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Volumetric modulated arc therapy with flattening filter free beams for isolated abdominal/pelvic lymph nodes: report of dosimetric and early clinical results in oligometastatic patients

Volumetric modulated arc therapy with flattening filter free beams for isolated abdominal/pelvic... Background: SBRT is a safe and efficient strategy to locally control multiple metastatic sites. While research in the physics domain for Flattening Filter Free Beams (FFF) beams is increasing, there are few clinical data of FFF beams in clinical practice. Here we reported dosimentric and early clinical data of SBRT and FFF delivery in isolated lymph node oligometastatic patients. Methods: Between October 2010 and March 2012, 34 patients were treated with SBRT for oligometastatic lymph node metastasis on a Varian TrueBeam treatment machine using Volumetric Modulated Arc Therapy (RapidArc). We retrospectively evaluated a total of 25 patients for isolated lymph node metastases in abdomen and/or pelvis treated with SBRT and FFF (28 treatments). Acute toxicity was recorded. Local control evaluation was scored by means of CT scan and/or PET scan. Results: All dosimetric results are in line with what published for the same type of stereotactic abdominal lymph node metastases treatments and fractionation, using RapidArc. All 25 FFF SBRT patients completed the treatment. Acute gastrointestinal toxicity was minimal: one patient showed Grade 1 gastrointestinal toxicity. Three other patients presented Grade 2 toxicity. No Grade 3 or higher was recorded. All toxicities were recovered within one week. The preliminary clinical results at the median follow up of 195 days are: complete response in 12 cases, partial response in 11, stable disease in 5, with an overall response rate of 82%; no local progression was recorded. Conclusions: Data of dosimetrical findings and acute toxicity are excellent for patients treated with SBRT with VMAT using FFF beams. Preliminary clinical results showed a high rate of local control in irradiated lesion. Further data and longer follow up are needed to assess late toxicity and definitive clinical outcomes. Keywords: Abdominal/pelvic lymphnodes, VMAT, FFF * Correspondence: filippo.alongi@humanitas.it IRCCS Istituto Clinico Humanitas, Radiation Oncology Dept, Rozzano-Milan, Italy Full list of author information is available at the end of the article © 2012 Alongi et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Alongi et al. Radiation Oncology 2012, 7:204 Page 2 of 9 http://www.ro-journal.com/content/7/1/204 Background deserving dedicated investigations. While research in the The detection of single or limited organ metastases, physics domain for FFF beams is increasing, there are defined oligometastases, has been recently increased by few clinical data where FFF beams are applied in clinical advancements in imaging technology [1]. In this subgroup practice, particularly in SBRT treatments [16]. of cancer patients, local treatments for oligometastases Here we reported dosimetric and early clinical data of have been widely investigated for many cancers with the SBRT with FFF in isolated lymph node oligometastatic objective to impact on disease control and survival [2]. In patients. selected oligometastatic patients, surgical resection of lim- ited metastatic burden of disease prolongs survival [1,2]. Methods However, the ideal candidates for local therapy are difficult Patient population to identify. Between October 2010 and March 2012, a total of 34 In this scenario, radiation treatments can play a role to patients were treated with SBRT for isolated lymph node achieve local control of oligometastatic focal disease. As metastases in abdomen and or pelvis on a Varian True- smaller foci of metastases are defined, highly conformal Beam treatment machine (Varian Medical Systems, Palo radiation therapy, such as Stereotactic Body Radiother- Alto, CA, USA) using RapidArc technology. Twenty-eight apy (SBRT) or similar techniques, can prove to be less of those patients were treated with SBRT and FFF beams; invasive and more effective than surgery because of de- among them 3 were lost to follow-up. The following will creasing morbidity, less costs and the potential of deli- refer to this 25 patient cohort with follow-up, for a total of vering ablative doses on an outpatient basis. Emerging 28 treatments. Patient data were collected and retrospect- data show that SBRT, in its various treatment modalities, ively analyzed. Table 1 summarized inclusion criteria and is a safe and efficient strategy to locally control multiple Table 2 summarized demographic data of the population metastatic sites [3]. SBRT does not replace systemic of study. Patients were stratified for metastatic disease site therapy but rather can augment its effects on focal areas (abdominal or pelvic). of gross disease, as well as metastatic lymph nodes. Previous published experiences in our Institute have Dose prescription, simulation procedures and target shown how SBRT for abdominal targets resulted to be feas- delineation ible with good early local control rate and acute toxicity Prescription doses were 45 Gy in 6 consecutive fractions profile [4]. In particular, the medium-term clinical outcome of 7.5 Gy for all 28 treatments. The inclusion criteria of hypofractionated SBRT seemed to be promising in a were: age ≥18years, WHO performance status ≤ 2, series of patients with either a solitary metastasis or oligo- histologically-proven of primary cancer disease, M1 metastases from different tumors to abdominal lymph stage with primary cancer site radically treated with nodes [5]. complete response/resection or stable, no other site of Recently, two new technological platforms have been disease in progression (a maximum of 3 lymph node sites made available to clinical practice in radiation therapy of disease to treat), diameter of lymph node Target less departments. Firstly, Volumetric Modulated Arc Therapy than 5 cm, Abdomen/pelvic site, no previous surgery or (VMAT) in its RapidArc format, allowed a significantly RT in the region to treat, obtained informed consent. time reduction to deliver complex intensity modulated Chemotherapy, when prescribed, was interrupted from plans, permitting to treat with hypofractionated regimes 20 days before the simulation to the first evaluation after within few minutes [6-8]). Secondly, there has been in- the end of SBRT treatment, as scheduled. creasing interest into the clinical use of linear accelera- tors (LINAC) with photon beams generated without Table 1 Inclusion criteria usage of the flattening filter [9-15]. It seems possible to Age: ≥18years predict a reduction of out-of-field dose when flattening WHO performance status: ≤ 2 filter free (FFF) beams are used. This is mainly related to the reduced head scattering and the residual electron Histologically-proven of primary cancer disease contamination. FFF beams should therefore lead to M1 stage with primary cancer site radically treated