DVHs evaluation in brain metastases stereotactic radiotherapy treatment plans

Radiotherapy and Oncology 87 (2008) 110–115 www.thegreenjournal.com

CNS treatment planning

DVHs evaluation in brain metastases stereotactic radiotherapy treatment plans Katia Pasciutia,*, Giuseppe Iaccarinoa, Antonella Soriania, Vicente Bruzzanitia, Simona Marzia, Sara Gomellinib, Stefano Arcangelib, Marcello Benassia, Valeria Landonia a

Laboratory of Medical Physics and Expert Systems, and bRadiotherapy Department, Regina Elena National Cancer Institute, Rome, Italy

Abstract Purpose: The aim of this work is to report a retrospective study of radiobiological indicators based on Dose–Volume Histograms analysis obtained by stereotactic radiotherapy treatments. Methods and materials: Fifty-five patients for a total of sixty-seven brain metastases with a mean target volume of 8.49 cc were treated by Dynamic Conformal Arc Therapy (DCAT) and Intensity-Modulated Stereotactic Radiotherapy (IMRST). The Delivered prescription dose was chosen on the basis of tumor size and location so as to ensure a 100% isodose coverage to the target volume. Results: The treatment plans reported a mean value of 10% and 2.19% for the inhomogeneity and conformal index, respectively. The F factor showed we overdosed sixty-three patients delivering an additional 7% dose more than calculated values. The radiobiological parameters: TCP and NTCP showed a complete tumor control limiting the organs at risk damage. Conclusion: One goal of stereotactic radiotherapy is to design a treatment plan in which the steep dose gradient achievable minimizes the amount of radiation delivered outside the tumor region. This technique allows to deliver a much larger dose to the target without exceeding the radiation-related tolerance of normal tissues and improving patients’ quality of life. c 2007 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 87 (2008) 110–115.



Keywords: Stereotactic radiotherapy; Brain metastases; Dynamic conformal arcs; Intensity-modulated stereotactic radiotherapy

Stereotactic radiotherapy is a technique of extremely localized irradiation that allows to deliver a high dose to a defined target volume while depositing the lowest possible dose to the surrounding non-target tissue in a single fraction. This minimizes the treatment-associated morbidity. Stereotactic radiotherapy is limited to the smallest lesions as the risk of radiation-induced side effects increases with the treatment volume. The survival of patients with brain metastases is generally poor, so the aim of this technique is to control the growing of metastases or at least maintain a good level of life quality for the patients [1,2]. A study conducted by the Radiation Therapy Oncology Group (RTOG 9508) on patients with one to three metastatic brain lesions, each 64 cm, which received whole-brain radiation therapy (WBRT) versus WBRT plus stereotactic radiosurgery (SRS) validates the efficacy and the favourable adverse event profile of SRS in treatment of brain metastases showing how patients who underwent radiosurgery are less likely to develop neurological symptoms [20]. The radiation dose–volume histogram is one of the analysis tools used to assess different treatment plans and two possible radiosurgery techniques: Dynamic Conformal Arcs



versus Intensity-Modulated Stereotactic Radiotherapy (DCAT/IMRST). Dose–volume histograms (DVHs) were used to evaluate and approve treatment plans by both the radiation oncologist and medical physicist. Moreover the Inhomogeneity Index (II) and the Conformal Index (CI) were used to describe the conformity of the prescription isodose line that completely encompasses the target volume [3,4]. Using the DVHs values we calculated, by the F factor, a reference dose level (optimal prescription dose) so as to achieve the same disease’s control that we could obtain by delivering a homogeneous distribution dose. The F factor, carried out using the Linear Quadratic (LQ) model, depends on prescribed total dose, fraction size and weakly form LQ model parameters a and b. The aim of radiotherapy is to give a dose sufficient to control the tumor’s growth without inducing severe complications in the healthy surrounding tissue. So we investigated, for each treatment, the radiobiological parameters: Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP) to evaluate the damage’s percentage to the organs at risk (OARs) and the control disease into the target volume.

