Eric Foucault
email: eric.foucault@univ-poitiers.fr

Philippe Szeger
email: philippe.szeger@univ-poitiers.fr

Unsteady Flowmeter

Keywords: Unsteady flow rate, flowmeter, intake combustion engine, pulsating flow, backflow

An original method is presented to measure time resolved unsteady flow rate. From the kinetic energy theorem, the balance equation of the kinetic energy is integrated on a conical control volume (Venturi type). A non-linear ODE is obtained, simple enough to be resolved in real-time (that is to say in less than one time step). The two coefficients of the ODE depend only on the geometry of the device and are hence known by construction, it is therefore not necessary to calibrate the device. Experimental measurements at the intake of a combustion engine show that the device provides unsteady flow rate. By temporal integration, the unsteady measurements give a mean flow rate close to the reference flowmeter.

The same analysis is then applied to a cylindrical control volume with a singular pressure drop (induce by a grid for example). In this case, one of the two coefficients of the ODE must be determined experimentally. Experimental measurements carried out with this device at the intake of a combustion engine show that this second method follows the flow fluctuations. A good agreement is found between unsteady measurements integrated over a whole number of periods and reference mass flowmeter. The inversions of direction of the flow are taken into account by the prototype. This device, more compact than the conical version (Venturi type), allows real-time measurements of the unsteady flow rate.

Introduction :

The flow measurement in pipes goes back to the origin of fluid mechanics and has remained one of a most common operations. There are virtually innumerable numbers of more or less advanced techniques for measuring average flow rates, but there are currently no flowmeters for time resolved measurements of unsteady flow rates. In a number of cases, only the mean flow rate is of interest to the user, either because more information is not useful to the process, or because it ignores the possibility of having access to unsteady flow rate. However it is necessary that the techniques used to measure the mean flow rate are not disturbed if there is also a more or less strongly unsteady velocity component. A large number of articles are devoted to this problem, and look at ways to prevent fluctuations from disturbing average measurements. (e.g. [START_REF] Gajan | The influence of pulsating flows on orifice plate flowmeters[END_REF], [START_REF] Bokhorst | Optimisation of flow measurements in a pulsating flow-experiences from field measurements[END_REF], [START_REF] Laurantzon | Response of common flowmeters to unsteady flow[END_REF]).

Several ways have been proposed to access unsteady flow rate without having to spatially integrate spot velocity measurements. In case of pulsating laminar flows, authors [START_REF] Durst | Method for defined mass flow variations in time and its application to test a mass flow rate meter for pulsating flows[END_REF][START_REF] Ray | Mass Flow Rate Controlled Fully Developed Laminar Pulsating Pipe Flows[END_REF] have shown that for low frequencies (≤ 1 Hz) the mass flow rate of the mean flow and that of the pulsating flow can be separated and both can be accurately measured.

It appears that it would be much better to measure the actual flow rate, even if it means to average it, than to try to measure only the continuous component of it. The purpose of this article is to propose a solution to measure the unsteady flow rate in a pipe.

Patents from 2005 and 2007 [START_REF] Foucault | Unsteady Flow Meter, Brevet n o WO2005080924A1[END_REF][START_REF] Foucault | Real-time Non-stationary Flowmeter[END_REF] claim to be able to access the unsteady flow rate in a pipe from pressure drop. An ordinary differential equation (ODE) similar to Eq. [START_REF] Lambossy | Oscillations forcées d'un liquide incompressibile et visqueux dans un tube rigide et horizontal. Calcul de la force frottement[END_REF] below is suggest without giving any justification.

This idea is taken up by Beaulieu et al [START_REF] Beaulieu | A flowmeter for unsteady liquid flow measurements[END_REF] which show that this principle can be use to measure the pulsating flow rate that enters a mechanical breathing system with sufficient precision. However this does not justify the geometric constants A and B of Eq. [START_REF] Lambossy | Oscillations forcées d'un liquide incompressibile et visqueux dans un tube rigide et horizontal. Calcul de la force frottement[END_REF]. The results were experimentally validated and the prototype was tested using water. The velocity profiles were measured by particle image velocimetry (PIV) and the equipment was calibrated using an ultrasonic meter. The Venturi discharge coefficient was determined as a function of the Reynolds number for steady flows and pulsating flows of low frequencies (≤ 4 Hz) with concurrence of the results. Doblhoff-Dier et al. [START_REF] Doblhoff-Dier | Time resolved measurement of pulsating flow using orifices[END_REF] also obtained time-resolved measurements using orifice plates with an equation very similar to Eq. [START_REF] Lambossy | Oscillations forcées d'un liquide incompressibile et visqueux dans un tube rigide et horizontal. Calcul de la force frottement[END_REF]. They concluded that this equation might yield fair results as long as the ratio of the velocity pulsating component v to ωd/2 is no higher than 10. They argue that for higher ratios other effects, such as nonlinear impedance come into play. In spite of all the care brought to the pressure measurements, in particular to the tube connections and the phenomena of resonance, the bandwidth of their system was not sufficient for the higher modes of pulsation. This delicate point will be addressed below when describing the system. A recent review of pulsed flow measurements by orifices plates flowmeters can be found in Reis and Hanriot [START_REF] Reis | Incompressible pulsating flow for low Reynolds numbers in orifice plates[END_REF]. This shows that for low Reynolds number values at least,the inertial effects significantly affect the value of the discharge coefficient of the orifice plate, reducing the discharge values. It can be concluded in any case, orifice flowmeters, because of the recirculation they generate upstream and downstream of the orifice, are not good candidates for precise pulsated flow measurements. Johnston et al. [START_REF] Johnston | Use of Pipeline Wave Propagation Model for Measuring Unsteady Flow Rate[END_REF] have presented original measurement methods based on the wave propagation model to determine the flow rate using measured pressures as boundary conditions. Experiments have show that method with three transducers is robust and reliable but the implementation requires relatively long pipes length (typically several meters). This method must be further developed to allow the measurement of the mean flow rate and be relevant in turbulent regime.

The present work focuses on the measurement of unsteady flow in a pipe from a differential pressure measurement. First it is necessary to establish a differential equation allowing access to the unsteady flow rate in a pipe. This will show that the two constants A and B can be known by construction and that the proposed model therefore requires no calibration. Then two applications of the system are proposed: a flowmeter whose differential pressure is due to an increase in the flow velocity (Venturi type flowmeter) and a flowmeter whose differential pressure is due to a singular pressure drop (flowmeter with a grid). The system can extend to many other configurations using for example a pressure drop already present in the pipe where flow is to be known. The main applications targeted by this study are pulsated flows at the intake or exhaust of combustion engines.

Theorical framework:

A relationship between unsteady mass flow and the associated pressure drop is easy to find in pipe flow. The equation kinetic energy balance is well appropriated for this because it avoids the assumptions of non-viscosity and irrotational flow (c.f. [START_REF] Bon | Relation pression-vitesse d'une classe d'écoulement instationnaire : application à la mesure des débits instantanés[END_REF], [START_REF] Peube | Fundamentals of Fluid Mechanics and Transport Phenomena[END_REF]).

Kinetic energy balance:

Application of the kinetic energy balance equation to Hagen-Poiseuille flow.

The kinetic energy balance is obtained by integrating, over a domain D, the local form given by the kinetic energy theorem:

∂ ∂t D 1 2 ρV 2 dτ (I) + ∂D 1 2 ρV 2 ( - → V . - → n ) dσ (II) + ∂D p( - → V . - → n ) dσ (III) + D - → f . - → V dτ (IV ) = ∂D - → τ . - → V dσ (V ) - D φ 1 dτ (V I) (1)
Thus, the temporal variation of kinetic energy over the domain D, added to the kinetic energy and pressure flux across the boundaries of D, is equal to the sum of the power of external viscous stresses exerted on ∂D and the power dissipated in D by viscosity. This means that in inviscid flows, the temporal variation of kinetic energy in D is only due to the kinetic energy and pressure fluxes across the boundaries of D. If the effects of viscosity are not negligible, it will be necessary to estimate them by experimental measurements.