with complete response/resection or stable. reduced peripheral doses and patients can benefit by decreased exposure of healthy tissue to scattered doses No other site of disease in progression (a maximum of 3 lymph node sites of disease to treat) outside the radiation field. Removal of the flattening filter implies also the possibility to deliver treatments with Diameter: <5 cm higher dose rates, up to factor 4 at 10 MV, and with a Abdomen/pelvic site much higher dose per pulse. This, beside further improv- No previous surgery or RT in the region to treat ing time efficiency for delivery, might have subsequent Informed consent. potential radiobiology implications; now still unclear and Alongi et al. Radiation Oncology 2012, 7:204 Page 3 of 9 http://www.ro-journal.com/content/7/1/204 Table 2 Demographic patient and treatment data The clinical target volume (CTV) included macro- Patient Gender (Nb of patients) scopic (for practical reasons, the gross tumor volume GTV was not explicitely outlined) and microscopic dis- Male 19 ease, based on CT as well as on PET imaging when Female 6 available. Set-up margin was minimised using the cone- Age (y) beam CT (CBCT) verification before each treatment ses- Median (range) 70 (32, 83) sion. The overall CTV to PTV (planning target volume) Tumour Primary (Nb of patients) margin was of 6–10 mm in all directions, based on pre- Colon 6 vious study on 4DCT acquisitions as mentioned above. Margins were differentiated depending on the lesion lo- Stomach 2 cation. Since the residual internal organ motion was lim- Biliary tract / pancreas 3 ited due to abdominal compression, no planning organ Breast 1 at risk volumes (PRV) was defined for any organ at risk Lung 4 (OAR) nor included in the optimization process. Sarcoma 1 Ovary 2 Planning objectives Prescription dose was defined as the mean dose to the Kidney 3 PTV, aiming to cover the PTV with 95% of the pre- Prostate 3 scribed dose. If organs at risk tolerance doses did not Metastasis site (Nb of treatments) allow that coverage, the prescription was then applied to Abdominal 8 the mean dose to the CTV, aiming to cover the CTV Pelvic 20 with 95% of the prescribed dose, and the PTV with 80% Nb of metastases (Nb of treatments) of the same prescribed dose. Maximum dose was to be kept below 107% of the prescription. Solitary 23 Main OAR considered were: stomach, duodenum, Oligometastases 5 small bowel, liver, spinal cord, kidneys. Plans were CTV volume (cm ) required to meet the following physical dose objectives Mean±SD (range) 17.4±21.0 (1.2, 103,8) (which account for the used fractionation): PTV volume (cm ) Mean±SD (range) 56.8±42.0 (9.6, 185.9) – Stomach and duodenum: V <1cm 36G – Small bowel: V <3cm 36Gy Previous chemotherapy (Nb of patients) – Liver: V <(total liver volume – 700cm ) 21Gy Yes 20 – Spinal cord: D <18Gy 1cm3 No 5 – Kidneys: V <35% 15Gy Patient preparation for planning CT and each treat- SBRT planning and delivery procedure ment session foresees a 3-hour fast to avoid large dis- Flattening filter-free (FFF) photon beams of nominal 6 placement of stomach and bowel during daily treatment or 10 MV from a Varian TrueBeam were used for all 28 with respect to planning CT anatomy. treatments, using the maximum available dose rate of CT scans for planning were acquired for all patients in 1400 or 2400 MU/min (for 6 or 10 MV FFF, respect- supine position, with the arms above their head and immo- ively). Plans were individually set-up with the VMAT bilized with a thermoplastic body mask including a styro- using the RapidArc technology. Full arcs were used in foam block for abdominal compression to minimize 9 cases, while for the other plans partial arcs setting was internal organ motion. Contrast free and contrast- chosen. Single arc was planned for only 4 cases, and enhanced CT scans were acquired in free breathing mode multiple arcs (mostly two) were preferred according to at 3 mm slice thickness in the same patient treatment pos- patient anatomy and mutual PTV and OAR location in ition during the same acquisition session. The abdominal order to obtain the best adherence to planning objectives compression was assessed in our clinic to adequately for each patient. All dose distributions were computed minimize the internal motion, with 4DCT acquisitions in with the Anisotropic Analytical Algorithm (AAA, ver- some past cases to assess the residual movement being of sion 8.9) implemented in the Eclipse treatment planning < 5mm. Such an immobilization is the standard in our system (Varian). The ‘jaw tracking’ option available for clinic for all stereotactic (or hypofractionated) abdominal TrueBeam facilities was applied during the optimization irradiations, without adding a 4DCT acquisition for ITV phase. With this tool the main jaws are driven by the (internal target volume) delineation. control system to follow the actual minimum MLC Alongi et al. Radiation Oncology 2012, 7:204 Page 4 of 9 http://www.ro-journal.com/content/7/1/204 aperture during the arc delivery. For multiple lesions the Local control was evaluated on CT images at the first attempt was to keep one single isocentre, but the choice of follow-up for all cases; patients who had a PET scan before single or multiple isocentre was driven by the obtained SBRT, the same metabolic examination and response were dose distribution in the two competitor plans. Only one also evaluated during the follow-up and scored according case of multiple lesions was treated with two isocentres. PERCIST criteria. Local control evaluation was scored Treatment was possibly delivered in 6 consecutive work- according to the WHO criteria as complete remission ing days. Treatment delivery was preceded by CBCT (CR), partial remission (PR), stable disease (SD) for each image guidance with, whenever needed, on-line couch ad- treatment. Distant progression disease (PD) scored the justment. Image matching was performed on bony struc- clinical results on possible lesions out of the local target. tures and, when visible, on tumors and/or other soft tissue Although obviously very early, a first assessment of structures (e.g. main blood vessels). initial treatment outcome was performed at first and Prior to the first session, pre-treatment quality assur- second follow up visits. ance was performed using the MatriXX (IBA Dosimetry, Shwarzenbruck, Germany) 2D array of ion chambers Results (distance between detectors: 0.76 cm) placed in a PMMA Dosimetric data slab phantom. The dose at the detectors plane was calcu- Figure 1 illustrates two examples of dose distributions of lated with the same patient plan in the phantom and com- abdominal and pelvic lymph node treatments in axial, pared with measurement. Evaluation was based on γ index, sagittal and coronal views. Figure 2 presents the average with criteria of 3 mm and 3% as distance to agreement and cumulative dose volume histograms for the PTV and the dose difference. Acceptability was set to 95% of the points involved organs at risk. Table 3 shows results from DVH passing the threshold