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MVP and vinorelbine for malignant pleural mesothelioma



  Research by the Organisation for          commodity derivatives trading and                       a pathologist. Several studies have
Economic Co-operation and Develop-          food price increases, its magnitude,                    highlighted the necessity for central
ment3 and testimony presented by            and, eventually, the causal direction                   pathological review because 30% can
Masters to the US Senate4 state that        of this relation. However, the case for                 have misleading diagnoses.2,3 Third,
the sharp increase in prices might          improved market transparency and                        addition of vinorelbine showed a non-
be caused by increasingly large long        regulation is urgent.                                   significant survival advantage over
positions (buying contracts) placed         We declare that we have no conflict of interest.         active symptom control alone (hazard
by institutional investors, also called                                                             ratio 0·80, 95% CI 0·63–1·02; p=0·08)
index traders, such as corporate
                                            *Noemi Pace, Andrew Seal,                               in an exploratory analysis.
                                            Anthony Costello
and government pension funds,                                                                         The standard chemotherapy regi-
sovereign wealth funds, and university                                                              men since 2003 has now moved to
                                            UCL Centre for International Health and
endowments. Masters4 highlights how         Development, 30 Guilford St, London WC1N 1EH, UK
                                                                                                    cisplatin plus pemetrexed. This com-
institutional investors buy futures                                                                 bination showed a significant benefit
                                            1    Chan KC, Fung HG, Leung WK. Daily volatility
and then extend their positions by               behavior in Chinese futures markets.               in overall survival in a randomised trial
buying calendar spreads. In this way,            J Int Financial Markets Institutions Money 2004;   when compared with cisplatin alone.4
                                                 14: 491–505.
they consume liquidity and provide          2    Yang J, Balyeat RB, Leatham DJ. Futures trading
                                                                                                    For all these reasons, we believe
zero benefit to the futures markets.              activity and commodity cash price volatility.      that pemetrexed-based regimens
Two of his three proposed actions could          J Business Finance Accounting 2005; 32: 297–323.   are to date the best option in this
                                            3    Organisation for Economic Co-operation and
be implemented—ie, to modify the                 Development. A note on the role of                 setting. Active symptom control or
regulations of pension funds to prohibit         investment capital in the US agricultural          vinorelbine offer the advantage of
                                                 futures markets and the possible effect on cash
commodity index replication strategies           prices. Document TAD/CA/APM/CFS/
                                                                                                    immediate tolerability and lower cost,
and to act to close the swaps loophole.          MD(2008)6. Paris: OECD, 2008.                      but evidence clearly favours a more
  Second, we agree with Power that          4    Testimony of Michael W Masters, Managing           aggressive option for these patients.
                                                 Member/Portfolio Manager Masters Capital
commodity exchanges already have                 Management, LLC before the Committee on            We declare that we have no conflict of interest.
an incentive to increase margin levels,          Homeland Security and Governmental Affairs,
as an insurance mechanism, during                United States Senate.     *P Mordant, Y Loriot, J C Soria,
                                                 public/_files/052008Masters.pdf (accessed           E Deutsch
periods of high volatility. However,             Aug 5, 2008).
even though the effect of margin             5    Dutt HR, Wein IL. Revisiting the empirical
                                                 estimation of the effect of margin changes on       Department of Medicine, Institut Gustave Roussy,
requirements is controversial, we                futures trading volume. J Futures Markets 2003;    94805 Villejuif Cedex, France
support the findings of Dutt and Wein,5           23: 561–65.
                                                                                                    1    Muers MF, Stephens RJ, Fisher P, et al. Active
which suggest that, after adjusting                                                                      symptom control with or without
for risk, there is an economically and                                                                   chemotherapy in the treatment of patients
                                                                                                         with malignant pleural mesothelioma (MS01):
statistically significant negative effect     MVP and vinorelbine for                                      a multicentre randomised trial. Lancet 2008;
of margin requirements on trading                                                                        371: 1685–94.
volume as predicted by theory.
