Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data.

BACKGROUND: Many randomised controlled trials have investigated the effect of adjuvant chemotherapy in operable non-small-cell lung cancer. We undertook two comprehensive systematic reviews and meta-analyses to establish the effects of adding adjuvant chemotherapy to surgery, or to surgery plus radiotherapy. METHODS: We included randomised trials, not confounded by additional therapeutic differences between the two groups and that started randomisation on or after Jan 1, 1965, which compared surgery plus adjuvant chemotherapy versus surgery alone, or surgery plus adjuvant radiotherapy and chemotherapy versus surgery plus adjuvant radiotherapy. Updated individual patient data were collected, checked, and included in meta-analyses stratified by trial. The primary endpoint was overall survival, defined as time from randomisation until death by any cause. All analyses were by intention to treat. FINDINGS: The first meta-analysis of surgery plus chemotherapy versus surgery alone was based on 34 trial comparisons and 8447 patients (3323 deaths). We recorded a benefit of adding chemotherapy after surgery (hazard ratio [HR] 0.86, 95% CI 0.81-0.92, p<0.0001), with an absolute increase in survival of 4% (95% CI 3-6) at 5 years (from 60% to 64%). The second meta-analysis of surgery plus radiotherapy and chemotherapy versus surgery plus radiotherapy was based on 13 trial comparisons and 2660 patients (1909 deaths). We recorded a benefit of adding chemotherapy to surgery plus radiotherapy (HR 0.88, 95% CI 0.81-0.97, p=0.009), representing an absolute improvement in survival of 4% (95% CI 1-8) at 5 years (from 29% to 33%). In both meta-analyses we noted little variation in effect according to the type of chemotherapy, other trial characteristics, or patient subgroup. INTERPRETATION: The addition of adjuvant chemotherapy after surgery for patients with operable non-small-cell lung cancer improves survival, irrespective of whether chemotherapy was adjuvant to surgery alone or adjuvant to surgery plus radiotherapy. FUNDING: UK Medical Research Council, Institut Gustave-Roussy, Programme Hospitalier de Recherche Clinique (AOM 05 209), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.

Chemotherapy versus supportive care in advanced non-small cell lung cancer: improved survival without detriment to quality of life.

BACKGROUND: In 1995 a meta-analysis of randomised trials investigating the value of adding chemotherapy to primary treatment for non-small cell lung cancer (NSCLC) suggested a small survival benefit for cisplatin-based chemotherapy in each of the primary treatment settings. However, the meta-analysis included many small trials and trials with differing eligibility criteria and chemotherapy regimens. METHODS: The aim of the Big Lung Trial was to confirm the survival benefits seen in the meta-analysis and to assess quality of life and cost in the supportive care setting. A total of 725 patients were randomised to receive supportive care alone (n = 361) or supportive care plus cisplatin-based chemotherapy (n = 364). RESULTS: 65% of patients allocated chemotherapy (C) received all three cycles of treatment and a further 27% received one or two cycles. 74% of patients allocated no chemotherapy (NoC) received thoracic radiotherapy compared with 47% of the C group. Patients allocated C had a significantly better survival than those allocated NoC: HR 0.77 (95% CI 0.66 to 0.89, p = 0.0006), median survival 8.0 months for the C group v 5.7 months for the NoC group, a difference of 9 weeks. There were 19 (5%) treatment related deaths in the C group. There was no evidence that any subgroup benefited more or less from chemotherapy. No significant differences were observed between the two groups in terms of the pre-defined primary and secondary quality of life end points, although large negative effects of chemotherapy were ruled out. The regimens used proved to be cost effective, the extra cost of chemotherapy being offset by longer survival. CONCLUSIONS: The survival benefit seen in this trial was entirely consistent with the NSCLC meta-analysis and subsequent similarly designed large trials. The information on quality of life and cost should enable patients and their clinicians to make more informed treatment choices.

Monitoring of large randomised clinical trials: a new approach with Bayesian methods.