It then remains to establish the conservation of kinetic energy in an axisymmetric domain (i.e. to write the conservation equation of the kinetic energy of a fluid motion in pipe of variable section).

Hypothesis:

1. motion generated by a unsteady longitudinal pressure gradient P = p(x, t) 2. one-dimensional flow:

- → V (x, y, z, t) = V (x, y, z, t) - → x
3. no other volume force than gravity 4. negligible gravitational forces1 : Ω = gz = 0 2.3. Venturi type control volume:

Applying the relation [START_REF] Gajan | The influence of pulsating flows on orifice plate flowmeters[END_REF] to the domain D defined in Fig. 1:

x x S 1 S 2 x D 1 2
Fig. 1. Venturi type cylindrical pipe with axis x and cross-section S(x).

∂ ∂t D 1 2 ρV 2 dτ (I) + S 1 ∪S 2 1 2 ρV 2 ( - → V . - → n ) dσ (II) + S 1 ∪S 2 p( - → V . - → n ) dσ (III) = S 1 ∪S 2 - → τ . - → V dσ (V ) - D φ 1 dτ (V I) (2)
Thus, these terms according to the mass flow q m (t) at the abscissa x:

q m (t) = ρ(x, t)q v (x, t) = ρ(x, t) S(x) - → V (x, y, z, t). - → n dσ = ρ(x, t)S(x)V (x, t) (3)

Time variation of kinetic energy (I) :

The first term (I) of Eq. ( 2) becomes :

∂ ∂t D 1 2 ρ(x, t)V 2 dτ = 1 2 ∂ ∂t q 2 m (t) x 2 x 1 ρ(x, t) q 2 m (t) S(x) V 2 dσ dx = 1 2 ∂ ∂t q 2 m (t) x 2 x 1 ρ(x, t) ρ(x, t) 2 S(x) 1 S(x)V 2 (x, t) S(x) V 2 dσ dx = 1 2 ∂ ∂t q 2 m (t) x 2 x 1 β(x, t) ρ(x, t)S(x) dx = 1 2 ∂ ∂t q 2 m (t)f (t) (4)
with :

f (t) = x 2 x 1 β(x, t) ρ(x, t)S(x) dx (5)
and

β(x, t) = 1 S(x)V 2 (x, t) S(x) - → V 2 (x i , y, z, t)dσ (6)
The function f (t) depends on the shape of the pipe, on the shape of the velocity profile and also on density ρ(x, t).

The dimensionless number β(x, t) characterizes the momentum distribution in the section pipe S(x) at the instant t (i.e. momentum coefficient or shape factor of the velocity profile).

Kinetic energy flux (II) throught

S 1 ∪ S 2 :
The term (II) of the Eq. ( 2) can be expressed in terms of the mass flow rate q m (t) :

S 1 ∪S 2 1 2 ρV 2 ( - → V . - → n )dσ = S 2 1 2 ρ(x 2 , t)V 3 (x 2 , y, z, t)dσ - S 1 1 2 ρ(x 1 , t)V 3 (x 1 , y, z, t)dσ = 1 2 ρ(x 2 , t)α(x 2 , t)S 2 V 3 (x 2 , t) - 1 2 ρ(x 1 , t)α(x 1 , t)S 1 V 3 (x 1 , t) = q 3 m (t) 2 α(x 2 , t) ρ(x 2 , t) 2 S 2 2 - α(x 1 , t) ρ(x 1 , t) 2 S 2 1 (7) with : α(x i , t) = α i (t) = 1 S i V 3 (x i , t) S i - → V 3 (x i , y, z, t)dσ (8)
and

ρ(x i , t) = ρ i (t) (9)
thus :

S 1 ∪S 2 1 2 ρV 2 ( - → V . - → n )dσ = q 3 m (t) 2 α 2 (t) ρ 2 (t) 2 S 2 2 - α 1 (t) ρ 1 (t) 2 S 2 1 (10)
The dimensionless number α i (t) characterizes the distribution of kinetic energy in section S i at instant t (i.e. kinetic energy coefficient or shape factor of the kinetic energy profile). It plays the same role as the β(x, t) coefficient for the shape of the momentum profile.

Power of pressure forces (III) :

Using again the definition of the mass flow rate q m (t) in term (III) of the Eq. ( 2), yields:

S 1 ∪S 2 p( - → V . - → n )dσ = p(x 2 , t) S 2 V (x 2 , t)dσ -p(x 1 , t) S 1 V (x 1 , t)dσ = p(x 2 , t)V (x 2 , t)S 2 -p(x 1 , t)V (x 1 , t)S 1 = q m (t) p(x 2 , t) ρ(x 2 , t) - p(x 1 , t) ρ(x 1 , t) (11)
thus :

S 1 ∪S 2 p( - → V . - → n )dσ = q m (t) p 2 (t) ρ 2 (t) - p 1 (t) ρ 1 (t) (12)
with :

p(x i , t) = p i (t) (13)
Power of the external viscous stress (V):

∂D - → τ . - → V dσ = S 1 ∪S 2 - → τ . - → V dσ = P vs (t) (14)
Without moving walls, the power of external viscous forces exerted on the S 1 ∪ S 2 border of the D domain are summed up by the power of the viscous stress on the sections S 1 and S 2 . Often negligible when compared to the power of pressure forces.

Power dissipated by viscosity (VI) :

D φ 1 dτ = P vD (t)
The power P vD (t) dissipated in D by viscosity is a priori negligible compared to other terms (parallel flow) except in the cases where fluids undergo shear stress in D (e.g. meet an obstacle, a grid, a porous material) as will be seen further on.

Finally:

1 2 ∂ ∂t q 2 m (t)f (x, t) + q 3 m (t) 2 α 2 (t) ρ 2 (t) 2 S 2 2 - α 1 (t) ρ 1 (t) 2 S 2 1 = q m (t) p 1 (t) ρ 1 (t) - p 2 (t) ρ 2 (t) + P vs (t) -P vD (t)

Additional assumptions:

1. In case of fully-developed flows (i.e. whose velocity profile shape, but not amplitude, remains the same at all times), it may be admitted that shape factors α and β are independent of time. 2. If, in addition, we consider only turbulent flows or entrance regimes (i.e.

the velocity is uniformly distributed over the pipe width), the shape factors α and β are uniform and (the thickness to the boundary layers close) are equal to one. Thus:

- → V (x, y, z, t) = V (x, y, z, t) - → x = V (x, t) - → x ; ρ(x, y, z, t) = ρ(x, t
). For pulsating flow, as soon as the frequency exceeds a few Hz, the velocity profile remains constant over the pipe diameter (with the exception of boundary layers of course), regardless of the mean flow. This point is detailed in Appendix A.