                                            malignant pleural                                       2    Betta PG, Andrion A, Donna A, et al. Malignant
                                                                                                         mesothelioma of the pleura: the
  Finally, we agree, of course, that the    mesothelioma                                                 reproducibility of the immunohistological
laws of supply and demand are driving                                                                    diagnosis. Pathol Res Pract 1997; 193: 759–65.
                                                                                                    3    Andrion A, Magnani C, Betta PG, et al.
the slow upward trend noticeable since      Martin Muers and colleagues                                  Malignant mesothelioma of the pleura:
2000. However, they still fail to explain   (May 17, p 1685)1 found that addition                        interobserver variability. J Clin Pathol 1995;
the recent sharp increase in prices.        of chemotherapy, either with MVP                             48: 856–60.
                                                                                                    4    Vogelzang NJ, Rusthoven JJ, Symanowski J,
Moreover, the same Commodity                (mitomycin, vinblastine, cisplatin)                          et al. Phase III study of pemetrexed in
Futures Trading Commission com-             or vinorelbine, to active symptom                            combination with cisplatin versus cisplatin
                                                                                                         alone in patients with malignant pleural
munication cited by Power states            control had no significant benefit in                          mesothelioma. J Clin Oncol 2003;
that “it is clear that more analysis and    terms of overall survival in patients                        21: 2636–44.
research about index trading needs to       with malignant mesothelioma. Their
occur in order to inform this debate        conclusion suggests that vinorelbine                    Authors’ reply
and CFTC staff will be studying ways         merits further investigation. However,                  Improving the outcomes of patients
to improve the transparency and             this conclusion is misleading, because                  with malignant pleural mesothelioma
efficiency of the markets regarding           of potential methodological pitfalls.                   is a major challenge. Mesothelioma
these types of traders”.                      First, the trial design was changed                   is a relatively rare disease, patients
  We are aware that more technical          from a three-group to a two-group                       tend to be elderly and symptomatic,
studies, involving time series and          comparison because of a slow accrual.                   and, beyond palliation, treatment
causality tests, are needed to confirm       Second, the pathological diagnosis                      options are limited: radical surgery
any relation between the volume of          was not systematically reviewed by                      is only possible for a small minority Vol 372 August 23, 2008                                                                                                                              629

                   of patients, radical radiotherapy is       for the use of cisplatin, for the                          The knowledge gained through
                   inappropriate, and few chemotherapy        cisplatin/gemcitabine regimen, for                       scientific inquiry undertaken within
                   drugs have shown sufficient activity in      single-agent pemetrexed, for the use                     the NHS benefits patients and im-
                   phase II studies to be taken forward to    of any new agents, or indeed to show                     proves national prosperity. Since our
                   randomised trials. Our paper is one of     that more aggressive treatment is the                    2003 report, Strengthening clinical
                   the few large randomised trials in this    preferred option. However, the current                   research,2 the Academy of Medical
                   disease and therefore provides some        lack of randomised evidence does not                     Sciences has championed the need
                   of the most reliable treatment data.       justify comparing median survivals                       for greater partnership between uni-
                      P Mordant and colleagues question       across trials (as used by Vogelzang4),                   versities, industry, and the NHS to
                   our conclusion that vinorelbine merits     since this is clearly unreliable given                   drive innovation and deliver better
                   further investigation. We stand by         the variability in patient selection.                    health care. The Academic Health
                   our conclusion. Our reference histo-       Although new randomised trials                           Science Centres and proposed Health
                   pathologist (a professor of respi-         are urgently needed, the future, as                      Innovation and Education clusters will
                   ratory pathology) reviewed 105 slides      with most cancers, probably lies in                      build on the momentum generated
                   and did not reject any outright. The       the identification of biomarkers and                      by David Cooksey’s review of UK
                   two interobserver variation studies        subsequent targeted treatment.                           health research, the establishment
                   referenced by Mordant and colleagues       RJS has received honoraria from Pierre Fabre             of the National Institute for Health
                   predate the wealth of published data on    Oncology for lecturing at meetings. The other            Research, and the formation of the
                                                              authors declare that they have no conflict of interest.