BACKGROUND: In judging whether or not to continue enrolling patients into a randomised clinical trial, most data-monitoring and ethics committees (DMECs) rely on the p value for the difference in effect between the study groups. In the 1990s, two randomised controlled trials-one in patients with lung cancer and one in those with head and neck cancer-were instead monitored by Bayesian methods. We assessed the value of this approach in the monitoring of these clinical trials. METHODS: Before the trials opened, participating clinicians were asked their opinions on the expected difference between the study treatment (continuous hyperfractionated accelerated radiotherapy [CHART]) and conventional radiotherapy. These opinions were used to form an "enthusiastic" and a "sceptical" prior distribution. These prior distributions were combined with the trial data at each of the annual DMEC meetings. If, during monitoring, a result in favour of CHART was seen, the DMEC was to decide whether the results were sufficiently convincing to persuade a sceptic that CHART was worthwhile. Conversely, if there was apparently no or little difference, the DMEC was asked whether they thought the results sufficiently convincing to persuade an enthusiast that CHART was not worthwhile. FINDINGS: At each of the annual meetings, the DMEC concluded that there was insufficient evidence to convert either sceptics or enthusiasts, and that the trials should therefore remain open to recruitment. Neither trial was closed to recruitment earlier than planned. However if a conventional (p-value-based) stopping rule had been used, the lung-cancer trial would probably have been stopped. INTERPRETATION: This Bayesian approach to monitoring is simple to implement and straightforward for members of the DMEC to understand. In our opinion, it is more intuitively appealing than conventional approaches.

A phase II study of cisplatin, ifosfamide and doxorubicin in operable primary, axial skeletal and metastatic osteosarcoma. European Osteosarcoma Intergroup (EOI).

BACKGROUND: Despite advances in the treatment of primary limb osteosarcoma, the outcome of patients with primary metastatic and axial skeletal disease remains poor. The European Osteosarcoma Intergroup have assessed a combination chemotherapy regimen consisting of ifosfamide (IFOS) 3 g/m2/dl-2, doxorubicin (DOX) 25 mg/m2/dl-3 i.v. bolus and cisplatin (CDDP) 100 mg/m2/dl. PATIENTS AND METHODS: One hundred nine previously untreated patients with primary osteosarcoma were registered. Eligibility was confirmed in 103. At presentation, 45 eligible patients had metastatic disease, 15 axial skeletal primary tumours and 43 non-metastatic limb tumours. RESULTS: The major toxicities were myelosuppression (90%, grade 3 or 4) and nausea and vomiting (74%, grade 3 or 4). Overall mean relative dose intensity (RDI) was 80% (88% CDDP, 75% IFOS, 81% DOX). Clinical response as measured by reduction in tumour volume occurred in 36% (95% confidence interval (95% CI): 27%-47%) of primary tumours. Response of pulmonary metastases to chemotherapy was seen in 33% (95% CI: 19%-49%). Good histological response (> or = 90% necrosis of the tumour) occurred in 33% (95% CI: 22%-45%) of resected tumours. Five-year survival was 62% in limb-non-metastatic, 41% in axial skeletal and 16% in limb metastatic patients. CONCLUSIONS: This regimen is active in osteosarcoma but does not appear to be more active than the two-drug CDDP-DOX regimen currently recommended by EOI.

Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life.

PURPOSE: Chemotherapy for non-small-cell lung cancer (NSCLC) remains controversial. We describe the two largest reported, randomized, parallel trials designed to determine whether the addition of chemotherapy influences duration and quality of life in localized, unresectable (mitomycin, ifosfamide, cisplatin [MIC]1 trial) and extensive (MIC2 trial) disease. PATIENTS AND METHODS: Ambulatory patients with NSCLC, aged 75 years or younger, with localized disease, were randomized in MIC1 to receive up to four cycles of chemotherapy (CT: mitomycin 6 mg/m(2), ifosfamide 3 g/m(2), and cisplatin 50 mg/m(2)) every 21 days, followed by radical radiotherapy (CT + RT) or radiotherapy (RT) alone. Extensive-stage patients were randomized in MIC2 to identical chemotherapy plus palliative care (CT + PC) or palliative care (PC) alone. Short-term change in quality of life (QOL) was assessed in a subgroup of patients. Data from the two trials were combined to allow multivariate and stratified survival analyses. RESULTS: Seven hundred ninety-seven eligible patients were randomized, 446 in MIC1 and 351 in MIC2. MIC CT improved survival in both trials (significantly in MIC2). The median survival time in MIC1 was 11.7 months (CT + RT) versus 9.7 months (RT alone) (P =.14); whereas in MIC2, median survival time was 6.7 months (CT + PC) compared with 4. 8 months (PC alone) (P =.03). QOL, assessed in 134 patients from start of trial to week 6, showed improvement with chemotherapy and deterioration with standard treatment. In the combined analysis of 797 randomized patients, the positive effect of MIC on survival was significant overall (P =.01) and after adjusting for prognostic factors (P =.01). CONCLUSION: MIC chemotherapy prolongs survival in unresectable NSCLC without compromising QOL.