3. Except in special cases, the terms (V) and (VI) are negligible. More on this point in the section 2.4.

Taking into account these additional assumptions, a simplification is obtained:

1 2 ∂ ∂t q 2 m (t)f (x, t) + q 3 m (t) 2 1 ρ 2 2 S 2 2 - 1 ρ 2 1 S 2 1 = q m (t) p 1 (t) ρ 1 (t) - p 2 (t) ρ 2 (t) (15)
with:

f (x, t) = x 2 x 1 1 ρ(x, t)S(x) dx
Note that the function f (t) contains ρ(x, t) and will therefore be constant only if the compressibility effects are negligible. If gas density is assumed not to vary between positions 1 and 2, ρ(x, t) = ρ(t):

f (t) = x 2 x 1 1 ρ(x, t)S(x) dx = 1 ρ(t) x 2 x 1 1 S(x) dx = 1 ρ(t) A with : A = x 2 x 1 dx S(x) and df (t) dt = - A ρ(t) 2 dρ(t) dt
the different terms of Equation ( 15) are then written:

(I) 1 2 d dt (q 2 m (t)f (t)) = q m dq m (t) dt f (t) + 1 2 q 2 m (t) df (t) dt (II) q 3 m (t) 2 1 ρ 2 (t) 2 S 2 2 -1 ρ 1 (t) 2 S 2 1 = q 3 m (t) 2ρ(t) 2 1 S 2 2 - 1 S 2 1 = q 3 m (t) ρ(t) 2 B with : B = 1 2 1 S 2 2 - 1 S 2 1 (III) q m (t) p 1 (t) ρ 1 (t) -p 2 (t) ρ 2 (t) = q m (t) ρ(t) (p 1 (t) -p 2 (t)) = q m (t) ρ(t) ∆P (t)
The equation ( 15) becomes :

q m dqm(t) dt 1 ρ(t) A -1 2 q 2 m (t) A ρ(t) 2 dρ(t) dt + q 3 m (t) ρ(t) 2 B = q m (t) ρ(t) ∆P (t) ⇔ dqm(t) dt A -1 2 q m (t) A ρ(t) dρ(t) dt + q 2 m (t) ρ(t) B = ∆P (t)

Taking into account the reversal of the flow direction:

When the direction of the flow is reversed (e.g. intake of combustion engine) the preceding equations must be re-written because they come from global balance equations related to the reference frame (1-D flow and one direction -→ x ). To take this into account in the kinetic energy term (II), thus:

dq m (t) dt A - 1 2 q m (t) A ρ(t) dρ(t) dt + q m (t)|q m (t)| ρ(t) B = ∆P (t) (16)
with

: A = x 2 x 1 dx S(x) and B = 1 2 1 S 2 2 - 1 S 2 1
It is a much simpler and more natural method than the method used by Werner et al. [START_REF] Werner | Bidirectional flow measurement based on the differential pressure method for surge analysis on a small centrifugal compressor[END_REF] to calculate the bidirectional flow from the stationary Bernoulli equation.

Cases of incompressible fluids:

As long as the flow velocity is not too high (i.e. M a < 0, 3) the flow can be considered as incompressible and the density ρ is only a function of local temperature and static pressure. The Eq. ( 16) becomes:

A dq m (t) dt + B q m (t)|q m (t)| ρ(t) = ∆P (t) (17)
with

: A = x 2 x 1 dx S(x) and B = 1 2 1 S 2 2 - 1 S 2 1
An ordinary nonlinear differential equation (ODE) is obtained that it looks like the unsteady Bernoulli equation. It is simple enough to be computed in real-time, that is to say in less than one time step. The two constants A and B depend only on the geometry of the device and are therefore known a priori : There is no calibration to perform. The flow measurement is deduced from the pressure drop induced by the Venturi (the flow velocity is different between the inlet and the outlet of the control volume), but the total energy carried by the fluid is conserved. It is assumed that head loss due to the friction in the control volume is negligible, which is true over a wide range of flow rates. To gain precision it is possible to estimate the head loss and take it into account in the flow rate computation but it will be significant only for high flow rate and increases the computation time.

The principle require a fully developed flow profile and so this device is sensitive to disturbed flow conditions. The flowmeter should be inserted as far away as possible from any flow disturbances with a inlet length (and outlet if there is backflow) of at least 10 diameters.

Attention must be paid to the change of direction of the flow (backflow), which for a too high flow rate, would cause separation of the flow from the wall. The equation ( 17) would no longer be valid and the measurements would be wrong. This principle of measurement with a pressure drop induced by a Venturi is therefore only relevant without backflow or for reverse flow rate very small.

Example of an application to the intake of a combustion engine:

Fig. 2 shows an example of unsteady flow rate measured at the intake of a 2.0 L four-cylinder combustion engine at 2271 rpm. It is compared with the mean flow measured by a reference mass flowmeter placed in series.

Control volume with a singularity:

A control volume is defined as shown in Fig. 3, consisting of a right circular cylinder of diameter D inside which is placed a grid (for example). Eq. ( 2) always applies and each of its terms written as previously except terms (II) and (VI).

Kinetic energy flux (II) throught S 1 ∪ S 2 :

If the inlet cross section S 1 and outlet S 2 are equal, the term (II) is then zero.

Viscosity dissipation (VI) :

It has been assumed previously that the power dissipated by viscous friction P vD (t) in domain D of Venturi type control volume is usually negligible in front of the other terms. This is not the case if the fluid undergoes shear stress within the bulk, for example in the case where the fluid passes through a grid or a porous material. The integral of the dissipation rate in D is usually defined by the product of the head loss ∆ξ and the volumetric flow rate

q v : D φ 1 dτ = ∆ξ × q v (t) = ∆ξ × q m (t) ρ wiyh ∆ξ = Λ 1 2 ρV 2 hence: D φ 1 dτ = q m (t) 3 ρ 2 C with C = Λ 8 π 2 D 4
The constant C is the coefficient of head loss due to the singularity, it must be determined experimentally (or the dimensionless friction factor Λ).

The equation ( 15) becomes :

1 2 ∂ ∂t q 2 m (t)f (x, t) + q 3 m (t) ρ 2 C = q m (t) p 1 (t) ρ 1 (t) - p 2 (t) ρ 2 (t)
With the same assumptions as previously, it is coming for an incompressible fluid:

A dq m (t) dt + C q m (t)|q m (t)| ρ = ∆P (t) (18)
with :

A = x 2 x 1 dx S(x) and C = Λ 8 π 2 D 4
Here again, an ordinary nonlinear differential equation (ODE) is obtained sufficiently straightforward to be computed in real-time, in the sense that all computations can be done in less than one time step and the flow rate obtained in less than 100 µs for an acquisition frequency of 10 kHz. The explicit Euler method, for example, provides sufficient precision while not requiring much computing time. The precision of a higher order Euler scheme would be obtained at the expense of the calculation time.

The flow measurement is deduced from the pressure drop due to the singularity introduced into the pipe and, unlike the Venturi, it is energy dissipated in the form of heat and thus lost for flow.

However, this device with a grid to create the pressure drop is much less sensitive to the disturbed flow conditions than the Venturi device.

The constant A depends only on the geometry of the device and is therefore known a priori. On the other hand, the constant C (or the friction factor Λ) must be determined beforehand, this configuration consequently requires a calibration of the flowmeter prototype.

Calibration:

The device causing the pressure drop, must be calibrated according to the maximum flow rate to be measured and the range of the differential pressure sensor.

A prototype of unsteady flowmeter was built with a grid to produce the pressure drop. It consists of a cylindrical pipe of diameter D = 63 mm provided with a square mesh grid (Stainless Steel Wire, mesh square 1 mm, wire diameter 0.3 mm ), a differential pressure sensor (FirstSensor, HCL series, range ±2500 Pa, calibrated and temperature compensated) , a K-type thermocouple with 1.5 probe diameter and static pressure sensors (FirstSensor, HMA series, range ±100 hPa) for estimating the flow density ρ(t). The differential pressure sensor is positioned near the grid, the pressure taps are separated by a distance equal to the half pipe diameter on both side of the grid.