of γ<1. analysis for the analyzed structures. Efficiency of the treatment was evaluated in terms of We compared the present data using FFF beams with beam on time, that is reduced by the usage of FFF previous dosimetric data of the same group, for the same beams, allowing dose rates up to 2400 MU/min. type of stereotactic abdominal lymph node metastases treatments and fractionation with RapidArc technology Evaluation of dosimetric data [8]. All dosimetric results are in line with what we previ- The quantitative evaluation of plans was performed by ously published without FFF, as reported in the last col- means of dose–volume histograms (DVH) data. For PTV umn of Table 3 for the published data. The differences and CTV, the values of D and D (dose received by between the two dataset are that they are based on a dif- 99% 1% 99%, and 1% of the volume) were defined as metrics for ferent group of patients, and that the published data minimum and maximum doses; V (the volume receiv- refer to standard flattened beams, while the present 95% ing at least 95% of the prescribed dose), homogeneity as work reports on FFF results. Standard Deviation parameter of DVH and D -D ,as In particular a very highly degree of conformality is 5% 95% well as the conformity index CI (defined as the ratio be- available in the present study with FFF, with very high tween the patient volume receiving 95% of the prescription volume fraction receiving the 95% of the dose prescrip- dose and the PTV volume) were also reported. tion: around 98 and 100% of the PTV and CTV respect- For OARs, the analysis included the mean dose, the ively. The PTV coverage was 90% for non-FFF beams. maximum dose expressed as D , and a set of appropri- For OARs, it was possible to respect the planning 1% ate V and D values. objectives in all the cases, also the V for stomach, X(Gy) Y(% or ccm) 36Gy Average cumulative DVH for PTV, CTV and OARs were duodenum and bowels. Dose reduction in the CTV to determined from the individual DVHs. These histograms PTV margin (requiring minimum dose to PTV higher were obtained by averaging the corresponding volumes than 80% while keeping the 95% coverage for CTV) was over the whole patient cohort for each dose bin of 0.05 Gy. required for organs at risk tolerance dose in three cases. Delivery accuracy determined by the pre-treatment qual- Evaluation of clinical data ity assurance was recorded, for the patients of this study, Patients had clinical evaluations planned before and dur- as the percentage of the point passing the gamma criteria ing the treatment, at the end of the last fraction. Then, of 3 mm/3%. The average of this value over all the patient the first follow-up visit was scheduled, based on site and cohort was 99.2±0.5, with a range of 97.3-99.9. All cases general condition, within 45–120 days from the end of were carefully analysed, not only fixing the attention on the treatment, then every 3–4 months, Acute toxicity the number of gamma passing point, in the whole dose induced from the radiation treatment were scored and map, and considered acceptable. recorded according to the National Cancer Institute’s Arc delivery with FFF beams was with a maximum Common Terminology Criteria for Adverse Events of 2400 MU/min for 10 FFF beam, with an average (CTCAE version 3.0). beam on time of 1.47±0.44 min [range: 0.82-2.02 min]. Alongi et al. Radiation Oncology 2012, 7:204 Page 5 of 9 http://www.ro-journal.com/content/7/1/204 Figure 1 Dose colorwash from 50% dose level for an abdominal lymph node case (left) and a pelvic lymph node case (right). For a comparison, the plans were delivered also with a Clinical results maximum dose rate of 600 MU/min, that is the usual Clinical results as acute gastrointestinal GI toxicity as maximum dose rate available in normal linacs using well treatment outcome are summarized in numbers in standard flattened beams. With this setting, the aver- Table 4. age beam on time would have been 3.49±0.81 min [range: All 25 FFF SBRT patients completed the treatment, as 2.52-5.72 min] and thus, for this dose per fraction, the programmed, with no interruptions. maximum dose rate of 2400 MU/min reduced the beam Acute gastrointestinal toxicity was minimal: one patient on time more than 200%. showed Grade 1 gastrointestinal toxicity, as gastralgia. Figure 2 Average DVH of the main structures on the whole patient cohort. Alongi et al. Radiation Oncology 2012, 7:204 Page 6 of 9 http://www.ro-journal.com/content/7/1/204 Table 3 Dose distribution statistics Structure Parameter Objective Mean±SD From Bignardi PTV Mean [Gy] 50.0 44.9±0.7 44.5±0.3 Volume [cm]D [Gy] 2.8±1.5 3.8±0.8 5%-95% 56.7±42.0 Standard Dev [Gy] 0.9±0.5 D [Gy] <48.15 46.2±0.8 46.4±0.3 1% D [Gy] >42.75 (36) 42.0±2.4 40.8±1.0 99% V [%] 97.7±3.2 90.2±5.2 95% CI 1.0 1.1±0.1 1.0±0.1 95% CTV Mean [Gy] 45.1±0.8 45.0±0.0 Volume [cm]D [Gy] 1.4±0.8 1.4±0.3 5%-95% 17.4±21.0 Standard Dev [Gy] 0.4±0.3 D [Gy] <48.15 45.9±0.8 46.0±0.2 1% D [Gy] >42.75 43.8±1.8 44.1±0.2 99% V [%] 100 99.7±1.3 100.0±0.0 95% Stomach Mean [Gy] 4.2±1.9 4.0±5.5 Volume [cm]D [Gy] 17.9±9.0 12.2±11.7 1% 228.8±129.2 V [%] 11.2±12.1 10Gy V [%] 5.0±6.2 15Gy V [cm ] <1 0.05±0.08 0.1±0.5 36Gy Duodenum Mean [Gy] 11.0±7.5 7.0±5.6 Volume [cm]D [Gy] 22.9±14.2 22.4±13.8 1% 34.5±24.2 V [%] 60.8±42.6 10Gy V [%] 14.4±19.2 20Gy V [cm ] <1 0.09±0.19 0.5±0.9 36Gy Small Bowel Mean [Gy] 5.1±3.5 3.0±2.3 Volume [cm]D [Gy] 23.3±6.7 18.0±10.8 1% 1900.9±1764.5 V [%] 18.6±17.0 10Gy V [%] 3.6±4.6 20Gy V [cm ] <3 2.9±3.9 0.1±0.2 36Gy Liver Mean [Gy] 3.4±2.5 3.6±3.9 Volume [cm]D [Gy] 19.2±14.5 20.2±17.3 1% 1450.5±287.3 V [%] 10.2±9.6 10Gy V [%] 2.0±2.6 20Gy (V -700)-V [cm ] >0 724±285 liver 21Gy Spinal Cord D [Gy] 10.1±3.2 7.8±2.3 1% Volume [cm]D [Gy] <18Gy 9.5±3.1 1ccm 32.6±19.7 V [%] 12.2±19.9 10Gy Left Kidney Mean [Gy] 4.2±3.4 2.2±2.5 Volume [cm]D [Gy] 11.6±8.7 8.3±8.1 1% 162.4±36.8 V [%] <35 3.1±7.5 1.7±5.9 15Gy Right Kidney Mean [Gy] 3.9±3.6 3.1±2.9 Volume [cm]D [Gy] 10.7±6.9 10.4±11.2 1% 163.4±39.9 V [%] <35 2.9±8.6 2.8±7.1 15Gy Alongi et al. Radiation Oncology 2012, 7:204 Page 7 of 9 http://www.ro-journal.com/content/7/1/204 Table 4 Toxicity and response results Of the patient cohort of this study, 6 presented distant G/I toxicity Nb of patients (total 25) progressive disease (outside the treated region) at the first follow-up. This number increase to 15 for the 195 Grade 0 21 median days follow-up. Grade 1 1 Grade 2 3 Discussion and conclusions Grade 3-4 0 Rationale of local therapy for oligomestases is that when Response Nb of treatments (total 28) primary cancer is controlled, the solitary or few metasta- At first Follow-up: ses can be cured locally to effort systemic therapy [1,2]. Actually, few published data do exist on local control CR 11 rates of radiotherapy in the context of isolated or few PR 13 lymph node metastases. Although dose and fractionation SD 4 schedules are extremely heterogeneous, early data from Nb of treatments (total 28) some recent series are promising in term of local control At median Follow-up of 152 months: rates [3]. Because small volumes are irradiated for meta- CR 13 static lymph nodes, a dose escalation might improve effi- cacy without prohibitive toxicity. PR 9 Most of reported experiences regarded oligometastatic SD 6 lymph node in pelvis or abdomen and are summarized in Table 5. Three other patients presented Grade 2 toxicity, one with The results of the current study with SBRT by RapidArc gastric pyrosis, one with epigastralgia and one with nausea/ and FFF, at the median follow up of 195 days confirm a re- vomiting. No severe acute toxicity with Grade 3 or more sponse rate of 82% and no local progression was recorded. was recorded. All toxicities were recovered within one week Local control provided by the current initial experience (G1 without intervention, G2 with symptomatic drugs). may be potentially significant for preserving quality of life No late toxicity, as per the rather short follow-up time, and delaying further systemic treatments. Obviously, the was found. most significant criticism remain: a) the heterogeneity of The median follow-up was 195 days (range 48–589 the population of study, composed by a miscellaneous of days). All patients had at least the first follow up at a cases from different primary tumors (see Table 1) b) the median of 92 days (minimum 47 days) from the end of short follow-up (median of 195 days), c) the retrospective the radiation treatment. nature of the study in patient data analysis. Nevertheless, At the first follow-up, early clinical outcome was as- the end point of the study was to define the dosimetric and sessable at diagnostic evaluation of last control with PET early clinical results of SBRT by RapidArc with FFF, and and/or CT in 25 patients (28 treatments). At the end of this finding was largely confirmed: all plan objectives were the first follow-up evaluation, a complete response met and no toxicity were recorded in acute setting, achiev- (according to World Health Organization criteria) was ing an intial high rate of local control. found in 11 cases. A partial response was achieved in 13 Concerning FFF beams, previous our report showed as cases. The overall response rate was of 86% (24/28 treat- the treatment delivery with FFF beams for abdominal le- ments). Four patients had stable disease. No local pro- sion is faster and more efficient, improving patient’s gression was found. comfort and thus reducing intra-fraction motion, char- The results at the median follow up of 195 days (18 acteristic that becomes particularly important in SBRT patients had a second follow-up) are: complete response [21]. Some preliminary studies for SBRT using FFF in 12 cases, partial response in 11, stable disease in 5, beams are present in literature [11,22] and in a recent with an overall response rate of 82%; no local progres- study performed in our institute it was described our sion was recorded. early experience in the use of FFF beams for SBRT Table 5 Clinical details of published studies of SBRT for oligometastases lymph nodes Reference Primary N° of patients Radiation Dose Median FUP [months] Outcomes Jereckzek et al. [17] prostate 34 30 Gy in 4/5 fractions 16.9 LC: 91% at 17 months Choi et al. [18] cervix 30 33-45 Gy in 3 fractions 15 LC:67.4% at 4 years Kim et al. [19,20] gastric 7 36/51 in 3/fractions 26 OS:43% at 3 years Bignardi et al. [5] miscellaneous 19 45 in 6 fractions 12 LC: 77,8% at 1 year LC= local control; OS= overall survival. Alongi et al. Radiation Oncology 2012, 7:204 Page 8 of 9 http://www.ro-journal.com/content/7/1/204 treatments including liver metastases, lung primitive and next clinical studies for thoracic and abdominal stereo- metastases, isolated abdominal lymph nodes, adrenal tactic irradiations. glands, and pancreas [16]. Also in the present report, Considering these promising results, a prospective acute toxicity profile was excellent: no severe acute study of dose escalation in 4 fraction of SBRT with FFF Grade 3 toxicity or more was recorded and all toxicities beams for pelvic/abdominal lymph node oligometastatic (2 cases of Grade 1 and 3 cases of Grade 2) were recov- patients (genito-urinary and gynecology primary) was re- ered within one week. cently proposed and accepted by internal ethical com- From the radiobiological point, some literature starts mittee of our Institute and preliminary results will be to show that FFF beams, relatively to standard flattened reported in a further study. beams, have higher efficacy, possibly in reducing survival Competing interests fraction for the same delivered physical dose, due to the L. Cozzi acts as Scientific Advisor to Varian Medical Systems and is Head of higher dose per pulse of such beams (up to 4 times) Research and Technological Development at the Oncology Institute of Southern Switzerland, Bellinzona. Other authors report no conflict of interest. [23]. This fact is today only a suggestion coming from sparse laboratory studies on cell lines, and not yet clinic- Authors’ contributions ally proven in terms of patient studies. In principle the FA, MS and AF coordinated the entire study. Data collection and clinical data analysis were conducted by FA, EC, PN, AT, TC, AMA, MS. Dosimetric data improvement is present, but the increased cell killing ef- collection and analysis were conducted by AF, AC, FL, GR, LC, PM, ST. All fect is rather minimal, so difficult to be proven at the authors read and approved the final manuscript. present stage with small clinical studies. To clinically Author details demonstrate the differences in cell killing effect between IRCCS Istituto Clinico Humanitas, Radiation Oncology Dept, Rozzano-Milan, standard beams and beams with high dose per pulse, Italy. Oncology Institute of Southern Switzerland, Medical Physics Unit, clinical trials should be set on a rather large scale. Also Bellinzona, Switzerland. the time factor, not only the dose per pulse, is known to Received: 24 July 2012 Accepted: 21 November 2012 have a role the on radiation induced damage. This was Published: 5 December 2012 subject of different studies where, both on theoretical References bases and in vitro irradiations [24,25] it is demonstrated 1. Weichselbaum RR, Hellman S: Oligometastases revisited. Nat Rev Clin Oncol that the shorter is the treatment session time, the higher 2011, 8:378–382. is the tumor control probability for the same physical 2. Rubin P, Brasacchio R, Katz A: Solitary metastases: Illusion versus reality. 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Wang JZ, Li XA, D’Souza WD, Stewart RD: Impact of prolonged fraction delivery times on tumor control: a note of caution for intensity- modulated radiation therapy (IMRT). Int J Radiat Oncol Biol Phys 2003, 57:543–552. 25. Moiseenko V, Duzenli C, Durand RE: In vitro study of cell survival following dynamic MLC intensity-modulated radiation therapy dose delivery. Med Phys 2007, 34:1514–1520. doi:10.1186/1748-717X-7-204 Cite this article as: Alongi et al.: Volumetric modulated arc therapy with flattening filter free beams for isolated abdominal/pelvic lymph nodes: report of dosimetric and early clinical results in oligometastatic patients. Radiation Oncology 2012 7:204. 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Volumetric modulated arc therapy with flattening filter free beams for isolated abdominal/pelvic lymph nodes: report of dosimetric and early clinical results in oligometastatic patients