0167-8140/$ - see front matter c 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2007.12.019

K. Pasciuti et al. / Radiotherapy and Oncology 87 (2008) 110–115

Methods and material Patients selection Between April and November 2006, fifty-five patients were treated with stereotactic radiotherapy: forty-four had single brain metastasis; ten had two lesions and only one patient had three metastases. Overall sixty-seven metastases were treated radiosurgically. Patients’ age ranged from 30 to 80 years with a mean age of 61 years, a median of 62 and a standard deviation of 11.78. Twenty-nine of them were female (52.7%) and twenty-six were male (47.3%). Lung cancer represented the most common primary disease and was identified in twenty patients (36.36%). A significant percentage of patients of about 18.18% suffered from breast cancer (ten patients), seven patients suffered from malignant melanoma (9.1%), four patients suffered from renal tumor (7.27%) and the remaining sixteen patients had other primary diseases. Fifteen out of sixty-seven metastases were located in the frontal lobes, sixteen in the parietal lobe, eleven in the temporal lobe, ten in the cerebellar lobe, five were occipital lesions, eight were apical lesions and two were basal lesions. The mean treatment volume was 8.49 cc with a range from a minimum value of 0.20 cc to a maximum of 50 cc, a median and standard deviation, respectively, of 6.54 and 9.41 cc; the respective mean diameter was 2.58 cm (Table 1). No tumors with diameter longer than 3 cm were treated.

Patients immobilization and contouring Patients were immobilized with BrainLAB CT localizer frame made of a box with fiducial rods attached to the BrainLAB head frame [5–7]. For thirty-nine patients, treated in a single fraction, a head fixation system was used so that the stereotactic frame was placed on the patient’s head with screws penetrating the skin after application of a local anesthetic and induction of a mild sedation. This method allows radiosurgical treatment in a single fraction at a high level of precision. For patients with brain tumors that required more fractionated dose the head localizer was a stereotactic mask in thermoplastic material individually moulded around the patient’s head. An intravenous contrast material was used during the acquisition phase of CT scans to emphasize the tumoral region in all patients and the presence of brain metastasis was confirmed with a magTable 1 Patients’ characteristics Median Number of patients Number of lesions Singular metastases Two metastases Three metastases Male Female Age Mean target volume

55 67 44 10 1 26 29 30–81 8.49 cc

SD

netic resonance in every case. The CT images were taken in 3 mm thick slices in the target zone and 5 mm thick slices outside the tumor’s volume. After that the Clinical Target Volume (CTV) and the organs at risk (OARs) were delineated on the CT slices by the radiation oncologist, the planning target volume (PTV) was defined as the CTV plus a 3 mm of margin. Contouring was determined using the ICRU guidelines. Due to the high positional accuracy it was possible to limit the field margins, adding 3 mm to the PTV. Critical structures mostly involved were: the optic nerves, brainstem, eyes and chiasm.

Treatment planning and delivery The Prescription dose was chosen on the basis of tumor size, location and proximity to critical structures. The goal of treatment planning was the optimal conformation of the therapeutic isodose to the edge of the target volume and simultaneously to keep the dose at OARs within tolerance values so as to minimize the risk of radiation necrosis to the healthy proximal tissues. The Prescribed dose was delivered to 100% isodose line at the tumor margin. Specific dose selection was based on several factors including surgical history, neurological status, tumor location and tumor volume in particular the prescribed dose to the tumor edge was delivered according to the lesion’s maximal diameter: for lesions 20 mm or less the prescribed dose was 21–24 Gy in a single fraction; for lesions 21 to 30 mm or more a dose ranging from 15 to 21 Gy was delivered in three fractions. The minimum required acceptable dose to the target volumes was 95%. A maximum dose value not bigger than 115% with a median value of 110% among all plans was required. Forty-nine treatments were performed with the dynamic conformal arcs technique (DCAT) and seventeen treatments with the intensity-modulated stereotactic radiotherapy (IMSRT). The Plans were generated by a BrainSCAN v.5.3 (BrainLAB AG, Germany). For spherical and ellipsoidal tumor volumes, that were irradiated by a dynamic conformal multiple non-coplanar arc plan, the beam’s-eye view visualization was used to avoid the beams passing directly through the critical structures. In the beam’s-eye view a MLC margin of 3 mm was added around the PTV to obtain the desired dose coverage. Multiple isocenters were used for patients with two or three lesions. For targets that had relatively large volumes and were close or even encompassed critical structures as brainstem, chiasm and optical nerves it was necessary to generate high gradients of dose outside the target so as to have a steep decrease of dose to the OARs. In this case IMRST technique was preferred. Treatment plans were evaluated in terms of 2 Gy equivalent dose per fraction according to the linear-quadratic model [8,9]: D ¼ Ds