Measurement of DNA cross-linking in patients on ifosfamide therapy using the single cell gel electrophoresis (comet) assay.

The single cell gel electrophoresis comet assay has become established as a sensitive technique for measuring DNA strand breaks. The technique has been modified to allow the sensitive detection and quantitation of DNA interstrand cross-linking at the single cell level. Cells are irradiated immediately before analysis to deliver a fixed level of random strand breakage. After embedding of cells in agarose and lysis, the presence of cross-links retards the electrophoretic mobility of the alkaline denatured cellular DNA. Cross-links are, therefore, quantitated as the decrease in the comet tail moment compared with irradiated controls. Using this method, a linear response of cross-linking versus dose of chlorambucil over a wide dose range was demonstrated in human lymphocytes after drug treatment ex vivo. The method was also sensitive enough to determine cross-linking in clinical samples after chemotherapy. For example, crosslinking was observed in the lymphocytes of patients receiving ifosfamide (3 g/m2/day) as a continuous infusion for 3-5 days or as a 3-h infusion daily for 3 days. Cross-links were detected in all patients within 3 h, with no evidence of DNA single strand break formation. In patients receiving continuous infusion, a plateau of cross-linking was reached by 24 h. In the patients receiving ifosfamide over 3 h, a clear decrease in the peak level of cross-linking was observed before subsequent infusions.

Gene and human tumour cell line specific differencesin nitrogen mustard induced DNA alkylation and interstrand crosslinking frequencies.

The levels of N-alkyl purine and DNA interstrand crosslink formation, produced by the clinically used nitrogen mustard antitumour drug mechlorethamine (HN2), were quantitated at the level of specific genes in a panel of human tumour cell lines using modified Southern blotting methods. When purified genomic DNA was treated with HN2 in vitro, no significant difference in the extent of N-alkyl purine or interstrand crosslink formation in the N-ras, c-myc or CD3delta genes was observed. When the cell lines LS174T, Colo320HSR, J6 and U937 were treated with HN2, however, there was significant heterogeneity in the levels of N-alkyl purine formation in the three genes. The rank order of the extent of damage in the three genes was also different in the cell lines. The level of alkylation did not correlate with either the transcriptional activity of a gene or drug sensitivity. Crosslinks were not detectable in the N-ras or c-myc genes of LS174T, J6 or U937 cells treated with HN2, and only detectable in the amplified c-myc gene of the Colo320HSR cell line. In the related cell line Colo320DM, which has both native and translocated c-myc alleles which are both amplified and episomal, crosslinks were detected in the amplified native and rearranged c-myc alleles, and also in the N-ras gene which is also amplified in this cell line. For bifunctional alkylating agents such as HN2, therefore, heterogeneity of DNA damage can occur between different genes in human cells and can also vary for different lesions produced by the same agent. In addition, this heterogeneity can differ between human tumour cell lines.

The pharmacokinetics and metabolism of ifosfamide during bolus and infusional administration: a randomized cross-over study.

In a randomized cross-over trial, 11 patients received ifosfamide (IFOS) in 21-day cycles, which alternated between 3 g m(-2) x (2 or 3) days given as a 1-h bolus doses, or the same total dose as a continuous infusion. Patients who received four or more cycles also alternated between two cycles on dexamethasone 4 mg 8 hourly for 3 days starting 8 h before IFOS, and two cycles off dexamethasone. A total of 34 patient cycles were studied and serum and urinary levels of IFOS, 2 dechloroethylifosfamide (2DC), 3 dechloroethylifosfamide (3DC), carboxyifosfamide (CX) and isophosphoramide mustard (IPM) were measured by thin-layer chromatography. No significant differences could be detected in the areas under the curve (AUCs) of serum concentration, nor in the proportion of IFOS or its metabolites found in the urine. There was no significant effect of dexamethasone on IFOS metabolism. These results indicate that there is no identifiable pharmacokinetic basis for insistence on either bolus or infusional methods of IFOS administration.

Long-term neurotoxicity of chemotherapy in adolescents and young adults treated for bone and soft tissue sarcomas.