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Springer Journals
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Copyright © 2012 by Alongi et al.; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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1748-717X
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10.1186/1748-717X-7-204
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23216821
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Abstract

Background: SBRT is a safe and efficient strategy to locally control multiple metastatic sites. While research in the physics domain for Flattening Filter Free Beams (FFF) beams is increasing, there are few clinical data of FFF beams in clinical practice. Here we reported dosimentric and early clinical data of SBRT and FFF delivery in isolated lymph node oligometastatic patients. Methods: Between October 2010 and March 2012, 34 patients were treated with SBRT for oligometastatic lymph node metastasis on a Varian TrueBeam treatment machine using Volumetric Modulated Arc Therapy (RapidArc). We retrospectively evaluated a total of 25 patients for isolated lymph node metastases in abdomen and/or pelvis treated with SBRT and FFF (28 treatments). Acute toxicity was recorded. Local control evaluation was scored by means of CT scan and/or PET scan. Results: All dosimetric results are in line with what published for the same type of stereotactic abdominal lymph node metastases treatments and fractionation, using RapidArc. All 25 FFF SBRT patients completed the treatment. Acute gastrointestinal toxicity was minimal: one patient showed Grade 1 gastrointestinal toxicity. Three other patients presented Grade 2 toxicity. No Grade 3 or higher was recorded. All toxicities were recovered within one week. The preliminary clinical results at the median follow up of 195 days are: complete response in 12 cases, partial response in 11, stable disease in 5, with an overall response rate of 82%; no local progression was recorded. Conclusions: Data of dosimetrical findings and acute toxicity are excellent for patients treated with SBRT with VMAT using FFF beams. Preliminary clinical results showed a high rate of local control in irradiated lesion. Further data and longer follow up are needed to assess late toxicity and definitive clinical outcomes. Keywords: Abdominal/pelvic lymphnodes, VMAT, FFF * Correspondence: filippo.alongi@humanitas.it IRCCS Istituto Clinico Humanitas, Radiation Oncology Dept, Rozzano-Milan, Italy Full list of author information is available at the end of the article © 2012 Alongi et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Alongi et al. Radiation Oncology 2012, 7:204 Page 2 of 9 http://www.ro-journal.com/content/7/1/204 Background deserving dedicated investigations. While research in the The detection of single or limited organ metastases, physics domain for FFF beams is increasing, there are defined oligometastases, has been recently increased by few clinical data where FFF beams are applied in clinical advancements in imaging technology [1]. In this subgroup practice, particularly in SBRT treatments [16]. of cancer patients, local treatments for oligometastases Here we reported dosimetric and early clinical data of have been widely investigated for many cancers with the SBRT with FFF in isolated lymph node oligometastatic objective to impact on disease control and survival [2]. In patients. selected oligometastatic patients, surgical resection of lim- ited metastatic burden of disease prolongs survival [1,2]. Methods However, the ideal candidates for local therapy are difficult Patient population to identify. Between October 2010 and March 2012, a total of 34 In this scenario, radiation treatments can play a role to patients were treated with SBRT for isolated lymph node achieve local control of oligometastatic focal disease. As metastases in abdomen and or pelvis on a Varian True- smaller foci of metastases are defined, highly conformal Beam treatment machine (Varian Medical Systems, Palo radiation therapy, such as Stereotactic Body Radiother- Alto, CA, USA) using RapidArc technology. Twenty-eight apy (SBRT) or similar techniques, can prove to be less of those patients were treated with SBRT and FFF beams; invasive and more effective than surgery because of de- among them 3 were lost to follow-up. The following will creasing morbidity, less costs and the potential of deli- refer to this 25 patient cohort with follow-up, for a total of vering ablative doses on an outpatient basis. Emerging 28 treatments. Patient data were collected and retrospect- data show that SBRT, in its various treatment modalities, ively analyzed. Table 1 summarized inclusion criteria and is a safe and efficient strategy to locally control multiple Table 2 summarized demographic data of the population metastatic sites [3]. SBRT does not replace systemic of study. Patients were stratified for metastatic disease site therapy but rather can augment its effects on focal areas (abdominal or pelvic). of gross disease, as well as metastatic lymph nodes. Previous published experiences in our Institute have Dose prescription, simulation procedures and target shown how SBRT for abdominal targets resulted to be feas- delineation ible with good early local control rate and acute toxicity Prescription doses were 45 Gy in 6 consecutive fractions profile [4]. In particular, the medium-term clinical outcome of 7.5 Gy for all 28 treatments. The inclusion criteria of hypofractionated SBRT seemed to be promising in a were: age ≥18years, WHO performance status ≤ 2, series of patients with either a solitary metastasis or oligo- histologically-proven of primary cancer disease, M1 metastases from different tumors to abdominal lymph stage with primary cancer site radically treated with nodes [5]. complete response/resection or stable, no other site of Recently, two new technological platforms have been disease in progression (a maximum of 3 lymph node sites made available to clinical practice in radiation therapy of disease to treat), diameter of lymph node Target less departments. Firstly, Volumetric Modulated Arc Therapy than 5 cm, Abdomen/pelvic site, no previous surgery or (VMAT) in its RapidArc format, allowed a significantly RT in the region to treat, obtained informed consent. time reduction to deliver complex intensity modulated Chemotherapy, when prescribed, was interrupted from plans, permitting to treat with hypofractionated regimes 20 days before the simulation to the first evaluation after within few minutes [6-8]). Secondly, there has been in- the end of SBRT treatment, as scheduled. creasing interest into the clinical use of linear accelera- tors (LINAC) with