6.54 cc

9.41 cc

111

Ds þ a=b 2 þ a=b

where Ds is the planned radiotherapy single dose and the a/ b ratio was assumed to be constant and equal to 10 Gy for the target and equal to 2 Gy for brainstem. The delivered dose to the optical nerve/chiasm, brainstem and crystalline

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was never higher than 8, 15 and 2 Gy, respectively, when administered as 2 Gy/fr. For healthy brain (defined as brain minus target) the constraint of no more than 30 Gy to no more than 30% of volume was respected. Treatments were delivered by a VARIAN 2100CD Linac equipped with a Millenium multileaf collimator (120 leaves).

The F factor and other radiobiological indicators Isodose distribution and DVHs for tumor’s volume and critical structures together with the inhomogeneity and conformal index were used to evaluate the treatment plans. The inhomogeneity index is described mathematically as [3,4]: II ¼

Dmax  Dmin Dmean

where Dmax, Dmin and Dmean are the maximum, minimum and mean doses to the PTV, respectively. It represents the homogeneity level reached irradiating the target to the prescription dose. We analyzed the geometry of the radiosurgical targets founding that they showed a spherical or quasi-spherical shape (Fig. 1) so we decided to measure the conformity index (CI) for each plan to evaluate the dose distribution, as defined in BrainLAB system, instead of taking into consideration the conformity distance index (CDI) that is much more useful for complex target shapes (i.e., very irregular, extreme ellipsoid or concave ‘‘C’’ shape) [15]. The formula used for CI was: CI ¼ 1 þ

Vn Vt

where the Vn is the volume of normal tissue and Vt is the tumor’s volume both receiving the prescribed dose. It provides a single numerical value to represent the degree of plan conformity.

The DVHs data, calculated for all structures involved in the treatment planning, were used to calculate tumor control probability and the normal tissue complication probability (TCP and NTCP) for target, normal brain and where it was possible, brainstem. The TCP was calculated following the Poisson model [10]. TCP ¼ exp½N  expðða þ b  dÞ  DÞ where a and b are the radiobiological parameters (0.59 Gy1, 0.071 Gy2) [11], D is the total dose, d is the dose per fraction and N = qV is the clonogenic cell number obtained setting the cell density q equal to 107 m3. As it is impossible to obtain a homogeneous dose distribution in the tumor’s volume and due to the high correlation between it and the TCP, it is important to find out a reference dose level Lr that, for a non-uniform distribution, maximizes the TCP so as to eradicate all clonogenic tumor cells. Assuming a uniform dose Dj in all subvolumes vj/V, TCP can be expressed as follows: TCPðfej g; fDj gÞ ¼ TCPp ð1; Dp ÞF where ej is the fraction of volume vj/V, Dvp is the prescription dose, TCPp(1, Dp) is the tumor control probability for the entire target volume receiving an uniform irradiation and the F factor is expressed as: F¼

   Lr  Lj ej  exp aDp Lr j¼1     Lr  Lj Lr  Lj 2  2 þðb=nf ÞDp Lr Lr N X

The best Lr value is that which makes F = 1 so that the delivered inhomogeneous dose distribution’s TCP equals TCPp(1, Dp) [12,13]. The Lr value was calculated from the DVHs data relative to the Dp prescribed for each treatment plan. It represents the percentage of overdosing or underdosing in respect to the prescribed dose. The Lr value is obtained by the percentage dose level Lj of the dose distribution normalized to the maximum, corresponding to the dose Dj administered to the volume fraction ej, so that (Dj = Dp(Lj)/Lr). The Lymann and Burman’s model was used to calculate NTCP[14] 1 NTCP ¼ pffiffiffiffiffiffi 2p

