensity and duration of irradiation induced side effects. It is postulated that there may not be a significant difference in good quality survival or 'quality adjusted survival' between the two regimens and this requires testing in prospective trials.

External validity of a prediction rule for residual mass histology in testicular cancer: an evaluation for good prognosis patients.

We assessed the external validity of a prediction rule for nonseminomatous testicular cancer patients. The rule was developed to predict the probability of retroperitoneal metastases being benign (only necrosis/fibrosis) after chemotherapy treatment. Patients with a high probability of benign residual masses might be offered surveillance as opposed to patients with a low probability, who should undergo retroperitoneal lymph node dissection (RPLND). We compared the observed histology with the predicted probability in 105 patients with good prognosis germ cell cancer who underwent RPLND between 1995 and 1998. We found that predicted probabilities higher than 5% were in good agreement with the observed frequencies of benign masses. The area under the receiver operating characteristic curve was 0.76, suggesting that the rule could reasonably discriminate between benign masses and tumour. However, nearly all predicted probabilities (n=101) were lower than 70%, which might be considered as the lowest value at which surveillance offers a reasonable alternative to RPLND. Further, 35% of patients currently under surveillance (84 out of 241) had predicted probabilities lower than 70%. In conclusion, the clinical relevance of the prediction rule was limited for the patients who underwent RPLND; use of the rule would change the policy from RPLND to surveillance in only a few. On the other hand, the rule might support selection of patients for RPLND, who currently are under surveillance.

DNA markers predicting benefit from adjuvant fluorouracil in patients with colon cancer: a molecular study.

BACKGROUND: Present clinical algorithms assign adjuvant chemotherapy according to prognosis, but clinical decision-making would be greatly improved if reliable predictive markers were available to identify which subsets of patients benefit most from treatment. We examined molecular markers in preserved tissue from patients with Dukes' B or C colon cancer randomised to receive, or not, adjuvant fluorouracil, and assessed each marker's prognostic and predictive value. METHODS: Formalin-fixed paraffin-embedded paired normal and tumour samples were obtained from 393 patients with colon cancer from the UK AXIS trial of postoperative portal vein infusion fluorouracil versus control. We measured loss of heterozygosity (LOH) and microsatellite instability at four loci: P53 (17p13), D18S61 (18q22.3), D18S851 (18q21.1), and DP1 (5q21). The prognostic value of each marker was assessed with the log-rank test, and the predictive value by comparison of treatment hazard ratios with the chi(2) test for heterogeneity (CSH). FINDINGS: In 228 (58%) patients informative for LOH at D18S61, this marker was significantly predictive: benefit from fluorouracil was significantly greater in patients retaining heterozygosity than in those with LOH (CSH p=0.02). Conversely, LOH at D18S61 was a significant prognostic marker of improved outcome in untreated patients. 314 (80%) patients were informative for LOH at at least one of the three 17p and 18q sites, of whom half retained heterozygosity at one or more site. The effect of chemotherapy in these patients was striking (hazard ratio 0.45, 95% CI 0.28-0.73), whereas chemotherapy had no effect in patients with no retained heterozygosity (0.91; 0.56-1.48), CSH p=0.039. INTERPRETATION: Retention of heterozygosity at one or more 17p or 18q sites was associated with the ability to benefit from adjuvant fluorouracil. These results support the principle of developing molecular markers as predictive factors in treatment decisions.

An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom Lymphoma Group LY06 study.

BACKGROUND: Burkitt's lymphoma (BL) is a rare and rapidly progressive form of B-cell non-Hodgkin's lymphoma. Cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate (CODOX-M)/ifosfamide, etoposide and high-dose cytarabine (IVAC) is a highly effective alternating non-cross-resistant regimen developed by Magrath et al. (Magrath I., Adde M., Shad A. et al. J Clin Oncol 1996; 14: 925-934) at the US National Cancer Institute. The aim was to confirm these results in a larger, international, multi-centre study using International Prognostic Index-based criteria to assign prognostic groups, whilst slightly simplifying the protocol. PATIENTS AND METHODS: A phase II study where: (i) low risk (LR) patients were treated with three cycles of modified CODOX-M; and (ii) high risk (HR) patients received treatment with four cycles of alternating modified CODOX-M and IVAC chemotherapy. Target of 60 patients, fit for protocol treatment, from 16 to 60 years of age with locally diagnosed, non-HIV-related, non-organ-transplant-related BL. RESULTS: Results are given for 52 of 72 registered patients whose pathological eligibility was confirmed by central pathology review: 12 LR plus 40 HR. The majority of patients (n = 41) completed protocol treatment, but toxicity was severe, especially myelosuppression and mucositis. Overall, 2-year event-free survival (EFS) was 64.6% (95% CI 50.4% to 78.9%) and 2-year overall survival (OS) was 72.8% (95% CI 59.4% to 86.3%). For LR, 2-year EFS was 83.3% and OS was 81.5%. For HR, 2-year EFS was 59.5% and OS was 69.9%. CONCLUSIONS: This study confirms high cure rates with this CODOX-M/IVAC approach.

A medical research council randomized trial of single agent carboplatin versus etoposide and cisplatin for advanced metastatic seminoma. MRC Testicular Tumour Working Party.