This flowmeter prototype is placed in a steady flow in series with a reference mass flowmeter (Proline t-mass Endress+Hauser, maximum measured error ±1.5%). The pressure loss coefficient C was determined for the two flow regimes: transition and turbulent (c.f. Fig. 4). 2.4.2. Example of pulsating flow at the intake of a driven single-cylinder combustion engine: An example of the unsteady flow rate measured at the intake of a driven single-cylinder engine of 0.5 litre is shown in the Fig. 5. The unsteady flowmeter and the reference mass flowmeter are placed in series immediately upstream of the cylinder head and the intake is done at atmospheric pressure. The figure shows that the flow is strongly pulsated and changes direction several times per period. The unsteady flowmeter prototype tracks flow fluctuations even when it changes direction. The mean flow rate given by the reference flowmeter is 7.3 g/s while the unsteady measurements provided by the prototype, and integrated over a whole number of periods, gives 7.46 g/s, that is to say barely 2.2% difference. Unsteady Flowmeter Reference Mean Flow Rate = 7.30 g/s Fig. 5. flow rate at the inlet of a single-cylinder combustion engine electrically driven at 1709 rpm.

Results and Discussion:

A particular care must be taken in the differential pressure measuring chain by a remote sensor.

Bandwidth of the differential pressure measurement system:

The bandwidth of the system must be as wide as possible and in all cases wider than the double of the higher frequency of the unsteady flow to be measured according to the Shannon's theorem (at least larger than the double of the the frequencies that carry the most energy). This bandwidth must also be as flat as possible despite the resonances that can appear in the whole data chain acquisition of the differential pressure (orifice, connecting tube and pressure sensor), as explained for example in Doblhoff-Dier et al. [START_REF] Doblhoff-Dier | Time resolved measurement of pulsating flow using orifices[END_REF]. An anechoic termination of the connection tubes allow to significantly extend the flat part of the spectral bandwidth of the differential pressure sensor.

The remote pressure probes (i.e. differential pressure sensor, connecting tube 0.8 mm inner diameter and 15 cm long) are frequency calibrated by comparison to 1/4" GRAS type BP40 microphone. For this both measuring systems are connected in a coupler crossed by a pressurized jet of air used as acoustic source. The phase measurement (c.f. Fig. 6) allow to estimate the group delay to a little less than 0.8 ms (-dφ/dω = 0.77) for the 0 -400 Hz frequency band. The bandwidth was also examined and compared with the bandwidth of a device with an anechoic termination added to the connecting tube.

Fig. 7 shows that the bandwidth of the system is significantly improved by the anechoic termination and that at up to 400 Hz it remains flat, which goes well beyond the 200 Hz that can be considered as the main target for combustion engines applications.

Unsteady flow rate at the intake of a combustion engine:

It is difficult to evaluate the accuracy of measurements of a device that is the only one that can provide them.There are mainly three systems that can be used to estimate an unsteady flow in a pipe. It is possible to use a Hot Wire Anemometer and then integrate the local velocity measurement on the section of the pipe. However, the hot wire is intrusive and can not be used when the flow velocity is less than about 5 m/s (it induces convection which is not negligible when the flow velocity is low) but moreover it is not sensitive in the velocity direction and therefore the measurements are rectified when -It is also possible to use Laser Doppler Velocimetry (LDV). As the Hot Wire Anemometer it provides an almost local measurement of the flow velocity, which must be then integrated on the section of the pipe to obtain flow rate. In addition it is necessary to seed the flow with particles and the measurements are not well time resolved (the velocity is measured only when particle passes through the measurement volume). The accuracy of flow measurement by LDV is not easy to estimate; it is therefore not a reference measurement.

Measurements by Particle Image Velocimetry (PIV) are also possible but they impose constraining optical accesses and, as with the LDV, it is necessary to seed the flow with particles and then to integrate the velocity field onto the section of the pipe. The measurements are not very well time resolved and their accuracies are not easy to estimate; it is still not a reference measurement. On the other hand there are several devices allowing with a good accuracy to measure mean flow rate.The choice was made to compare the results obtained by our device averaged in time with the mean flow measurements given by Thermal Mass Flowmeter.

Two examples of unsteady flow rates measured at the intake of a threecylinder combustion engine are shown below.

Fig. 9 and 10 show measurements obtained with a rotational speed of 1200 rpm and 2500 rpm, respectively. The sampling frequency was 10 kHz. It can be seen that in this configuration the rate of pulsation is much lower than on the single-cylinder and there is no longer any backflow. It can be noted that the convergence time of the flow rate computation is about 40 ms for 1200 rpm and 25 ms for 2500 rpm, about half a period.

As explained above, the accuracy of experimental results is difficult to evaluate, as it is difficult to establish the unsteady flow by other means in order to obtain a meaningful comparison. However results presented here show good agreement with the mean flow rate. The expected mean flow rate is 12.5 g/s for 1200 rpm while the unsteady measurements provided by the prototype and integrated over a whole number of periods gives 11.46 g/s. The difference is slightly less than 9%, but the mean flow measured by the thermal reference flowmeter on the engine test stand is not accurate to more than 5% . For the 2500 rpm case, the expected mean flow rate is 33.6 g/s while the unsteady measurements integrated over a whole number of periods gives 31 g/s.

Response time:

The nonlinear ODE equations ( 17) & ( 18) on which the device is based can be seen as "low-pass filters". It is therefore useful to examine the step response of these equations. The following figure Fig. [START_REF] Johnston | Use of Pipeline Wave Propagation Model for Measuring Unsteady Flow Rate[END_REF] shows the response of equation ( 18) to steps of different amplitudes. It shows that the response time of the system is shorter as the amplitude of the excitation increased. The response time is defined as the moment when 99% of the step amplitude is reached. device is therefore mainly due to the behavior as a low-pass filter of equation [START_REF] Gündoǧdu | A critical review on pulsatile pipe flow studies directing towards future research topics[END_REF].

Conclusion

Two methods in order to measure unsteady flow rate in real time (that is to say in less than one time step) from a differential pressure in a pipe were presented. Both methods are based on two similar nonlinear ordinary differential equations obtained from the equation kinetic energy balance.

The first method gives the unsteady flow rate from the pressure drop measured at a Venturi throat. It is demonstrated that there is no calibration to perform (except eventually for the differential pressure sensor) because the two constants in the ODE depend only on the geometry of the device and then known a priori . The principle requires a fully developed flow profile and so this device is sensitive to disturbed flow conditions. be inserted as far away as possible from any flow disturbances with a inlet length (and outlet if there is backflow) of at least 10 diameters. However this method is mainly relevant without backflow or for small reversed flow rate to avoid separation.

-The second method is based on a nonlinear ordinary differential equation similar to the former one but one of the two constants in the ODE must be determined experimentally. The flow measurement is deduced from the pressure drop due to a grid introduced into the pipe (or similar singularity); unlike the first method (Venturi throat), this device with a grid is clearly less sensitive to the disturbed flow conditions. The device causing the pressure drop, must be calibrated according to the maximum flow rate reached in the pipe and according to the range of the differential pressure sensor.

A prototype of unsteady flowmeter was built on this principle and calibrated with a steady flow and a reference mass flowmeter. The remote differential pressure measurement must be performed with care of the system is founded significantly improved by an anechoic termination and remains flat up to 400 Hz which is broadly sufficient for the targeted applications, the intake or exhaust of combustion engines. It has been shown that the convergence time of the device is shorter as the amplitude of the excitation increased, according to the behaviour of a low-pass filter of the ODE.

-The accuracy of experimental results is challenging to evaluate, as it is difficult to measure unsteady flow by other means in order to obtain a meaningful comparison. However results obtained show good agreements with unsteady measurements integrated over a whole number of periods and reference mass flowmeter.

The presented device and methodology yield adequate performances for the combustion engine application context.

  part of complex quantity ()

Fig. 2 .

 2 Fig. 2. Example of unsteady flow rate at the intake of a 2.0 l 4-cylinder combustion engine at 2271 RPM. Comparison between unsteady prototype flow meter (blue) and reference mass flowmeter (red) : mean Flow Rate = 34 ± 2 g/s.