Z

t

1

exp

 2 t dt 2

the effective volume is meff ¼

P i

Di Dmax

1=n

v i , in where Dmax is

the maximum dose, mi is the fractional volume receiving Di, t = D-TD50(m)/(m Æ TD50(m)) and TD50(m) = TD50(1) Æ mn. The parameters m, n and TD50 were estimated to be 0.15, 0.25 and 60 Gy for normal brain, and 0.14, 0.16 and 65 Gy for brainstem, respectively, in agreement with typical Emami’s values (11). Fig. 1. Example of circular brain metastases treated with stereotactic radiotherapy. The inner line includes the target volume and the three other contours show the 100%, 90% and 80% isodose lines, respectively.

Follow up Patients were followed-up at 3 months. Neurological status and all health complications were recorded. Patients at

K. Pasciuti et al. / Radiotherapy and Oncology 87 (2008) 110–115

that time underwent a magnetic resonance examination; the tumor size was obtained by direct measurements and compared to the pre-treatment CT/MR images used in the treatment plans. Local control was evaluated measuring the dimension of the lesion and its volume change.

Results The indexes II and CI represent the good quality of a treatment plan. Their smaller values indicate a better plan and particularly it would be desirable to have: II = 0 which represents inhomogeneous irradiation of the target to the prescription dose and CI close to 1 even if it will be always >1, as defined in BrainSCAN system, the CI index will be <2 if the target’s volume is bigger than the normal tissue’s volume receiving the prescribed dose. Index II describes the percentage of inhomogeneity between the minimum and maximum delivered dose to the target volume. Fig. 2 shows the II profile vs patients’ number. Inhomogeneity ranges from a minimum value of 4.8% to a maximum value of 15.5% with a mean value of 9.9% and a standard deviation of 2.5%. Fig. 3 shows the CI profile vs patients’ number with minimum and maximum values set, respectively, to 1.31 and 3.58. The CI mean value is 2.19 and its standard deviation is 0.38. From the comparison of the DCAT and the IMRT technique it was possible to see how the IMRT avoids the OARs close to the target volume delivering a better coverage to the PTV with respect to the DCAT [15,16].

The IMRT plan carried out a homogeneity of 95% and the relative values obtained for the inhomogeneity and conformal index were equal to 6% and 1.53%, respectively. The TCP was calculated for each patient at the prescribed dose. We obtained an overall mean TCP value of 0.95 ranging from a minimum value of 0.89 to a maximum value of 1. The NTCP was calculated for the brain and for the brainstem only when the lesions were close to it. The NTCP mean value was 5.55 Æ 103 with a median of 1.26 Æ 105. The maximum tumor control probability was obtained for each patient. Increasing dose to the tumor, TCP increases, but its maximum is limited by the acceptable value for NTCP. The low value of complication with respect to the control probability emphasizes a high probability of complicationfree cure which depends strongly on the horizontal distance between the TCP and the NTCP curves [9,17–19]. The TCP and NTCP values have been normalized to the minimum value for each volume’s interval. The histograms in Fig. 4 show how the TCP and brainstem’s NTCP increase raising the target’s volume. The TCP value is almost equal to 1 for volumes ranging from 1 to 10 cc and it increases for volume lesion with a value higher than 10 cc. We obtained high NTCP values for target volumes larger than 10 cc. We calculated through Lr the optimal dose value that would make the F factor equal to 1. Our study carried out the percentage of overdosing or underdosing with respect to the prescribed dose for each plan. We observed an overdosing in sixty-three patients ranging from 4% to 12% with a mean value of 7%, in two cases there was an underdosing of 4% and in only one case the prescribed dose corresponded to the optimal dose level that makes the inhomogeneous TCP value equal to the relative homogeneous TCPp value.

25 20

1.10

15 10 5 0 0

10

20

30 40 Patient Number

50

60

70

Normalized TCP

Inomogeneity Index %

30

2

1

0 0

10

20

30

40

50

60

Patient Number Fig. 3. Conformity index vs patients’ number.