photon beams generated without Table 1 Inclusion criteria usage of the flattening filter [9-15]. It seems possible to Age: ≥18years predict a reduction of out-of-field dose when flattening WHO performance status: ≤ 2 filter free (FFF) beams are used. This is mainly related to the reduced head scattering and the residual electron Histologically-proven of primary cancer disease contamination. FFF beams should therefore lead to M1 stage with primary cancer site radically treated with complete response/resection or stable. reduced peripheral doses and patients can benefit by decreased exposure of healthy tissue to scattered doses No other site of disease in progression (a maximum of 3 lymph node sites of disease to treat) outside the radiation field. Removal of the flattening filter implies also the possibility to deliver treatments with Diameter: <5 cm higher dose rates, up to factor 4 at 10 MV, and with a Abdomen/pelvic site much higher dose per pulse. This, beside further improv- No previous surgery or RT in the region to treat ing time efficiency for delivery, might have subsequent Informed consent. potential radiobiology implications; now still unclear and Alongi et al. Radiation Oncology 2012, 7:204 Page 3 of 9 http://www.ro-journal.com/content/7/1/204 Table 2 Demographic patient and treatment data The clinical target volume (CTV) included macro- Patient Gender (Nb of patients) scopic (for practical reasons, the gross tumor volume GTV was not explicitely outlined) and microscopic dis- Male 19 ease, based on CT as well as on PET imaging when Female 6 available. Set-up margin was minimised using the cone- Age (y) beam CT (CBCT) verification before each treatment ses- Median (range) 70 (32, 83) sion. The overall CTV to PTV (planning target volume) Tumour Primary (Nb of patients) margin was of 6–10 mm in all directions, based on pre- Colon 6 vious study on 4DCT acquisitions as mentioned above. Margins were differentiated depending on the lesion lo- Stomach 2 cation. Since the residual internal organ motion was lim- Biliary tract / pancreas 3 ited due to abdominal compression, no planning organ Breast 1 at risk volumes (PRV) was defined for any organ at risk Lung 4 (OAR) nor included in the optimization process. Sarcoma 1 Ovary 2 Planning objectives Prescription dose was defined as the mean dose to the Kidney 3 PTV, aiming to cover the PTV with 95% of the pre- Prostate 3 scribed dose. If organs at risk tolerance doses did not Metastasis site (Nb of treatments) allow that coverage, the prescription was then applied to Abdominal 8 the mean dose to the CTV, aiming to cover the CTV Pelvic 20 with 95% of the prescribed dose, and the PTV with 80% Nb of metastases (Nb of treatments) of the same prescribed dose. Maximum dose was to be kept below 107% of the prescription. Solitary 23 Main OAR considered were: stomach, duodenum, Oligometastases 5 small bowel, liver, spinal cord, kidneys. Plans were CTV volume (cm ) required to meet the following physical dose objectives Mean±SD (range) 17.4±21.0 (1.2, 103,8) (which account for the used fractionation): PTV volume (cm ) Mean±SD (range) 56.8±42.0 (9.6, 185.9) – Stomach and duodenum: V <1cm 36G – Small bowel: V <3cm 36Gy Previous chemotherapy (Nb of patients) – Liver: V <(total liver volume – 700cm ) 21Gy Yes 20 – Spinal cord: D <18Gy 1cm3 No 5 – Kidneys: V <35% 15Gy Patient preparation for planning CT and each treat- SBRT planning and delivery procedure ment session foresees a 3-hour fast to avoid large dis- Flattening filter-free (FFF) photon beams of nominal 6 placement of stomach and bowel during daily treatment or 10 MV from a Varian TrueBeam were used for all 28 with respect to planning CT anatomy. treatments, using the maximum available dose rate of CT scans for planning were acquired for all patients in 1400 or 2400 MU/min (for 6 or 10 MV FFF, respect- supine position, with the arms above their head and immo- ively). Plans were individually set-up with the VMAT bilized with a thermoplastic body mask including a styro- using the RapidArc technology. Full arcs were used in foam block for abdominal compression to minimize 9 cases, while for the other plans partial arcs setting was internal organ motion. Contrast free and contrast- chosen. Single arc was planned for only 4 cases, and enhanced CT scans were acquired in free breathing mode multiple arcs (mostly two) were preferred according to at 3 mm slice thickness in the same patient treatment pos- patient anatomy and mutual PTV and OAR location in ition during the same acquisition session. The abdominal order to obtain the best adherence to planning objectives compression was assessed in our clinic to adequately for each patient. All dose distributions were computed minimize the internal motion, with 4DCT acquisitions in with the Anisotropic Analytical Algorithm (AAA, ver- some past cases to assess the residual movement being of sion 8.9) implemented in the Eclipse treatment planning < 5mm. Such an immobilization is the standard in our system (Varian). The ‘jaw tracking’ option available for clinic for all stereotactic (or hypofractionated) abdominal TrueBeam facilities was applied during the optimization irradiations, without adding a 4DCT acquisition for ITV phase. With this tool the main jaws are driven by the (internal target volume) delineation. control system to follow the actual minimum MLC Alongi et al. Radiation Oncology 2012, 7:204 Page 4 of 9 http://www.ro-journal.com/content/7/1/204 aperture during the arc delivery. For multiple lesions the Local control was evaluated on CT images at the first attempt was to keep one single isocentre, but the choice of follow-up for all cases; patients who had a PET scan before single or multiple isocentre was driven by the obtained SBRT, the same metabolic examination and response were dose distribution in the two competitor plans. Only one also evaluated during the follow-up and scored according case of multiple lesions was treated with two isocentres. PERCIST criteria. Local control evaluation was scored Treatment was possibly delivered in 6 consecutive work- according to the WHO criteria as complete remission ing days. Treatment delivery was preceded by CBCT (CR), partial remission (PR), stable disease (SD) for each image guidance with, whenever needed, on-line couch ad- treatment. Distant progression disease (PD) scored the justment. Image matching was performed on bony struc- clinical results on possible lesions out of the local target. tures and, when visible, on tumors and/or other soft tissue Although obviously very early, a first assessment of structures (e.g. main blood vessels). initial treatment outcome was performed at first and Prior to the first session, pre-treatment quality assur- second follow up visits. ance was performed using the MatriXX (IBA Dosimetry, Shwarzenbruck, Germany) 2D array of ion chambers Results (distance between detectors: 0.76 cm) placed in a PMMA Dosimetric data slab phantom. The dose at the detectors plane was calcu- Figure 1 illustrates two examples of dose distributions