R L Souhami

University College London, Londinium, England, United Kingdom

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Publications (159)1271.45 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: SummaryBackground 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
    The Lancet 01/2010; 375(9722):1267-1277. · 39.21 Impact Factor
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    ABSTRACT: A case of T-cell lymphoma with an unusual phenotype is described. The majority of malignant tumour cells did not form E-rosettes, and lacked surface immunoglobulin but reacted with an antiserum to T cells and thymocytes. Localised acid phosphatase and non-specific alpha naphthol acid esterase activities and a prominent, convoluted, nuclear pattern in some neoplastic cells also supported the T cell derivation. The results demonstrate the importance of using a panel of markers for identification of the cellular derivation of some lymphomas.
    European Journal Of Haematology 04/2009; 19(4):411 - 415. · 2.55 Impact Factor
  • J. Clin Oncology. 01/2008; 26:4617-4625.
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    ABSTRACT: A meta-analysis of trials comparing primary treatment with or without chemotherapy for patients with non-small cell lung cancer published in 1995 suggested a survival benefit for cisplatin-based chemotherapy in each of the primary treatment settings studied, but it included many small trials, and trials with differing eligibility criteria and chemotherapy regimens. Methods: The Big Lung Trial was a large pragmatic trial designed to confirm the survival benefits seen in the meta-analysis, and this paper reports the findings in the radical radiotherapy setting. The trial closed before the required sample size was achieved due to slow accrual, with a total of 288 patients randomised to receive radical radiotherapy alone (146 patients) or sequential radical radiotherapy and cisplatin-based chemotherapy (142 patients). There was no evidence that patients allocated sequential chemotherapy and radical radiotherapy had a better survival than those allocated radical radiotherapy alone, HR 1.07 (95% CI 0.84-1.38, P=0.57), median survival 13.0 months for the sequential group and 13.2 for the radical radiotherapy alone group. In addition, exploratory analyses could not identify any subgroup that might benefit more or less from chemotherapy. Despite not suggesting a survival benefit for the sequential addition of chemotherapy to radical radiotherapy, possibly because of the relatively small sample size and consequently wide confidence intervals, the results can still be regarded as consistent with the meta-analysis, and other similarly designed recently published large trials. Combining all these results suggests there may be a small median survival benefit with chemotherapy of between 2 and 8 weeks.
    Radiotherapy and Oncology 06/2005; 75(2):134-140. · 4.52 Impact Factor
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    ABSTRACT: 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. 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). 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. 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.
    Thorax 11/2004; 59(10):828-36. · 8.38 Impact Factor
  • The Lancet Oncology 10/2002; 3(10):590–591. · 25.12 Impact Factor
  • The Lancet 01/2002; 359(9300):76–77. · 39.21 Impact Factor
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    ABSTRACT: 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. 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. 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. 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.
    The Lancet 09/2001; 358(9279):375-81. · 39.21 Impact Factor
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    ABSTRACT: 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. 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. 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). MIC chemotherapy prolongs survival in unresectable NSCLC without compromising QOL.
    Journal of Clinical Oncology 11/1999; 17(10):3188-94. · 18.04 Impact Factor
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    ABSTRACT: 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.
    Clinical Cancer Research 04/1999; 5(3):507-12. · 7.84 Impact Factor
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    ABSTRACT: 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.
    Nucleic Acids Research 01/1999; 26(24):5617-23. · 8.81 Impact Factor
  • The Lancet 10/1998; 352(9137):1385–1386. · 39.21 Impact Factor
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    ABSTRACT: 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.
    European Journal of Cancer 10/1998; 34(10):1554-9. · 5.06 Impact Factor
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    ABSTRACT: 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.
    British Journal of Cancer 03/1998; 77(6):978-84. · 5.08 Impact Factor
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    ABSTRACT: 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.
    Sarcoma 01/1998; 2(2):97-105.
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    ABSTRACT: Progress in the assessment and introduction of new treatments is impeded by the failure to recruit eligible patients into clinical trials. Little is known about the attitudes of U.K. cancer specialists towards trial participation, therefore a postal survey was conducted of 553 British clinical, medical and surgical oncologists. A 45-item questionnaire was returned by 357 clinicians (65% response rate). Although 353 (99%) of respondents stated that they were participating in trials, median 3 (range 0-62), 269 (75%) of clinicians were entering fewer than 50% of eligible patients. Differences were seen between professional groups within oncology; medical oncologists placed more emphasis on research than on clinical activities, felt greater pressure to participate in trials and were more likely to value being known by national and international colleagues than did surgeons or clinical oncologists. Surgeons were more likely to rely on clinical experience rather than enter patients into a trial but were more likely to keep patients on study following relapse. The survey identified constraints imposed by the healthcare system which impede trial participation including lack of time, communication difficulties and conflicts between the role of clinician and scientist. Such factors need consideration when trials are designed. Comparison of British data with those from the U.S. clinicians were broadly similar. The few differences found suggest that the more protocol-driven culture of the U.S. might encourage recruitment and a greater commitment to keep patients on trials.
    European Journal of Cancer 12/1997; 33(13):2221-9. · 5.06 Impact Factor
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    ABSTRACT: 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.
    Clinical Cancer Research 10/1997; 3(9):1507-18. · 7.84 Impact Factor
  • Lung Cancer 07/1997; 18:5-5. · 3.39 Impact Factor
  • Lung Cancer 07/1997; 18:20-20. · 3.39 Impact Factor
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    ABSTRACT: 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.
    European Respiratory Journal 07/1997; 10(7):1552-8. · 6.36 Impact Factor

Publication Stats

3k Citations
1,271.45 Total Impact Points

Institutions

  • 1984–2001
    • University College London
      • • Royal Free Hospital
      • • Department of Oncology
      • • Department of Haematology
      • • Department of Statistical Science
      • • Division of Medicine
      Londinium, England, United Kingdom
  • 1999
    • Queen Elizabeth Hospital Birmingham
      Birmingham, England, United Kingdom
  • 1998
    • Medical Research Council (UK)
      • MRC Clinical Trials Unit
      Londinium, England, United Kingdom
  • 1997
    • University of London
      Londinium, England, United Kingdom
  • 1989–1994
    • Middlesex University, UK
      Londinium, England, United Kingdom
  • 1991–1992
    • The Courtauld Institute of Art
      Londinium, England, United Kingdom
    • Imperial College London
      Londinium, England, United Kingdom
  • 1988
    • Institut de Cancérologie Gustave Roussy
      • Department of Radiotherapy
      Villejuif, Ile-de-France, France
  • 1978
    • Saint Mary's Hospital Center
      Montréal, Quebec, Canada