*David Azria, Claire Lemanski
Department of Radiation Oncology and INSERM U896, Institut du Cancer Montpellier, 34298 Montpellier, France [email protected]
We declare that we have no conﬂicts of interest. 1
3 4 5
Gunderson LL, Cohen AC, Dosoretz DD, et al. Residual, unresectable, or recurrent colorectal cancer: external beam irradiation and intraoperative electron beam boost +/- resection. Int J Radiat Oncol Biol Phys 1983; 9: 1597–606. Dubois JB, Bussieres E, Richaud P, et al. Intra-operative radiotherapy of rectal cancer: results of the French multi-institutional randomized study. Radiother Oncol 2011; 98: 298–303. Dubois JB, Hay M, Gely S, et al. IORT in breast carcinomas. Front Radiat Ther Oncol 1997; 31: 131–37. Merrick HW 3rd, Battle JA, Padgett BJ, et al. IORT for early breast cancer: a report on long-term results. Front Radiat Ther Oncol 1997; 31: 126–30. Bartelink H, Horiot JC, Poortmans PM, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001; 345: 1378–87. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Eﬀect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10 801 women in 17 randomised trials. Lancet 2011; 378: 1707–16. Vaidya JS, Wenz F, Bulsara M, et al, on behalf of the TARGIT trialists’ group. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast-cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet 2013; published online Nov 11. http://dx.doi.org/10.1016/S0140-6736(13)61950-9. Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol 2013; published online Nov 11. http://dx.doi.org/10.1016/S1040-2045(13)70497-2.
Vaidya JS, Joseph DJ, Tobias JS, et al. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial. Lancet 2010; 376: 91–102. Lemanski C, Azria D, Gourgou-Bourgade S, et al. Electrons for intraoperative radiotherapy in selected breast-cancer patients: late results of the Montpellier phase II trial. Radiat Oncol 2013; 8: 191. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys 2009; 74: 987–1001. Schiller DE, Le LW, Cho BC, et al. Factors associated with negative margins of lumpectomy specimen: potential use in selecting patients for intraoperative radiotherapy. Ann Surg Oncol 2008; 15: 833–42. Poortmans P, Struikmans H, Kirkove C, et al. Irradiation of the internal mammary and medial supraclavicular lymph nodes in stage I to III breast cancer: 10 year results of the EORTC Radiation Oncology and Breast Cancer Groups phase III trial 22922/10925. European Cancer Congress; Amsterdam; Sept 27–Oct 1, 2013. Abstract BA2. Andre F, Broglio K, Pusztai L, et al. Estrogen receptor expression and docetaxel eﬃcacy in patients with metastatic breast cancer: a pooled analysis of four randomized trials. Oncologist 2010; 15: 476–83. Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol 2013; 31: 2382–87. Haviland JS, Owen JR, Dewar JA, et al. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol 2013; 14: 1086–94. Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med 2010; 362: 513–20. Bartelink H, Arriagada R. Hypofractionation in radiotherapy for breast cancer. Lancet 2008; 371: 1050–52.
Management of unruptured brain arteriovenous malformations The goal of treatment of arteriovenous malformations is to eliminate risk of intracerebral haemorrhage and to preserve functional status. After diagnosis of an unruptured or asymptomatic arteriovenous malformation, the patient can be conservatively monitored with the understanding that future haemorrhage or seizure might occur. Alternatively, treatment can be oﬀered such that long-term beneﬁts of cure are weighed against the risks of that intervention. Microsurgery, endovascular embolisation, and radiosurgery are three major forms of intervention for arteriovenous malformations, and they have been used successfully as individual interventions and in combinations. Irrespective of the technique chosen, the ultimate goal is complete obliteration of the origin of the arteriovenous malformation (nidus obliteration), because subtotal treatment does not confer protection against future haemorrhage and can worsen disease history. For unruptured arteriovenous malformations, existing guidelines for treatment, long-term natural history, and outcomes of haemorrhage are controversial. A study1 www.thelancet.com Vol 383 February 15, 2014
of patients harbouring arteriovenous malformations without evidence of previous haemorrhage suggested that there was no diﬀerence in outcome between treated and untreated patients at the end of the third year of follow-up. This ﬁnding shows the need for further clariﬁcation of the natural history of the disorder and optimum management strategies for unruptured arteriovenous malformations. In this issue of The Lancet, Jay Mohr and colleagues2 present a prospective, multicentre, randomised trial comparing the eﬃcacy of medical management plus interventional therapy (which included microsurgery, embolisation, or radiosurgery, or combinations of these techniques) versus medical management alone (the ARUBA trial). The form of interventional therapy was determined by the treating physicians in the trial. The primary endpoint of the study was time until death or stroke, and the secondary endpoint was death or disability at 5 years. Enrolment was halted after 33 months, when data for 223 patients were available, because of apparently better outcomes of patients