70

Normalized NTCP Brainstem

3

1.05 1.00 0.95 0.90

Fig. 2. Inhomogeneity index percentage vs patients’ number.

Conformity Index

113

V≤5cc

5cc
V>16cc

V≤5cc

5cc
V>16cc

6.E+05 5.E+05 3.E+05 2.E+05 1.E+02

9cc
Fig. 4. TCP and brainstem’s NTCP vs volume’s gap histograms normalized to the lower and higher value respectively.

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Brain Metastases study in Stereotactic Radiotherapy

The overdosing of the 4% was observed in those patients (30% of the total) who showed a low inhomogeneity (5–6%). Among them the 60%, treated by IMRST, showed the lowest percentage difference between the prescribed dose and the Lr value. Stereotactic radiosurgery allows to have a complete tumor control probability and a low normal tissue complication probability in agreement with our follow-up at 3 months that confirmed a total remission in 7 patients and showed stability in 32 of them. Diseases not directly correlated to the radiotherapy treatment caused the death of 8 patients. In 5 patients who had an increase in the dimension of the lesion the failure of the treatment may have been caused by a low radiation dosage. Finally 3 patients showed in their RM an evident growth of radiation-induced necrosis following treatment.

Discussion In our study based on 66 brain tumors we found that high conformity index values corresponded to the lowest target volumes (<10 cc) independently of the treatment’s technique (DCAT/IMRST). A mean homogeneity of 90% was found for all treatments but it can decrease with the increasing importance weighting of the OARs. Treatment plans always showed high homogeneity and it can reach the 95% or more using the IMRST in patients having large targets close or overlapped to the critical structures where the DCAT plans cannot spare enough the OARs. We also observed that patients treated by IMRST were those who showed the lowest overdosing (4%) of the prescribed dose with respect to the reference level Lr. The gap between these two values increased up to 12% with the raising of the inhomogeneity. The overdosing might justify the presence of necrosis observed in the follow-up because 100% prescription isodose was delivered to the target’s edge so obtaining regions into the tumor volume in which the dose reached higher values (113%). Radiation-induced necrosis is among the most significant side effects stemming from radiation therapy of the nervous system. It typically develops as a focal process at or near the site of the tumor, thus being geographically associated with the highest dose of radiation treatment [21–23]. Studies have shown that the incidence of radiation necrosis following conventional radiation therapy ranges from 5% to 24% [21]. Clearly, the risks associated with radiosurgery can be minimized keeping the dose relatively low and treating small volume even if it is difficult to determine the parameter that accurately describes this potential risk. Studies show so the lesion type was also a predisposing factor in radiation necrosis; gliomas were more likely to result in necrosis (17%) than brain metastases (5%) [24,25]. At the same time the high dose delivered to the target can explain the optimum tumor control probability value obtained for all treatments. We noticed how the calculated radiobiological parameters depended strongly on tumor volume and the normal tissue volume exposed to high radiation

dose as well as the dose conformity and steeper dose-gradient were correlated with reduced NTCP. Moreover the higher obtained NTCP values corresponded to two of four patients who, during the follow-up, reported the presence of necrosis around the tumoral region as well as the lowest TCP value belonged to those patients who, characterized by larger target volumes receiving a lower dose, underwent a worsening of their disease. The main advantage of Stereotactic Radiotherapy is the non-invasive approach that enables the local application of radiation without surgical intervention. Simultaneously this technique allows to deliver a high dose to a defined target volume in a single fraction with a sharp dose-gradient giving us precise daily patient’s device repositioning during the fractionated therapy for larger treatment volumes. The RTOG 9508 shows that the stereotactic radiotherapy prolongs functional independence 6 months posttreatment for patients with one to three unresectable brain metastases. In those cases in which this technique does not lead to a stability or decreasing of the disease nevertheless it can decrease the pain and improve the quality of patient’s life. * Corresponding author. Katia Pasciuti, Laboratory of Medical Physics and Expert Systems, Regina Elena National Cancer Institute, Via Benedetto Varchi 5, 00179 Rome, Italy. E-mail address: [email protected] Received 16 September 2007; received in revised form 12 December 2007; accepted 13 December 2007; Available online 18 January 2008

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