2 X 2 GridFig. 3 .

 223 Fig. 3. Control volume consisting of a right circular cylinder with x axis and cross section S i (x).

Fig. 4 .

 4 Fig. 4. Calibration curves of flowmeter prototype. Coefficient C = ρ∆P/q 2 m

Fig. 6 .

 6 Fig. 6. Phase and Group-Delay of the remote differential pressure sensor

1

 1

Fig. 7 .

 7 Fig. 7. Frequency response of remote differential pressure sensor, with and without damping.

Fig. 8 .

 8 Fig. 8. Scheme of the experimental setup

Fig.( 12 )

 12 is a zoom of Fig.[START_REF] Reis | Incompressible pulsating flow for low Reynolds numbers in orifice plates[END_REF] with response of equation (18) to a step of 31.08 equal to the mean flow rate measured. It can be seen that the convergence time of the unsteady flowmeter towards the mean flow rate corresponds to the response time of equation[START_REF] Gündoǧdu | A critical review on pulsatile pipe flow studies directing towards future research topics[END_REF]. The response time of the

Fig. 9 .

 9 Fig. 9. Unsteady flow rate at the intake of a 3 cylinders engine of 1.2 litre; torque 80 Nm at 1200 rpm.

Fig. 10 .

 10 Fig. 10. Unsteady flow rate at the intake of a 3 cylinders engine of 1.2 litre; torque 120 Nm at 2500 rpm.

  g/s Response Time =13 ms step=40.00 g/s Response Time =24 ms step=20.00 g/s Response Time =43 ms step=10.00 g/s Response Time =82 ms

Fig. 11 .

 11 Fig. 11.Step Response of equation[START_REF] Gündoǧdu | A critical review on pulsatile pipe flow studies directing towards future research topics[END_REF].

Fig. 12 .

 12 Fig. 12. Zoom of Fig. (10); comparison with Step Response of equation (18).

in fact this assumption is not essential, but is often verified.

Appendix A. Pulsating laminar flow in pipe

The error made on the mean flow rate measurement of a oscillatory flow by neglecting the boundary layers can be estimated. Consider laminar and incompressible flow in a circular cylindrical pipe. The flow is generated by a periodic pressure gradient in the longitudinal direction ∂p ∂x = [a 0 exp(jωt)]. Numbers of authors (e.g. : [START_REF] Womersley | Method for the calculation of velocity, rate of flow and viscous drag in arteries when the pressure gradient is known[END_REF][START_REF] Uchida | The pulsating viscous flow superposed on the steady laminar motion of incompressible fluid in a circular pipe[END_REF]) have shown that there is an exact solution of this problem with Bessel functions of order 0.

The first term of the right-hand side is the Poiseuille solution for a permanent flow with a constant longitudinal pressure gradient a 0 . It is easy to deduce the flow rate U 0 = a 0 R 2 8ν . The second term of the right-hand side corresponds to a periodic solution of zero mean flow. The relation between the inertial effects due to pulsatile flow frequency and the viscous effects is defined by the dimensionless number first proposed by Lambossy [START_REF] Lambossy | Oscillations forcées d'un liquide incompressibile et visqueux dans un tube rigide et horizontal. Calcul de la force frottement[END_REF] but known as Womersley number: α = R ω ν (where ω = 2πN (rad/s) is the angular velocity). It denotes the phase lag between pressure gradient and flow. When α is small (1.32 or less [START_REF] Gündoǧdu | A critical review on pulsatile pipe flow studies directing towards future research topics[END_REF]), the frequency of pulsations is sufficiently low that a parabolic velocity profile has time to develop during each cycle, thus the flow will be very nearly in phase with the pressure gradient. When α is large (10 or more), the velocity profile is relatively flat or plug-like and the mean flow lags the pressure gradient by about 90 degrees. However, when the flow is turbulent (Re over 2300), the time-averaged velocity profile in pipes remains approximately flat even if the Womersley Number is relatively small.

To get an idea, figure A.13 shows the velocity profile of a pulsed laminar flow at the same frequency as the flow rate measured at the inlet side of a single-cylinder engine driven at 1709 rpm(c.f. figure [START_REF] Ray | Mass Flow Rate Controlled Fully Developed Laminar Pulsating Pipe Flows[END_REF]).

Computed velocity profiles are plotted for different values of the phase angle ∈ [-180 • , 180 • ]. The phase shift between the boundary layers and the center of the pipe is clearly noticeable, as is the flat profile in much of the field.

In conclusion, for most applications considered, for example the air loop of combustion engines, the velocity is constant in most of the pipe. The error committed by neglecting the boundary layers will remain very small, either


MD Christophe Borg
email: christophe.borg@efs.sante.fr

MD Georges Mantion

MD Frank Boudghène

MD Françoise Mornex

MD François Ghiringhelli

MD Antoine Adenis

MD David Azria

Meher Jacques Balosso

Meher Ben Abdelghani

MD Jean Baptiste Bachet

MD Véronique Vendrely

MD Yves François

MD Thierry Conroy

MD Emmanuel Rio

MD Bernard Roullet

MD Dominique Spaëth

MD Laurent Quero

MD Zaher Lakkis

Mathieu Coudert

MD Miruna Ionescu-Goga

MD Alexandre Tanang

MD Thierry André

Pr Christophe Borg

Efficacy and Safety of Two Neoadjuvant Strategies With Bevacizumab in MRI-Defined Locally Advanced T3 Resectable Rectal Cancer: Final Results of a Randomized, Noncomparative Phase 2 INOVA Study

Keywords:

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Preoperative chemoradiotherapy (CT-RT) followed by total mesorectal excision (TME) is the current standard multimodal treatment for locally advanced rectal cancer (LARC). [START_REF] Glynne-Jones | Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF] However, recurrences and distant metastases remain a significant issue, [START_REF] Guetz | Does delaying adjuvant chemotherapy after curative surgery for colorectal cancer impair survival? A metaanalysis[END_REF] and consequently long-term survival suffers as well. [START_REF] Sauer | Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years[END_REF] Preoperative oxaliplatin/fluoropyrimidine (FP) and radiotherapy strategy with or without adjuvant chemotherapy was evaluated in several phase III trials and showed contradicting survival results. [START_REF] Gerard | Clinical outcome of the ACCORD 12/0405 PRODIGE 2 randomized trial in rectal cancer[END_REF][START_REF] Rodel | Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial[END_REF][START_REF] Allegra | Neoadjuvant 5-FU or Capecitabine Plus Radiation With or Without Oxaliplatin in Rectal Cancer Patients: A Phase III Randomized Clinical Trial[END_REF][START_REF] Schmoll | Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin vs. capecitabine alone in locally advanced rectal cancer. ESMO 2016 Congress[END_REF][START_REF] Aschele | Final results of STAR-01: A randomized phase III trial comparing preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer[END_REF] Bevacizumab, an antiangiogenic agent active in various types of tumor, has been shown to improve survival of metastatic colorectal cancer patients, [START_REF] Hurwitz | Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer[END_REF][START_REF] Saltz | Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study[END_REF] but not in adjuvant situation for stage II/III colon cancer. [START_REF] Allegra | Bevacizumab in stage II-III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial[END_REF][START_REF] De Gramont | Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial[END_REF][START_REF] Kerr | Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial[END_REF] The addition of oxaliplatin-based chemotherapies and bevacizumab to chemoradiotherapy is a potential solution to increase pathological response rate, disease-free survival (DFS) and overall survival (OS). Unfortunately, results for trials utilizing bevacizumab in the treatment of LARC patients remain scarce, though the studies that have been published indicate promising results in phase II trials. [START_REF] Spigel | Phase II study of bevacizumab and chemoradiation in the preoperative or adjuvant treatment of patients with stage II/III rectal cancer[END_REF][START_REF] Willett | Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study[END_REF][START_REF] Landry | Phase II Trial of Preoperative Radiation With Concurrent Capecitabine, Oxaliplatin, and Bevacizumab Followed by Surgery and Postoperative 5-Fluorouracil, Leucovorin, Oxaliplatin (FOLFOX), and Bevacizumab in Patients With Locally Advanced Rectal Cancer: 5-Year Clinical Outcomes ECOG-ACRIN Cancer Research Group E3204[END_REF][START_REF] Crane | Phase II trial of neoadjuvant bevacizumab, capecitabine, and radiotherapy for locally advanced rectal cancer[END_REF] The INOVA study assessed two different multimodal therapeutic approaches with bevacizumab combined with induction chemoradiotherapy, for patients with high-risk T3 resectable rectal cancer. Interim results that included the primary endpoint of pathologic complete response (pCR) have already been published; [START_REF] Borg | Pathological response and safety of two neoadjuvant strategies with bevacizumab in MRI-defined locally advanced T3 resectable rectal cancer: a randomized, noncomparative phase II study[END_REF] final results of the secondary endpoints including disease-free survival and overall survival, among others, after 5-year follow-up are presented here.