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in the medical management group (n=109) versus those in the interventional therapy group (n=114). Mohr and colleagues are to be commended for their eﬀorts to clarify the natural history of arteriovenous malformations and the treatment eﬀects of medical management versus interventional therapy on outcomes for patients. The results conﬁrm previous data with a 2·2% (95% CI 0·9–4·5) annualised haemorrhage risk for patients followed up without interventional therapy. Thereafter, the message of this study is less clear. First, only 13% (226 of 1740) of initially screened patients were randomised in the trial. The remainder were excluded mainly because they had evidence or history of previous haemorrhage or other mode of intervention. The exclusion criteria, therefore, eliminate patients with potentially more aggressive natural histories, incorporating selection bias into the study. However, such patients represent a large portion of those with unruptured arteriovenous malformations in the community, thereby compromising the generalisability of the study’s ﬁndings. Second, enrolment was halted because of the frequency with which the primary endpoint was reached in the interventional therapy group (30·7% [35 patients]) as compared with the medical management group (10·1% [11 patients]; hazard ratio 0·27, 95% CI 0·14–0·54). However, for a disease with a long natural history, mean follow-up of 33 months (SD 19·7) is potentially too short a follow-up period to meaningfully establish the long-term eﬃcacy of treatment. It is also clinically misleading to state that 582
patients managed conservatively will be less likely to reach the secondary endpoint, because patients remain at risk of arteriovenous malformation haemorrhage throughout their lives. The short follow-up also favours the medical management group because all risk is accepted early with interventional therapy, and bleeding risk might have a bimodal distribution in regard to age, not necessarily represented in the selection of patients.3,4 Finally, the bias for treatment in the interventional therapy group towards single-method therapy with predominantly either endovascular embolisation (n=30) or radiotherapy (n=31), and the resulting small number of patients referred for neurosurgery (microsurgical resection alone or in combination; n=17), is highly likely to have biased the trial in favour of medical management. Treatment protocols for speciﬁc Spetzler-Martin grades are also not clear, thereby creating heterogeneity in management approaches. Many centres use standard algorithms to create rational and consistent therapy.5 Embolisation and radiotherapy as unilateral treatment approaches arguably oﬀer suboptimum and delayed curative nidus obliteration compared with microsurgical resection, the gold standard. In large cohorts of patients treated with embolisation alone, achievement of cure is 15–50%.6–11 Equally controversial is the fact that subtotal embolisation can change the natural history of arteriovenous malformations for the worse, by altering ﬂow dynamics or preferentially obliterating venous drainage, resulting in iatrogenic haemorrhage. The study oﬀers no detailed description of the nature of the arteriovenous malformation in patients who received embolisation, and whether total embolisation was even accomplished in these patients. As for stereotactic radiosurgery, cure has been estimated to be 80%, at best, at 2-year follow-up.12,13 Although radiotherapy oﬀers better curative rates than embolisation alone, radiotherapy’s drawback is delay in obliteration, rendering the patient at continued risk for haemorrhage during that time period. Neither embolisation nor radiotherapy as sole treatment approaches oﬀer the immediate or longterm cure rates of microsurgical resection. Similarly, complication rates related to microsurgical resection have been well-described in the scientiﬁc literature, and historically are lower than those reported for the interventional therapy group in ARUBA, especially for smaller lesions (which were the majority of lesions in www.thelancet.com Vol 383 February 15, 2014
ARUBA).14 The primary and secondary endpoints for the interventional therapy group in no way represent previously reported pure surgical complication rates— perhaps indicative of expertise in the study centres. In summary, ARUBA is a valiant eﬀort to help improve understanding of brain arteriovenous malformation natural history and treatment risks. The study clearly shows the need for multimodal interventions and longterm follow-up, which were used on a limited basis in this study and aﬀected the outcomes. Embolisation and radiotherapy represent alternatives to the gold standard, which is microsurgical resection. To use them as the major form of treatment in the intervention group skews the results towards suboptimum nidus obliteration, and ultimately biases the medical management group of the study.
Jared Knopman, *Philip E Stieg
Weill Cornell Medical College, New York, NY 10021, USA [email protected]
We declare that we have no competing interests.