of lated with the same patient plan in the phantom and com- abdominal and pelvic lymph node treatments in axial, pared with measurement. Evaluation was based on γ index, sagittal and coronal views. Figure 2 presents the average with criteria of 3 mm and 3% as distance to agreement and cumulative dose volume histograms for the PTV and the dose difference. Acceptability was set to 95% of the points involved organs at risk. Table 3 shows results from DVH passing the threshold of γ<1. analysis for the analyzed structures. Efficiency of the treatment was evaluated in terms of We compared the present data using FFF beams with beam on time, that is reduced by the usage of FFF previous dosimetric data of the same group, for the same beams, allowing dose rates up to 2400 MU/min. type of stereotactic abdominal lymph node metastases treatments and fractionation with RapidArc technology Evaluation of dosimetric data [8]. All dosimetric results are in line with what we previ- The quantitative evaluation of plans was performed by ously published without FFF, as reported in the last col- means of dose–volume histograms (DVH) data. For PTV umn of Table 3 for the published data. The differences and CTV, the values of D and D (dose received by between the two dataset are that they are based on a dif- 99% 1% 99%, and 1% of the volume) were defined as metrics for ferent group of patients, and that the published data minimum and maximum doses; V (the volume receiv- refer to standard flattened beams, while the present 95% ing at least 95% of the prescribed dose), homogeneity as work reports on FFF results. Standard Deviation parameter of DVH and D -D ,as In particular a very highly degree of conformality is 5% 95% well as the conformity index CI (defined as the ratio be- available in the present study with FFF, with very high tween the patient volume receiving 95% of the prescription volume fraction receiving the 95% of the dose prescrip- dose and the PTV volume) were also reported. tion: around 98 and 100% of the PTV and CTV respect- For OARs, the analysis included the mean dose, the ively. The PTV coverage was 90% for non-FFF beams. maximum dose expressed as D , and a set of appropri- For OARs, it was possible to respect the planning 1% ate V and D values. objectives in all the cases, also the V for stomach, X(Gy) Y(% or ccm) 36Gy Average cumulative DVH for PTV, CTV and OARs were duodenum and bowels. Dose reduction in the CTV to determined from the individual DVHs. These histograms PTV margin (requiring minimum dose to PTV higher were obtained by averaging the corresponding volumes than 80% while keeping the 95% coverage for CTV) was over the whole patient cohort for each dose bin of 0.05 Gy. required for organs at risk tolerance dose in three cases. Delivery accuracy determined by the pre-treatment qual- Evaluation of clinical data ity assurance was recorded, for the patients of this study, Patients had clinical evaluations planned before and dur- as the percentage of the point passing the gamma criteria ing the treatment, at the end of the last fraction. Then, of 3 mm/3%. The average of this value over all the patient the first follow-up visit was scheduled, based on site and cohort was 99.2±0.5, with a range of 97.3-99.9. All cases general condition, within 45–120 days from the end of were carefully analysed, not only fixing the attention on the treatment, then every 3–4 months, Acute toxicity the number of gamma passing point, in the whole dose induced from the radiation treatment were scored and map, and considered acceptable. recorded according to the National Cancer Institute’s Arc delivery with FFF beams was with a maximum Common Terminology Criteria for Adverse Events of 2400 MU/min for 10 FFF beam, with an average (CTCAE version 3.0). beam on time of 1.47±0.44 min [range: 0.82-2.02 min]. Alongi et al. Radiation Oncology 2012, 7:204 Page 5 of 9 http://www.ro-journal.com/content/7/1/204 Figure 1 Dose colorwash from 50% dose level for an abdominal lymph node case (left) and a pelvic lymph node case (right). For a comparison, the plans were delivered also with a Clinical results maximum dose rate of 600 MU/min, that is the usual Clinical results as acute gastrointestinal GI toxicity as maximum dose rate available in normal linacs using well treatment outcome are summarized in numbers in standard flattened beams. With this setting, the aver- Table 4. age beam on time would have been 3.49±0.81 min [range: All 25 FFF SBRT patients completed the treatment, as 2.52-5.72 min] and thus, for this dose per fraction, the programmed, with no interruptions. maximum dose rate of 2400 MU/min reduced the beam Acute gastrointestinal toxicity was minimal: one patient on time more than 200%. showed Grade 1 gastrointestinal toxicity, as gastralgia. Figure 2 Average DVH of the main structures on the whole patient cohort. Alongi et al. Radiation Oncology 2012, 7:204 Page 6 of 9 http://www.ro-journal.com/content/7/1/204 Table 3 Dose distribution statistics Structure Parameter Objective Mean±SD From Bignardi PTV Mean [Gy] 50.0 44.9±0.7 44.5±0.3 Volume [cm]D [Gy] 2.8±1.5 3.8±0.8 5%-95% 56.7±42.0 Standard Dev [Gy] 0.9±0.5 D [Gy] <48.15 46.2±0.8 46.4±0.3 1% D [Gy] >42.75 (36) 42.0±2.4 40.8±1.0 99% V [%] 97.7±3.2 90.2±5.2 95% CI 1.0 1.1±0.1 1.0±0.1 95% CTV Mean [Gy] 45.1±0.8 45.0±0.0 Volume [cm]D [Gy] 1.4±0.8 1.4±0.3 5%-95% 17.4±21.0 Standard Dev [Gy] 0.4±0.3 D [Gy] <48.15 45.9±0.8 46.0±0.2 1% D [Gy] >42.75 43.8±1.8 44.1±0.2 99% V [%] 100 99.7±1.3 100.0±0.0 95% Stomach Mean [Gy] 4.2±1.9 4.0±5.5 Volume [cm]D [Gy] 17.9±9.0 12.2±11.7 1% 228.8±129.2 V [%] 11.2±12.1 10Gy V [%] 5.0±6.2 15Gy V [cm ] <1 0.05±0.08 0.1±0.5 36Gy Duodenum Mean [Gy] 11.0±7.5 7.0±5.6 Volume [cm]D [Gy] 22.9±14.2 22.4±13.8 1% 34.5±24.2 V [%] 60.8±42.6 10Gy V [%] 14.4±19.2 20Gy V [cm ] <1 0.09±0.19 0.5±0.9 36Gy Small Bowel Mean [Gy] 5.1±3.5 3.0±2.3 Volume [cm]D [Gy] 23.3±6.7 18.0±10.8 1% 1900.9±1764.5 V [%] 18.6±17.0 10Gy V [%] 3.6±4.6 20Gy V [cm ] <3 2.9±3.9 0.1±0.2 36Gy Liver Mean [Gy] 3.4±2.5 3.6±3.9 Volume [cm]D [Gy] 19.2±14.5 20.2±17.3 1% 1450.5±287.3 V [%] 10.2±9.6 10Gy V [%] 2.0±2.6 20Gy (V -700)-V [cm ] >0 724±285 liver 21Gy Spinal Cord D [Gy] 10.1±3.2 7.8±2.3 1% Volume [cm]D [Gy] <18Gy 9.5±3.1 1ccm 32.6±19.7 V [%] 12.2±19.9 10Gy Left Kidney Mean [Gy] 4.2±3.4 2.2±2.5 Volume [cm]D [Gy] 11.6±8.7 8.3±8.1 1% 162.4±36.8 V [%] <35 3.1±7.5 1.7±5.9 15Gy Right Kidney Mean [Gy] 3.9±3.6 3.1±2.9 Volume [cm]D [Gy] 10.7±6.9 10.4±11.2 1% 163.4±39.9 V [%] <35 2.9±8.6 2.8±7.1 15Gy Alongi et al. Radiation Oncology 2012, 7:204 Page 7 of 9 http://www.ro-journal.com/content/7/1/204 Table 4 Toxicity and response results Of the patient cohort of this study, 6 presented distant G/I toxicity Nb of patients (total 25) progressive disease (outside the treated region) at the first follow-up. This number increase to 15 for the 195 Grade 0 21 median days follow-up. Grade 1 1 Grade 2 3 Discussion and conclusions Grade 3-4 0 Rationale of local therapy for oligomestases is that when Response Nb of treatments (total 28) primary cancer