Patients and Methods

Study Population

Eligible patients were between 18 and 75 years of age and had histologically confirmed rectal adenocarcinoma, MRI-defined T3 LARC within 10 cm from the anal margin: T3N0-1-2 in the lower rectum with distal tumor edge <5 cm from the anal margin, or T3N0 in the mid-rectum with tumor spread >5 mm into perirectal fat or T3N1-N2, and 0-1 ECOG performance status.

Exclusion criteria and detailed information are available in the initial publication. [START_REF] Borg | Pathological response and safety of two neoadjuvant strategies with bevacizumab in MRI-defined locally advanced T3 resectable rectal cancer: a randomized, noncomparative phase II study[END_REF] All patients provided informed consent before study start. The study was approved by the local ethics committee and conducted in accordance with the Declaration of Helsinki and ICH GCP and registered on www.clinicaltrials.gov: NCT00865189.

Treatment Plan

Eligible patients were allocated to treatment by balanced, centralized randomization, stratified by: center, tumor site, and lymph node involvement. Patients in Arm A received 12-week bevacizumab in addition to fluorouracil (5-FU), leucovorin and oxaliplatin (Folfox-4) followed by bevacizumab-5-FU-RT before TME. Patients in Arm B were treated with only bevacizumab-5-FU-RT before TME. The treatment allocation was not blinded. An outline of the study protocol is shown in Figure S1, while the detailed treatment plan and dosage guidelines were published previously. [START_REF] Borg | Pathological response and safety of two neoadjuvant strategies with bevacizumab in MRI-defined locally advanced T3 resectable rectal cancer: a randomized, noncomparative phase II study[END_REF]

Assessment

For initial disease staging, patients underwent pelvic MRI and thoracoabdominal CT-Scan.

After surgery, patients were scheduled for follow-up visits every 6 months for 5 years in order to collect long-term safety and efficacy data. Follow-up examinations included patient history, physical examination, hematological and urinary analyses, abdominal and pelvic echography, and chest X-rays. Colonoscopies were performed at 6 months, 1 year, and 5 years.

Statistical Considerations

The primary endpoint was the proportion of patients achieving pCR (ypT0-N0) according to local review. Secondary efficacy endpoints included compliance, tumor downstaging (ypT0-pT2), recurrence rate, and 5-year DFS and OS, while the incidences of adverse events (AEs) and serious AEs (SAEs) were safety endpoints.

Forty-one patients had to be included in each arm to show a difference between 10% (estimated as the minimum acceptable by the scientific committee) and the expected proportion of 25% with α = 0.05 and a power of 80% using a binomial test.

Analyses were performed on the intent-to-treat (ITT) population per treatment arm, which included all randomized and treated patients. DFS and OS from treatment onset were analyzed using the Kaplan-Meier method.

All the selected patients with at least one treatment dose were included in the safety population.

A safety analysis was performed on the safety population per treatment period on all AEs and on AEs of special interest (see Table 2). AEs were graded and classified according to the Common Terminology Criteria for Adverse Events version 3.0 (CTC AE v 3.0) and the Medical Dictionary for Regulatory Activities (MedDRA version 18.1). Exploratory analyses of safety were performed for post-surgery and "late" fistulas, and for surgical and medical procedures carried out beyond 1 year after the surgery. Prognostic factors were also investigated for each treatment arm, separately, via a logistic regression model. No comparison between the arms was planned.

Results

Study Population and follow up

A total of 91 patients (46 in Arm A and 45 in Arm B) were included between October 2007 and July 2010, 60 of which completed the study: 34 patients (73.9%) in Arm A and 26 (57.8%) in Arm B. [START_REF] Borg | Pathological response and safety of two neoadjuvant strategies with bevacizumab in MRI-defined locally advanced T3 resectable rectal cancer: a randomized, noncomparative phase II study[END_REF] The follow-up was 5 years for both arms. The majority of withdrawals in both arms occurred during the late period of the follow-up period (n=12 in Arm A; n=19 in Arm B). The main reasons were lost to follow-up (n=6 in each arm) and death (n=4 in Arm A; n=11 in Arm B). Patient and disease characteristics are presented in Table 1. 18 (39%) and 24 (53.3%) of the patients included in ARM A and B respectively received an adjuvant chemotherapy (FOLFOX/XELOX for 17 and 22 patients in ARM A and B).

Safety

The safety analysis including the 8 weeks period following rectal surgery was previously reported. [START_REF] Borg | Pathological response and safety of two neoadjuvant strategies with bevacizumab in MRI-defined locally advanced T3 resectable rectal cancer: a randomized, noncomparative phase II study[END_REF] The final analysis of the clinical outcomes collected during the 5 year follow-up period is reported hereafter with specific emphasis on AEs that occurred during the "early" postsurgery period (date between the surgery and 4 weeks after) and "late" AEs (AEs that occurred more than 4 weeks after surgery but before the end of the study).

As reported previously, no deaths occurred from start of the study until 8-weeks post-surgery.

Incidence of adverse events by arm and by period is summarized by severity and relationship in Table 2. The 51 related grade 3-4 AEs reported during the entire study period in 30 patients (33.0%) are described in Table 3.

Of the AEs reported during the late follow-up period in Arm A, 10 were grade 3-4 AEs in 9 patients (19.6%). The most frequent grade 3-4 late AEs were anastomotic fistula, diarrhea, incisional hernia and intestinal anastomosis complication (2 patients each). Five grade 3-4 events were bevacizumab-related in 4 patients (8.7%) including anastomotic fistula (n=2), pelvic abscess (n=1), erectile dysfunction (n=1). There were 4 late fistulas occurring in 3 patients (6.5%), all recovered but one with sequelae. There were 4 deaths (8.7%) reported in Arm A during the follow-up period, 3 deaths (6.5%) due to disease progression and 1 death (2.2%) from lung cancer.

Late period AEs reported in Arm B included 12 grade 3-4 AEs in 6 patients (13.3%). The most frequent grade 3-4 late AE was postoperative abscess (2 patients). Four events were bevacizumab-related grade 3-4 AEs in 4 patients (8.9%) including perineal abscess (n=1), postoperative abscess (n=1), ischemic colitis (n=1) and deep vein thrombosis (n=1). Three fistulas occurred in 3 patients (6.7%); 2 fistulas resolved. Deaths were reported for 11 patients (24.4%) in Arm B due to: disease progression in 7 patients (15.6%), secondary cancer in 2 patients (4.4%), acute pulmonary edema and congestive heart failure in a single patient each (2.2%), and three-branch coronary artery disease in a patient with poor general health status.