Wedderburn CJ, van Beijnum J, Bhattacharya JJ, et al. Outcome after interventional or conservative management of unruptured brain arteriovenous malformations: a prospective, population-based cohort study. Lancet Neurol 2008; 7: 223–30.
Mohr JP, Parides MK, Stapf C, et al, for the international ARUBA investigators. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet 2014; 383: 614–21. Yamada S, Takagi Y, Nozaki K, et al. Risk factors for subsequent haemorrhage in patients with cerebral arteriovenous malformations. J Neurosurg 2007; 107: 965–72. Stapf C, Mast HH, Sciacca RR, et al. Predictors of haemorrhage in patients with untreated brain arteriovenous malformation. Neurology 2006; 66: 1350–55. Stieg PE, Janardhan V, Riina HA. Multimodality therapy: treatment algorithms. In: Steig PE, Batjer HH, Samson D, eds. Intracranial arteriovenous malformations. New York: Informa Healthcare USA, 2007: 135–44. Winn HR, Youmans JR. Endovascular management of arteriovenous malformations for cure. In: Winn RH, ed. Youmans neurological surgery, 6th edn. Philadelphia: W B Saunders, 2011: 4065–71. Katsaridis V, Papagiannaki C, Aimer E. Curative embolization of cerebral arteriovenous malformations (AVMs) with Onyx in 101 patients. Neuroradiology 2008; 50: 589–97. Mounayer C, Hammami N, Piotin M, et al. Nidal embolization of brain arteriovenous malformations using Onyx in 94 patients. AJNR Am J Neuroradiol 2007; 28: 518–23. Van Rooij WJ, Sluzewski M, Beute GN. Brain AVM embolization with onyx. AJNR Am J Neuroradiol 2007; 28: 172–78. Weber W, Kis B, Siekmann R, et al. Preoperative embolization of intracranial arteriovenous malformations with Onyx. Neurosurgery 2007; 61: 244–54. Florio F, Lauriola W, Nardella M, et al. Endovascular treatment of intracranial arterio-venous malformations with Onyx embolization: preliminary experience. Radiol Med (Torino) 2003; 106: 512–20. Lunsford LD, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for arteriovenous malformations of the brain. J Neurosurg 1991; 75: 512–24. Steiner L, Lindquist C, Adler JR, et al. Clinical outcome of radiosurgery for cerebral arteriovenous malformations. J Neurosurg 1992; 77: 1–8. Spetzler R, Martin N. A proposed grading system for arteriovenous malformations. J Neurosurg 1986; 65: 476–83.
Resistant hypertension and renal denervation: 3 years on In 2009, Henry Krum and colleagues1 published the initial report of the landmark Symplicity HTN-1 trial, which assessed the blood-pressure-lowering action of renal denervation (RDN) in patients with resistant hypertension (ﬁgure). It immediately created a ripple in the worldwide hypertension community and refocused attention on the kidney and its innervation as therapeutic targets for the treatment of chronically raised blood pressure.1,2 At the time of reporting, patients had been followed-up for 12 months. Now, in The Lancet, Krum and colleagues report the 3-year outcomes,3 which extend the observations in 88 of the original cohort of 153 patients. The data add solidity to the original ﬁndings. Substantial reductions were seen in systolic and diastolic blood pressure at 3 years (systolic –32·0 mm Hg, 95% CI –35·7 to −28·2, and diastolic –14·4 mm Hg, –16·9 to –11·9). Drops of 10 mm Hg or more in systolic blood pressure were taken to be clinically relevant, and the proportion of patients in whom such changes were seen increased over time: 69% of patients www.thelancet.com Vol 383 February 15, 2014
at 1 month, 81% at 6 months, 85% at 12 months, 83% at 24 months, and 93% at 36 months. The 2009 report gave rise to several questions and major criticisms, some of which are addressed by the long-term ﬁndings. An immediate question was whether re-innervation would be seen after 12 months, accompanied by a gradual return of blood pressure to hypertensive levels. Indeed, in heart-transplant recipients there is anatomical evidence of re-innervation beginning 2 years after transplantation, but the degree of functional eﬀectiveness is uncertain. Experimental evidence suggests that in the kidney sympathetic and aﬀerent reinnervation takes place at a similar rate.4,5 The persistently lowered blood pressures reported by Krum and colleagues, however, argue against re-innervation or, if it does take place, that the nerves no longer contribute in the same way to the positive feedback loop that causes the hypertensive state. Assessment of noradrenaline spillover would provide a deﬁnitive answer to this question, but would require substantial investment of resources.
Published Online November 7, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)61999-6 See Articles page 622