Purpose. To study the long-term neurotoxicity of chemotherapy in adolescents and young adults treated for bone and soft tissue sarcomas.Patients and Methods. Thirty-six adolescents and young adults (median age 17 years) were examined following chemotherapy for bone and soft tissue sarcomas. Twenty-nine (29/36) had received cisplatin (median 400 mg/m(2)), 15/36 ifosfamide (median 20 g/m(2)), and 12/36 vincristine (median 16 mg). Neurotoxicity was assessed at a median of 8 months (range, 1-54 months) after completion of chemotherapy by clinical examination, nerve conduction studies, audiograms and autonomic function tests. The same nerve conduction studies were carried out in 20 normal volunteers to define normal ranges in this age group.Results. Sixteen patients (44%) had a significant reduction in deep tendon reflexes, and this clinical parameter correlated well with abnormalities detected in nerve conduction studies. Vibration perception threshold (VPT) was raised in 20/36 patients (55%) and this was the most sensitive single test in the assessment of neuropathy. There was a significant correlation between VPT and cumulative cisplatin dose received in mg/m(-2) (r=0.607, p<0.01). Ten of 29 patients (35%) had abnormal nerve conduction studies with a pattern characteristic of sensory axonal neuropathy. No patient complained of auditory symptoms, but minor high tone hearing loss was detected by audiograms in 5/28 patients who had received cisplatin. No patients had symptoms of autonomic neuropathy, but autonomic function tests showed minor abnormalities in 4/22 patients tested, and all had received cisplatin.Conclusions. This study demonstrates significant, although asymptomatic, long-term neurotoxicity of cisplatin in adolescents and young adults receiving chemotherapy for bone and soft tissue sarcomas. Follow-up studies are planned to assess whether these neurological deficits improve with time.

Attitudes of patients to randomised clinical trials of cancer therapy.

The aim of this study was to test an instrument which might be useful for doctors in explaining the randomisation procedure to an individual patient. The sample comprised 323 patients with cancer attending for out-patient appointments and/or chemotherapy treatment in two major cancer centres in the U.K. 315 patients completed a self-report questionnaire--The Attitudes to Randomised Trials Questionnaire (ARTQ). The results show that the majority of subjects 287 (91.1%) believe that patients should be asked to take part in medical research, but only 242 (76.8%) would be prepared to take part in a study comparing two treatments. If treatment was randomised, only 141 (44.8%) would agree to participate. When given further information about the randomisation procedure, 119 (68.4%) of the 174 (55.2%) who initially said 'no' to randomisation or who were unsure, would change their minds and take part in a trial. The ARTQ discriminated between three categories of patient with the following prevailing attitudes: (a) those who seem comfortable with the concept of randomisation; (b) those with some concerns, who with fuller explanation are prepared to consider randomisation; and (c) those firmly against randomisation and participation in trials whatever information is provided. Prior knowledge of patients' attitudes might assist communication about trials and encourage more doctors to approach eligible patients.

High-dose busulphan/melphalan with autologous stem cell rescue in Ewing's sarcoma.

Eighteen patients with poor risk Ewing's sarcoma (including 11 patients with metastatic disease at presentation) received consolidation therapy of busulphan and melphalan with autologous stem cell rescue. There were nine females. The median age at diagnosis was 14.2 years (range 2.75-30 years). There was one early death due to cytomegalovirus pneumonitis. One patient developed a single generalised convulsion during busulphan therapy. Severe renal toxicity was not encountered. One patient developed veno-occlusive disease of the liver (VOD) which eventually resolved. With a median follow up of 2 years, 13 patients survive including six with initial metastatic disease. We conclude that high-dose busulphan/melphalan is well-tolerated and should be evaluated for efficacy in a larger series of patients with high risk Ewing's sarcoma.

Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup.