From treatment initiation to the end of the 5-year follow-up period, 11 events of fistulas were reported in 9 patients (19.6%) in Arm A, 7 fistulas in 6 patients were serious and 5 required surgical management. More than a half (54.4%) resolved without sequelae and 27.3% resolved with sequelae. Ten fistulas were recorded in 10 patients (22.2%) in Arm B, including 7 in 7 patients classified as serious AE. The majority (80%) resolved without sequelae.

Overall, all fistulas but one were anastomotic. Nearly all fistulas developed within the year following the surgery except 3 cases reported as occurring later in 2 patients (4.3%) in Arm A:

One patient developed anastomotic fistula with pelvic abscess more than three years following the surgery and the other patient had a pelvic abscess complicated by fistula more than 2 years after rectal surgery.

Efficacy

The primary end-point (pCR) and tumor downstaging were described in the previous publication. [START_REF] Borg | Pathological response and safety of two neoadjuvant strategies with bevacizumab in MRI-defined locally advanced T3 resectable rectal cancer: a randomized, noncomparative phase II study[END_REF] Key efficacy results are presented in Table 4.

In Arm A, during the 5-year follow-up, recurrences were reported in 10 patients [95% CI 0.1, 18.3]). Median DFS was not reached, 15 DFS-related events occurred, and the 3 and 5-year DFS rates were 75.1% [95% CI 59.5, 85.4] and 64.3% [95% CI 47.6, 76.9], respectively (Figure 1). Median OS was also not reached in Arm B, 11 deaths resulted in 3 and 5-year OS rates of 88.4% [95% CI 74.3; 95.0] and 72.7% [95% CI 56.0, 83.9], respectively (Figure 1).

Discussion

Various types of preoperative therapy were and continue to be assessed in LARC patients.

INOVA was designed to evaluate two different preoperative multimodal therapies in patients with high risk LARC. Altogether, these final results provide long-term efficacy outcomes (DFS and OS) and show a potential safety signal related to the occurrence of anastomotic fistula and late complications related to bevacizumab.

Regarding efficacy, in Arm A, local recurrences were uncommon (6.5%), which compared favorably with previous clinical trials: 6% in AIO-4 trial and 8.8% in the PRODIGE 02 trial [START_REF] Rodel | Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial[END_REF][START_REF] Azria | Late toxicities and clinical outcome at 5 years of the ACCORD 12/0405-PRODIGE 02 trial comparing two neoadjuvant chemoradiotherapy regimens for intermediate-risk rectal cancer[END_REF] and distant recurrences occurred in 17.4% of the patients. In Arm B, local and distant recurrences occurred in 8.9% and 13.3% of the patients respectively. The long term follow-up of patients included in INOVA trial confirmed that exposition to a neoadjuvant chemotherapy did not worsen the risk of local failure.

In the literature, surgery alone compared to preoperative RT followed by surgery reduced local recurrence and distant metastasis. [START_REF] Party | Randomised trial of surgery alone versus radiotherapy followed by surgery for potentially operable locally advanced rectal cancer. Medical Research Council Rectal Cancer Working Party[END_REF] Preoperative FP-RT reduced local recurrence in comparison with preoperative RT alone, [START_REF] Bosset | Chemotherapy with preoperative radiotherapy in rectal cancer[END_REF][START_REF] Gerard | Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203[END_REF] and resulted in a reduced local recurrence rate. [START_REF] Sauer | Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years[END_REF][START_REF] Sauer | Preoperative versus postoperative chemoradiotherapy for rectal cancer[END_REF] In Arm A of INOVA, the 3-year DFS of 84.6% reported compares favorably with those of the preoperative oxaliplatin-FP-RT arms in the phase III ACCORD 12 (72.7%), STAR-01 (74.2%), CAO/ARO/AIO-04 (75.9%) and PETACC-6 (75.4%), [START_REF] Gerard | Clinical outcome of the ACCORD 12/0405 PRODIGE 2 randomized trial in rectal cancer[END_REF][START_REF] Rodel | Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial[END_REF][START_REF] Allegra | Neoadjuvant 5-FU or Capecitabine Plus Radiation With or Without Oxaliplatin in Rectal Cancer Patients: A Phase III Randomized Clinical Trial[END_REF][START_REF] Aschele | Final results of STAR-01: A randomized phase III trial comparing preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer[END_REF][START_REF] Schmoll | Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer: Final Results of the NO16968 Randomized Controlled Phase III Trial[END_REF] while the 5-year DFS of 70% was similar with 69.2% in the STAR-01 and in the NSABP R-04. [START_REF] Allegra | Neoadjuvant 5-FU or Capecitabine Plus Radiation With or Without Oxaliplatin in Rectal Cancer Patients: A Phase III Randomized Clinical Trial[END_REF][START_REF] Aschele | Final results of STAR-01: A randomized phase III trial comparing preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer[END_REF] The combination of oxaliplatin and FP was also assessed as a neoadjuvant sequence in phase II studies before FP-RT. [START_REF] Chua | Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial[END_REF][START_REF] Calvo | Preoperative chemoradiation with or without induction oxaliplatin plus 5-fluorouracil in locally advanced rectal cancer. Long-term outcome analysis[END_REF][START_REF] Schou | Induction chemotherapy with capecitabine and oxaliplatin followed by chemoradiotherapy before total mesorectal excision in patients with locally advanced rectal cancer[END_REF][START_REF] Marechal | Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study[END_REF] DFS and OS results, when assessed were inconsistent, showing no impact or promising results. In the phase II trials of neoadjuvant oxaliplatin, the estimated 5-year DFS of 62% [START_REF] Fernandez-Martos | Chemoradiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemoradiation and surgery: long-term results of the Spanish GCR-3 phase II randomized trialdagger[END_REF] and 63.1% [START_REF] Schou | Induction chemotherapy with capecitabine and oxaliplatin followed by chemoradiotherapy before total mesorectal excision in patients with locally advanced rectal cancer[END_REF] were close but slightly lower to those of Arm A of INOVA.

The 5-year survival rate of 90.5% in Arm A of INOVA compares favorably with those of oxaliplatin-based chemoradiotherapy arm in the phase III STAR-01 (84.4%) and NSABP R-04 (81.3%). Similar trend in phase II trials with this combination was observed for estimated 5-year survival rate ranging from 66.7% to 80%. [START_REF] Chua | Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial[END_REF][START_REF] Schou | Induction chemotherapy with capecitabine and oxaliplatin followed by chemoradiotherapy before total mesorectal excision in patients with locally advanced rectal cancer[END_REF][START_REF] Asteria | Anastomotic leaks after anterior resection for mid and low rectal cancer: survey of the Italian Society of Colorectal Surgery[END_REF][START_REF] Hess | Capecitabine and Oxaliplatin Prior and Concurrent to Preoperative Pelvic Radiotherapy in Patients With Locally Advanced Rectal Cancer: Long-Term Outcome[END_REF] Survival outcomes with preoperative bevacizumab-oxaliplatin-FP-RT were reported for only one phase II trial with a 5-year survival rate of 80%. [START_REF] Landry | Phase II Trial of Preoperative Radiation With Concurrent Capecitabine, Oxaliplatin, and Bevacizumab Followed by Surgery and Postoperative 5-Fluorouracil, Leucovorin, Oxaliplatin (FOLFOX), and Bevacizumab in Patients With Locally Advanced Rectal Cancer: 5-Year Clinical Outcomes ECOG-ACRIN Cancer Research Group E3204[END_REF] Altogether, efficacy outcomes in Arm B were lower than those observed in Arm A. the DFS rates were 75.1% at 3 years and the survival rate at 5 years was 72.7%. Preoperative bevacizumab-FP-RT was assessed in several phase I/II trials. [START_REF] Spigel | Phase II study of bevacizumab and chemoradiation in the preoperative or adjuvant treatment of patients with stage II/III rectal cancer[END_REF][START_REF] Willett | Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study[END_REF][START_REF] Velenik | Neoadjuvant capecitabine, radiotherapy, and bevacizumab (CRAB) in locally advanced rectal cancer: results of an open-label phase II study[END_REF][START_REF] Resch | Preoperative treatment with capecitabine, bevacizumab and radiotherapy for primary locally advanced rectal cancer--a two stage phase II clinical trial[END_REF][START_REF] Gasparini | A phase II study of neoadjuvant bevacizumab plus capecitabine and concomitant radiotherapy in patients with locally advanced rectal cancer[END_REF][START_REF] Garcia | Phase II study of preoperative bevacizumab, capecitabine and radiotherapy for resectable locallyadvanced rectal cancer[END_REF][START_REF] Salazar | A randomized phase II study of capecitabine-based chemoradiation with or without bevacizumab in resectable locally advanced rectal cancer: clinical and biological features[END_REF] Actuarial DFS rate with such strategy was reported by Crane et al. to be 77.3% at 2 years. No OS outcomes or survival rates were reported in these studies.