The UK Medical Research Council conducted this trial of carboplatin chemotherapy in advanced seminoma to compare single agent carboplatin with a standard combination of etoposide with cisplatin. The use of single agent carboplatin was expected to be associated with reduced toxicity. A total of 130 patients with advanced seminoma were randomly assigned to treatment with either single agent carboplatin (C) at a dose of 400 mg/m(2)to be corrected for glomerular filtration rate outside the range 81-120 ml min(-1)and to be administered on day 1 of a 21 day cycle to a total of 4 cycles or to etoposide + platinum (EP). The trial was designed as an equivalence study aiming to exclude a reduction in the 3-year progression-free survival in patients allocated to carboplatin of between 10 and 15%, requiring initially a target accrual of 250 patients (90% power significance level 5% (one-sided)). The trial closed after 130 patients had been randomized following recommendation by an independent data monitoring committee. At a median follow-up time of 4.5 years, 81% of patients had been followed up for at least 3 years and 19 patients have died. The estimated PFS rate (95% Confidence Intervals (CI)) at 3 years was 71% (60-82%) in patients allocated C and 81% (71-90%) in those allocated EP; the 95% CI for the difference in 3 year PFS was - 6% to +19%. The hazard ratio of 0.64 (95% CI 0.32-1.28) favoured EP but the difference was not statistically significant (log rank chi-squared = 1.59 P = 0.21). The 3-year survival rate was 84% (75-92%) in those allocated C, and 89% (81-96%) in those allocated EP. The hazard ratio for survival was 0.85 with 95% CI, 0.35-2.10, log rank chi-squared = 0.12, P = 0.73. The trial has not demonstrated statistically significant differences in the major survival endpoints comparing single agent carboplatin with a combination of etoposide + cisplatin. This cannot be taken as an indication of equivalence since the limited size of this trial rendered it unable to exclude a 19% lower progression-free survival and survival in those treated with single agent carboplatin which would be important clinically. Standard initial chemotherapy for advanced seminoma should be based on cisplatin combinations and the role of carboplatin awaits the outcome of further studies.

A medical research council randomized trial in patients with primary cerebral non-Hodgkin lymphoma: cerebral radiotherapy with and without cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy.

BACKGROUND: The role of chemotherapy in the treatment of patients with primary central nervous system lymphoma (PCL) remains unclear, with no randomized trials available to aid in the interpretation of the current data. The Medical Research Council therefore conducted the current randomized trial to assess the impact on survival of postradiotherapy chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in nonimmunocompromised adult patients with pathologically proven PCL. METHODS: After surgery, patients were randomized at a ratio of 1:2 to radiotherapy alone (RT: 40 grays [Gy] in 20 fractions to the whole brain followed by a 14-Gy boost to the tumor plus a 2-cm tumor margin) or to the same radiotherapy followed by six cycles of CHOP chemotherapy given at 3-week intervals (RT-CHOP). The target sample size was 90 patients, which allowed 90% power to detect a doubling of the median survival time. RESULTS: Between 1988 and 1995, 53 patients were randomized: Fifteen patients were randomized to RT, and 38 patients were randomized to RT-CHOP. The trial closed earlier than planned through poor accrual. The median patient age was 57 years, 57% of the patients were male, and 75% of the patients had unifocal disease. The median number of chemotherapy cycles received was 6 (mean, 4 cycles). Forty-three patients have died, and the median follow-up of survivors is 5 years (range, 1-9 years). There was no evidence of a benefit from RT-CHOP with respect to overall survival (hazard ratio [HR], 1.19; 95% confidence interval, 0.51-2.76) after adjustment for prognostic factors (patient age and neurologic performance status) in an analysis in which HR > 1 favored the control (RT) group. CONCLUSIONS: CHOP has no clear role in the postradiotherapy treatment of patients with PCL. Chemotherapy is poorly tolerated and largely palliative in older, less fit patients. In younger patients, initial chemotherapy designed to penetrate the blood-brain barrier warrants further investigation.

Optimal planning target volume for stage I testicular seminoma: A Medical Research Council randomized trial. Medical Research Council Testicular Tumor Working Group.

PURPOSE: To compare relapse rates and toxicity associated with para-aortic (PA) strip or PA and ipsilateral iliac lymph node irradiation (dogleg [DL] field) (30 Gy/15 fractions/3 weeks) for stage I testicular seminoma. PATIENTS AND METHODS: Between July 1989 and May 1993, 478 men with testicular seminoma stage I (T1 to T3; no ipsilateral inguinoscrotal operation before orchiectomy) were randomized (PA, 236 patients; DL, 242 patients). RESULTS: Median follow-up time is 4.5 years. Eighteen relapses, nine in each treatment group, have occurred 4 to 35 months after radiotherapy; among these, four were pelvic relapses, all occurring after PA radiotherapy. However, the 95% confidence interval (CI) for the difference in pelvic relapse rates excludes differences of more than 4%. The 3-year relapse-free survival was 96% (95% CI, 94% to 99%) after PA radiotherapy and 96.6% (95% CI, 94% to 99%) after DL (difference, 0.6%; 95% confidence limits, -3.4%, +4.6%). One patient (PA field) has died from seminoma. Survival at 3 years was 99.3% for PA and 100% for DL radiotherapy. Acute toxicity (nausea, vomiting, leukopenia) was less frequent and less pronounced in patients in the PA arm. Within the first 18 months of follow-up, the sperm counts were significantly higher after PA than after DL irradiation. CONCLUSION: In patients with testicular seminoma stage I (T1 to T3) and with undisturbed lymphatic drainage, adjuvant radiotherapy confined to the PA lymph nodes is associated with reduced hematologic, gastrointestinal, and gonadal toxicity, but with a higher risk of pelvic recurrence, compared with DL radiotherapy. The recurrence rate is low with either treatment. PA radiotherapy is recommended as standard treatment in these patients.