BACKGROUND: A previous trial by the European Osteosarcoma Intergroup (EOI) suggested that a short intensive chemotherapy regimen with doxorubicin and cisplatin might produce survival of operable, non-metastatic osteosarcoma similar to that obtained with complex and longer-duration drug regimens based on the widely used T10 multi-drug protocol. We undertook a randomised multicentre trial to compare these two approaches. METHODS: 407 patients with operable, non-metastatic osteosarcoma were randomly assigned the two-drug regimen (six cycles [18 weeks] of doxorubicin 25 mg/m2 on days 1-3 and cisplatin 100 mg/m2 on day 1) or a multi-drug regimen (preoperatively vincristine, high-dose methotrexate, and doxorubicin; postoperatively bleomycin, cyclophosphamide, dactinomycin, vincristine, methotrexate, doxorubicin, and cisplatin; this protocol took 44 weeks). Surgery was scheduled for week 9 for the two-drug group and week 7 for the multi-drug group. Analyses of survival and progression-free survival were by intention to treat. FINDINGS: Of 407 randomised patients, 391 were eligible and have been followed up for at least 4 years (median 5-6 years). Toxic effects were qualitatively similar with the two regimens. However, 188 (94%) of 199 patients completed the six cycles of two-drug treatment, whereas only 97 (51%) of 192 completed 18 or more of the 20 cycles of the multi-drug regimen. The proportion showing a good histopathological response (> 90% tumour necrosis) to preoperative chemotherapy was about 29% with both regimens and was strongly predictive of survival. Overall survival was 65% at 3 years and 55% at 5 years in both groups (hazard ratio 0.94 [95% CI 0.69-1.27]). Progression-free survival at 5 years was 44% in both groups (hazard ratio 1.01 [0.77-1.33]). INTERPRETATION: We found no difference in survival between the two-drug and multi-drug regimens in operable, non-metastatic osteosarcoma. The two-drug regimen is shorter in duration and better tolerated, and is therefore the preferred treatment. However, 5-year survival is still unsatisfactory and new approaches to treatment, such as dose intensification, are needed to improve results.

Survey on the treatment of non-small cell lung cancer (NSCLC) in England and Wales.

As an adjunct to a meta-analysis of chemotherapy for non-small cell lung cancer (NSCLC), a survey was conducted in England and Wales of clinicians' views on the role of chemotherapy in NSCLC and the benefits it would have to offer to lead them to change their practice. Radiotherapists, medical oncologists, surgeons and physicians specializing in thoracic medicine, and physicians of palliative medicine were asked their views on the treatment of three case histories of 65 yr old men: Case 1, resected tumour involving a hilar lymph node (tumour (T)2, node (N)1, metastasis (M)0); Case 2, tumour that had spread to mediastinal lymph nodes bilaterally (T2, N3, M0); and Case 3, metastatic cancer (M1) accompanied by minor haemoptysis. Six hundred and ninety eight (85%) of the 821 clinicians responded. For Case 1, 74% would not recommend any adjuvant treatment, 24% would recommend radiotherapy, and <1% chemotherapy, and there was little expectation that adjuvant treatment would improve survival. For Case 2, 68% would recommend radiotherapy, 11% chemotherapy, and 1% surgery, 7% recommending a combination. Adjuvant treatment, regardless of modality, was expected to improve survival. For Case 3, only 11% would recommend chemotherapy, but 26% if the patient was aged < or = 50 yrs. There was little expectation of survival beyond 1 yr, or of improving survival with chemotherapy. For all three cases, most of those not recommending chemotherapy would require it to achieve substantially improved survival for them to use it routinely. Surgery alone is currently considered sufficient for resectable non-small cell lung cancer. Chemotherapy is rarely recommended for disease of any stage.

Anxiety and depression in adolescent cancer: findings in patients and parents at the time of diagnosis.

Adolescent cancer is uncommon and presents an exceptional stress for the young patient and their parents. The emotional needs of adolescents with cancer are a major factor in the recommendation for the establishment of adolescent cancer units in major cancer centres in the U.K. However, there have been no prospective, longitudinal studies assessing the psychological impact of a diagnosis of cancer on the adolescent patient and their family. In 1994 we began a longitudinal study of the emotional impact of the diagnosis of cancer in patients and their families presenting to an adolescent cancer unit and of the coping strategies they employ. This first report presents the results of the study at the time of diagnosis in 42 adolescents, 34 mothers and 27 fathers. The Beck Depression Inventory (BDI) was used to assess depression and anxiety levels were measured using Spielberger's State Trait Anxiety Inventory (STAI). Adolescents and their parents completed the questionnaires on first admission to the adolescent cancer unit. The median time since cancer diagnosis was approximately 3 weeks. To provide normative data for the U.K. adolescent population, control values were obtained from 173 pupils of the same age and background. The results showed that, contrary to expectation, adolescents with cancer were no more anxious or depressed than the control adolescent population. Nevertheless, a substantial minority of patients and controls had elevated anxiety or depression scores. Girls were significantly more anxious (P = 0.011) and depressed (P < 0.0001) than boys. Mothers were the most anxious family members and were significantly more anxious than fathers (P = 0.038). Parental anxiety scores, especially mothers, were much higher than reported norms. There was no significant difference between mothers' and fathers' depression scores. Although at the time of diagnosis adolescent cancer patients are not more anxious or depressed than their healthy peers, many adolescents without cancer are anxious or depressed. Staff on adolescent cancer units should therefore be aware of the frequency of emotional disturbance in this population. Mothers are the most anxious family members. Although the findings are relatively reassuring at the time of diagnosis, follow-up data from this cohort will show whether anxiety and depression change with treatment involving intensive chemotherapy, surgery and radiotherapy and will indicate the coping strategies which patients and their families adopt in dealing with both the disease and its treatment.

Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy.

BACKGROUND: Oral etoposide is an active single agent in small-cell lung cancer (SCLC) and is widely prescribed as first-line treatment as an alternative to intravenous combination chemotherapy in patients with extensive disease. PURPOSE: The intention of this study was to determine if the effects of oral etoposide therapy on survival and quality of life are equivalent to those of intravenous chemotherapy. METHODS: In a randomized trial of palliative treatment in advanced SCLC, oral etoposide (100 mg given twice daily for 5 days) was compared with intravenous chemotherapy consisting of alternating cycles of cisplatin and etoposide (PE) and cyclophosphamide, doxorubicin, and vincristine (CAV). Six cycles of chemotherapy were administered every 21 days in both regimens. Symptom control and quality of life were measured with the Rotterdam Symptom Checklist and a daily diary card. In January 1996, after 155 patients had been randomly assigned from a projected intake of 365 patients, an independent Data Monitoring Committee examined the interim results. Survival was determined by the Kaplan-Meier method, and the logrank test was used to compare treatments. For quality-of-life comparisons, average scores were calculated for each time point. The Mann-Whitney U test was used to determine any significant overall differences between treatments. For the Rotterdam Symptom Checklist, separate analyses were done for each subset (psychological well-being, physical symptoms, lung cancer symptoms, treatment symptoms, activity, and quality of life). Response rates and toxicity scores were compared by using chi2. All statistical tests were two-sided. RESULTS: Survival was inferior at 1 year in the oral etoposide group compared with intravenous therapy (9.8% for oral versus 19.3% for intravenous; difference = 9.5%; 95% confidence interval of difference = 0.3%-18.7%; P<.05), and there was a trend toward inferior overall survival. Median survival was 4.8 months for oral treatment and 5.9 months for intravenous therapy. Progression-free survival was worse in the oral etoposide arm (median = 3.6 months versus 5.6 months; P<.001), as well as overall response rate (32.9% versus 46.3%; P<.01). With the exception of acute nausea and vomiting associated with intravenous chemotherapy, all aspects of symptom control and quality of life were either the same or worse in the oral etoposide group. Study closure was recommended. CONCLUSIONS: These interim results show that this schedule of oral etoposide is inferior to intravenous chemotherapy in the treatment of advanced SCLC and should not be used as first-line treatment of this disease.

Cautionary tales of survival analysis: conflicting analyses from a clinical trial in breast cancer.

Data from a completed randomized trial in breast cancer are used to demonstrate and quantify the variation in estimated survival curves and log-rank statistics at different times throughout a trial. False 'plateaux' are common, as are wide fluctuations in chi2 values obtained from the log-rank test when there are few events. We show how analyses conducted at different times can demonstrate different effects. Long follow-up is often necessary to allow correct interpretation of results. We discuss the assumption of proportional hazards and the consequences of making that assumption inappropriately. We show how checking whether hazards are proportional can help in avoiding erroneous conclusions.

A Randomized Comparison of two Short Intensive Chemotherapy Regimens in Children and Young Adults With Osteosarcoma: Results in Patients With Metastases: A Study of the European Osteosarcoma Intergroup.