One of the main strength of INOVA trial was a long term follow-up with the monitoring of AEs of special interest which included fistulas and bevacizumab-related toxicities as well as the involvement of a data safety monitoring board. After the surgery and up to 5 years follow-up, 19.6% of patients in Arm A and 22.2% of patients in Arm B developed a fistula. Late fistulas (beyond 4 weeks after the surgery) were reported for 6.6% of Arm A patients and 4.4% of Arm B patients. The incidence of postoperative fistula is about two times higher when compared with a maximum of 8% observed after bevacizumab-oxaliplatin-FP-RT and surgery for LARC in clinical trials. [START_REF] Kennecke | Pre-operative bevacizumab, capecitabine, oxaliplatin and radiation among patients with locally advanced or low rectal cancer: a phase II trial[END_REF] Due to differences in post-surgery AEs reporting and analysis, comparison between trials may lead to incorrect interpretation. To allow comparison between multimodal strategies for the management of LARC, the use of standardized criteria for the definition and the evaluation of surgery and post-surgery complications should be included in trials. Other parameters such as preparation for surgery, surgery procedures and others need to be taken into account. The incidence of fistula and anastomotic leakage varies substantially between phase III trials. In the French ACCORD 12/0405-Prodige 2 with oxaliplatin-FP-RT, the incidence of anastomotic fistula was approximately 4%. In the randomized GRECCAR 5 trial, with 2 parallel arms (drain vs no drain), the rate of anastomotic leakage within the 30 days following surgery was 15%. [START_REF] Denost | To Drain or Not to Drain Infraperitoneal Anastomosis After Rectal Excision for Cancer: The GRECCAR 5 Randomized Trial[END_REF] In a meta-analysis including 14 randomized trials conducted by the Cochrane Collaboration, the rate of anastomotic leakage following laparoscopic or open TME for rectal cancer was estimated at 7.7% and 6.3% respectively. [START_REF] Vennix | Laparoscopic versus open total mesorectal excision for rectal cancer[END_REF] Asteria et al reported a rate of 15.2% of anastomotic leakage in 520 patients who had undergone low anterior resection in 2005. [START_REF] Asteria | Anastomotic leaks after anterior resection for mid and low rectal cancer: survey of the Italian Society of Colorectal Surgery[END_REF] A rate of 12.6% of anastomotic leakage was reported in a series of 2,085 patients who underwent TME surgery between January 2005 and December 2007, with/or without preoperative 5-FU-RT in Germany. 40 In conclusion, the final results of the phase II INOVA study reveals that induction bevacizumab-Folfox-4 followed by bevacizumab-5-FU-RT and TME for locally advanced rectal cancer may have the potential to increase survival outcomes. The role of bevacizumab cannot be established because combined with neo-adjuvant FOLFOX4. The use of bevacizumab-5-FU-RT before TME was associated with a high rate of anastomotic fistulas compared to known published data.

Further research of neoadjuvant strategies in LARC should be encouraged. Long-term safety follow-up using standardized criteria for the definition and assessment of surgery and postsurgery complications of rectal surgery needs to be implemented.

[40] Garlipp B, Ptok H, Schmidt U, Meyer F, Gastinger I, Lippert H. Neoadjuvant chemoradiotherapy for rectal carcinoma: effects on anastomotic leak rate and postoperative bladder dysfunction after non-emergency sphincter-preserving anterior rectal resection. Results of the Quality Assurance in Rectal Cancer Surgery multicenter observational trial. Langenbecks Arch Surg 2010;395(8):1031-8.

Tables Table 1: Patients and disease characteristics -ITT (n=91)

SURVIVAL RESULTS

N=46 N=45

DFS Events, n (%)

  (21.7% [95% CI10.9, 36.4]), 8 of whom (17.4% [95% CI7.8, 31.4]) had a distant recurrence and 3 (6.5% [95% CI 0.1, 14.8]) had a local recurrence. Median DFS was 68.3 months [95% CI 68.3, -] with 14 DFS-related events observed, resulting in a 3-year DFS rate of 84.6% [95% CI 70.3; 92.3] and a 5-year DFS rate of 70.0% [95% CI 53.9, 81.4] (Figure1). Four deaths occurred in Arm A; subsequently the median OS was not reached and the OS rates were 90.5% [95% CI 76.7, 96.3] at 5 years (Figure1).In Arm B, 9 patients (20.0% [95% CI 9.6, 34.6]) experienced a recurrence with distant recurrences occurring in 6 patients (13.3% [95% CI 5.1, 26.8]) and local recurrences in 4 (8.9%

FiguresFigure 1 :

 1 Figures

Table 2 :

 2 Summary of emerging adverse events by period according to treatment arm -Safety population

Table 3 :

 3 Grade 3-4 bevacizumab-related adverse events according to treatment arm during the entire study period -Safety population

Table 4 :

 4 Overview of efficacy -Key results -ITT population

Table 1 : Patients and disease characteristics -ITT (n=91)

 1

	Arm A	Arm B
	n=46	n=45

Table 2 : Summary of emerging adverse events by period according to treatment arm - Safety population (n=91)

 2

	n events	n pts (%)	n events	n pts (%)

Table 4 : Overview of efficacy -Key results -ITT population

 4

	Arm A	Arm B
	N=46	N=45
	n (%) -[95%CI]	n (%) -[95%CI]
	N=42	N=44

Acknowledgements

The authors are grateful to the physicians, patients and their families who participated in this study.

The authors would like to thank the study project team and Eltium for the support received in writing and editing this article.

Funding

This work was supported by Roche SAS France.

Conflict of interest Disclosure

Christophe Borg: Honoraria and Consulting from Roche; advisory boards from Bayer, Sanofi and Servier. Georges Mantion, Frank Boudghène, Jean Baptiste Bachet, Véronique Vendrely: honoraria from Roche. François Ghiringhelli: honoraria from Lilly, Sanofi, Amgen, Roche and advisory board for Merck Serano, Amgen, Sanofi, Roche. David Azria: Honoraria for Roche and Astellas. Meher Ben Abdelghani: Honoraria and Consulting for Amgen, Merck, Sanofi and Bayer. Mathieu Coudert, Miruna Ionescu-Goga and Alexandre Tanang: Employees of Roche.

Thierry André: Honoraria and Consulting/Advisory Role for Roche, Sanofi; Travel for Roche.

Françoise Mornex, Antoine Adenis, Thierry Conroy, Dominique Spaëth, Zaher Lakkis, Jacques Balosso, Laurent Quero, Yves François, Bernard Roullet and Emmanuel Rio have no conflicts of interest to disclose.