                   several“mesothelioma-associated”anti-                                                               Office for the Strategic Coordina-
                   bodies and the increased accuracy in       Martin F Muers, Patricia Fisher,                         tion of Health Research. Moreover,
                   premortem diagnosis,1,2 some of these      Andrew G Nicholson,                                      implementation of the reforms first
                   antibodies being used in the validation    *Richard J Stephens,                                     proposed by John Tooke will do much
                   of mesothelioma diagnosis in this trial.   Mahesh K B Parmar                                        to address the difficulties experienced
                      The change of trial design was                                         in medical training and education in
                   done without knowledge of the              Leeds General Infirmary, Leeds, UK (MFM); Weston          recent years.
                   accumulating results of the trial, and     Park Hospital, Sheffield, UK (PF); Royal Brompton            Innovation must be at the heart of
                                                              Hospital, London, UK (AGN); and Medical Research
                   we emphasised that the finding that         Council Clinical Trials Unit, London NW1 2DA, UK
                                                                                                                       future improvements in clinical service
                   the addition of vinorelbine to active      (RJS, MKBP)                                              for the benefit of patients. Darzi’s
                   symptom control resulted in about          1    Ordonez NG. The immunohistochemical                 report sets out this case clearly, and we
                   a 2-month survival benefit com-                  diagnosis of mesothelioma: a comparative            must all work together to deliver this
                                                                   study of epithelioid mesothelioma and lung
                   pared with active symptom control               adenocarcinoma. Am J Surg Pathol 2003;              agenda.
                   alone could only be considered as               27: 1031–51.                                        I declare that I have no confict of interest.
                   hypothesis-generating. This potential      2    Ordonez NG. Immunohistochemical diagnosis

                   survival benefit is on a par with that
                                                                   of epithelioid mesothelioma: an update.             John Bell
                                                                   Arch Pathol Lab Med 2005; 129: 1407–14.
                   seen with pemetrexed,3 and, given          3    Vogelzang NJ, Rusthoven JJ, Symanowski J,
                                                                   et al. Phase III study of pemetrexed in             Academy of Medical Sciences, London SW1Y 5AH,
                   the paucity of treatment options, we            combination with cisplartin versus cisplatin        UK
                   therefore continue to feel that this            alone in patients with malignant pleural
                                                                   mesothelioma. J Clin Oncol 2003;                    1     Horton R. The Darzi vision: quality,
                   drug should be investigated further,                                                                      engagement, and professionalism. Lancet
                                                                   21: 2636–44.
                   especially because a potential survival    4    Vogelzang NJ. Chemotherapy for malignant
                                                                                                                             2008; 372: 3–4.
                   benefit was seen compared with the               mesothelioma. Lancet 2008; 371: 1640–42.            2     Bell J, Day N, Dollery C, et al. Strengthening
                                                                                                                             clinical research. London: Academy of Medical
                   cisplatin-based regimen (hazard ratio                                                                     Sciences, 2003.
                   0·77, 95% CI 0·61–0·99; p=0·04).                                                                          index.php?pid=48&prid=18 (accessed Aug 13,
                      The treatment of mesothelioma           Medical research in the
                   cannot necessarily be extrapolated
                   from non-small-cell lung cancer,
                                                              Darzi review
                   and there could be a place for less        In response to Richard Horton’s
                   aggressive first-line single-agent          Comment (July 5, p 3),1 I would like
                   chemotherapy in patients deemed            to take this opportunity to applaud
                   unfit for platinum-based treatment,         Ara Darzi’s vision of putting quality
                   which will be the case for most            at the heart of the UK’s National
                   patients as the age at presentation        Health Service (NHS). It is particularly
Ara Darzi          increases remorselessly. Lack of           welcome to see that medical research
                   clinical trials means that we have         is given a central role in fulfilling this
                   no reliable randomised evidence            new quality-driven manifesto.

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