Purpose. To report the outcome of 37 patients with metastatic osteosarcoma entered into a large randomized trial (EOI 80831/MRC B002) comparing two different regimens of chemotherapy in patients with osteosarcoma.Methods. Patients with biopsy-proven osteosarcoma localized and metastatic, age 40 years or younger, were randomized to receive either two-drug treatment with doxorubicin/cisplatin (DOX 25 mg m(-2) day(-1) x 3 + DDP 100 mg m(-2) on day 1 q 3 weeks x 6 courses) or three-drug treatment comprising high-dose methotrexate (HDMTX 8 mg m(-2) administered every 4.5 weeks x 4 courses) given 10 days before DOX/DDP.Results. Twenty-four patients with metastatic disease received the two-drug arm treatment and 13 received three-drug treatment. Despite chance imbalance in numbers, there were no major differences in age, sex, primary site or performance status. Baseline alkaline phosphatase (AP) was elevated more frequently (96 vs 42%) in the two-drug arm. Twenty-one of 24 patients in the two-drug arm and 11/13 patients in the three-drug arm had evaluable primary tumors concurrent with metastases. Respective clinical response rates for the two- and three-drug arms were 48% and 40% for primary tumors, and 33% and 55% for metastases. Respective survivals at 2 and 4 years were 36% and 9% for the two-drug arm, and 69% and 52% for the three-drug arm, and survival was better for patients with normal AP at presentation. When adjusted for AP, survival was not significantly different between the two treatments (hazard ratio 0.52, 95% confidence interval 0.22-1.23, p = 0.14). There were three long-term survivors among the metastatic patients, all of whom received the three-drug therapy.Discussion. It is likely that random bias in the population (small numbers, imbalance in size of groups, uneven distribution of AP) accounts for the difference in outcome favoring the three-drug treatment in patients with metastatic disease. More reliance can be placed on the finding that disease-free and overall survival in the adjuvant component of this study (Bramwell et al., J Clin Oncol 1992; 10: 1579-91) were better after two-drug treatment.

Multi-focal, multi-centric angiosarcoma of bone.

A multi-focal multi-centric, malignant tumour of vascular origin arising in bone in a 55-year-old man is described. The presenting symptoms were pain and weight loss. Radiologically, multiple lytic lesions were demonstrated in the long bones of both legs and throughout the pelvis. Histological examination demonstrated an angiosarcoma which was predominantly low grade in nature but with focal areas of intermediate grade. Turnout cells expressed the endothelial markers CD31, CD34 and von Willebrand's factor. There was rapid radiological progression of disease with no response to radiotherapy. Pain abated within a few days of institution of doxorubicin, 75 mg m(-2), but the patient died of massive pulmonary thromboembolism 14 days later, 11 months after the first symptoms.

Urinary proton magnetic resonance studies of early ifosfamide-induced nephrotoxicity and encephalopathy.

Ifosfamide is an oxazophosphorine widely used in the treatment of cancer in children and adults. Nephrotoxicity and neurotoxicity are major side effects. The aim of this study was to use high-resolution proton nuclear magnetic resonance (1H NMR) spectroscopy of urine to identify novel biochemical markers of ifosfamide-induced toxicity. Urine samples were collected from 10 nonencephalopathic patients (who had not previously received nephrotoxic chemotherapy) immediately prior to the first ifosfamide dose and at timed intervals for up to four treatment cycles. The findings were compared with those for urine samples collected from five patients during acute encephalopathic episodes. 1H NMR urinalysis identified a series of characteristic time-related changes in the excretion profiles of low molecular weight endogenous metabolites during ifosfamide therapy. These changes included a decreased excretion of hippurate and an increased excretion of glycine, histidine, glucose, lactate, and trimethylamine-N-oxide. Two nonencephalopathic patients had marked but transient glutaric or adipic aciduria during the second cycle of ifosfamide treatment. Urinary retinol-binding protein rose acutely after each treatment cycle but usually returned to baseline levels. Maximum renal toxicity was observed by the fourth treatment cycle. The ratio of the urinary excretion of the uroprotectant mesna (active form) to dimesna (inactive form) correlated with the degree of renal toxicity. For the encephalopathic patients, the ifosfamide-induced changes in the urinary low molecular weight metabolite profile were similar to those for the nonencephalopathic group. In contrast to previous reports, none of the encephalopathic group developed glutaric aciduria, and i.v. methylene blue did not reverse neurotoxicity in the two patients who received it. The results suggest that ifosfamide nephrotoxicity involves both cortical and medullary regions of the nephron and that the urinary mesna:dimesna ratio may be important in assessing the degree of cytoprotection. This study demonstrates that 1H NMR can provide novel biochemical information on ifosfamide-induced toxicity and will be of value in the optimization of ifosfamide therapy.