is controlled, the solitary or few metasta- At first Follow-up: ses can be cured locally to effort systemic therapy [1,2]. Actually, few published data do exist on local control CR 11 rates of radiotherapy in the context of isolated or few PR 13 lymph node metastases. Although dose and fractionation SD 4 schedules are extremely heterogeneous, early data from Nb of treatments (total 28) some recent series are promising in term of local control At median Follow-up of 152 months: rates [3]. Because small volumes are irradiated for meta- CR 13 static lymph nodes, a dose escalation might improve effi- cacy without prohibitive toxicity. PR 9 Most of reported experiences regarded oligometastatic SD 6 lymph node in pelvis or abdomen and are summarized in Table 5. Three other patients presented Grade 2 toxicity, one with The results of the current study with SBRT by RapidArc gastric pyrosis, one with epigastralgia and one with nausea/ and FFF, at the median follow up of 195 days confirm a re- vomiting. No severe acute toxicity with Grade 3 or more sponse rate of 82% and no local progression was recorded. was recorded. All toxicities were recovered within one week Local control provided by the current initial experience (G1 without intervention, G2 with symptomatic drugs). may be potentially significant for preserving quality of life No late toxicity, as per the rather short follow-up time, and delaying further systemic treatments. Obviously, the was found. most significant criticism remain: a) the heterogeneity of The median follow-up was 195 days (range 48–589 the population of study, composed by a miscellaneous of days). All patients had at least the first follow up at a cases from different primary tumors (see Table 1) b) the median of 92 days (minimum 47 days) from the end of short follow-up (median of 195 days), c) the retrospective the radiation treatment. nature of the study in patient data analysis. Nevertheless, At the first follow-up, early clinical outcome was as- the end point of the study was to define the dosimetric and sessable at diagnostic evaluation of last control with PET early clinical results of SBRT by RapidArc with FFF, and and/or CT in 25 patients (28 treatments). At the end of this finding was largely confirmed: all plan objectives were the first follow-up evaluation, a complete response met and no toxicity were recorded in acute setting, achiev- (according to World Health Organization criteria) was ing an intial high rate of local control. found in 11 cases. A partial response was achieved in 13 Concerning FFF beams, previous our report showed as cases. The overall response rate was of 86% (24/28 treat- the treatment delivery with FFF beams for abdominal le- ments). Four patients had stable disease. No local pro- sion is faster and more efficient, improving patient’s gression was found. comfort and thus reducing intra-fraction motion, char- The results at the median follow up of 195 days (18 acteristic that becomes particularly important in SBRT patients had a second follow-up) are: complete response [21]. Some preliminary studies for SBRT using FFF in 12 cases, partial response in 11, stable disease in 5, beams are present in literature [11,22] and in a recent with an overall response rate of 82%; no local progres- study performed in our institute it was described our sion was recorded. early experience in the use of FFF beams for SBRT Table 5 Clinical details of published studies of SBRT for oligometastases lymph nodes Reference Primary N° of patients Radiation Dose Median FUP [months] Outcomes Jereckzek et al. [17] prostate 34 30 Gy in 4/5 fractions 16.9 LC: 91% at 17 months Choi et al. [18] cervix 30 33-45 Gy in 3 fractions 15 LC:67.4% at 4 years Kim et al. [19,20] gastric 7 36/51 in 3/fractions 26 OS:43% at 3 years Bignardi et al. [5] miscellaneous 19 45 in 6 fractions 12 LC: 77,8% at 1 year LC= local control; OS= overall survival. Alongi et al. Radiation Oncology 2012, 7:204 Page 8 of 9 http://www.ro-journal.com/content/7/1/204 treatments including liver metastases, lung primitive and next clinical studies for thoracic and abdominal stereo- metastases, isolated abdominal lymph nodes, adrenal tactic irradiations. glands, and pancreas [16]. Also in the present report, Considering these promising results, a prospective acute toxicity profile was excellent: no severe acute study of dose escalation in 4 fraction of SBRT with FFF Grade 3 toxicity or more was recorded and all toxicities beams for pelvic/abdominal lymph node oligometastatic (2 cases of Grade 1 and 3 cases of Grade 2) were recov- patients (genito-urinary and gynecology primary) was re- ered within one week. cently proposed and accepted by internal ethical com- From the radiobiological point, some literature starts mittee of our Institute and preliminary results will be to show that FFF beams, relatively to standard flattened reported in a further study. beams, have higher efficacy, possibly in reducing survival Competing interests fraction for the same delivered physical dose, due to the L. Cozzi acts as Scientific Advisor to Varian Medical Systems and is Head of higher dose per pulse of such beams (up to 4 times) Research and Technological Development at the Oncology Institute of Southern Switzerland, Bellinzona. Other authors report no conflict of interest. [23]. This fact is today only a suggestion coming from sparse laboratory studies on cell lines, and not yet clinic- Authors’ contributions ally proven in terms of patient studies. In principle the FA, MS and AF coordinated the entire study. Data collection and clinical data analysis were conducted by FA, EC, PN, AT, TC, AMA, MS. Dosimetric data improvement is present, but the increased cell killing ef- collection and analysis were conducted by AF, AC, FL, GR, LC, PM, ST. All fect is rather minimal, so difficult to be proven at the authors read and approved the final manuscript. present stage with small clinical studies. To clinically Author details demonstrate the differences in cell killing effect between IRCCS Istituto Clinico Humanitas, Radiation Oncology Dept, Rozzano-Milan, standard beams and beams with high dose per pulse, Italy. Oncology Institute of Southern Switzerland, Medical Physics Unit, clinical trials should be set on a rather large scale. Also Bellinzona, Switzerland. the time factor, not only the dose per pulse, is known to Received: 24 July 2012 Accepted: 21 November 2012 have a role the on radiation induced damage. This was Published: 5 December 2012 subject of different studies where, both on theoretical References bases and in vitro irradiations [24,25] it is demonstrated 1. Weichselbaum RR, Hellman S: Oligometastases revisited. Nat Rev Clin Oncol that the shorter is the treatment session time, the higher 2011, 8:378–382. is the tumor control probability for the same physical 2. Rubin P, Brasacchio R, Katz A: Solitary metastases: Illusion versus reality. 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Journal

Radiation OncologySpringer Journals

Published: Dec 5, 2012

References