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Target splitting in radiation therapy for lung cancer: further developments and exemplary treatment plans

Target splitting in radiation therapy for lung cancer: further developments and exemplary... Background: Reporting further developments evolved since the first report about this conformal technique. Methods: Technical progress focused on optimization of the quality assurance (QA) program, especially regarding the required work input; and on optimization of beam arrangements. Results: Besides performing the regular QA program, additional time consuming dosimetric measurements and verifications no longer have to be accomplished. 'Class solutions' of treatment plans for six patients with non-resected non-small cell lung cancer in locally advanced stages are presented. Target configurations comprise one central and five peripheral tumor sites with different topographic positions to hilus and mediastinum. The mean dose to the primary tumor is 81,9 Gy (range 79,2–90,0 Gy), to macroscopically involved nodes 61,2 Gy (range 55,8–63,0 Gy), to electively treated nodes 45,0 Gy. Treatments are performed twice daily, with fractional doses of 1,8 Gy at an interval of 11 hours. Median overall treatment time is 33 days. The set-up time at the linac does not exceed the average time for any other patient. Conclusion: Target splitting is a highly conformal and nonetheless non-expensive method with regard to linac and staff time. It enables secure accelerated high-dose treatments of patients with NSCLC. Background volumetric modulated arc therapies have been described In order to improve locoregional tumor control of lung recently and begin to be applied clinically [1,2]. Results of cancer patients by radiation therapy, raising of the tumor treatments of lung cancer patients with these latter tech- dose is mandatory. This constitutes a challenge to be over- niques are still missing. come only by the use of conformal, healthy tissue sparing techniques. Following rather simple 3D approaches, In 1999 our first report about the conformal technique of sophisticated forms of intensity modulated techniques target splitting in external radiotherapy of lung cancer has such as tomotherapy, intensity modulated arc therapies or been published [3]. Since then, we use this method rou- Page 1 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:30 http://www.ro-journal.com/content/4/1/30 tinely for lung cancer patients in all stages. During the past splitting (junction) plane, allow for set-up of highly con- years, this technique has continuously been evolved with formal treatment plans. regard to optimizing the procedures for quality assurance and raising conformity of the treatment plans. Progress in Quality Assurance (QA) since the first report In order to prevent over- or underdosages in or next to the This report gives an update about the technical innova- junction plane, special care has to be taken to ensure cor- tions and implications for workflow and demonstrates rect positioning of independent jaws at the central axis. As exemplary treatment solutions in 6 lung cancer patients an individual fine adjustment of MLC jaws for each with different tumor topographies (Figure 1, Figure 2, Fig- patient is time consuming, we developed and imple- ure 3, Figure 4, Figure 5 and Figure 6). mented a QA program which is periodically testing for over- or underdosages by means of amorphous silicon flat panel imaging (EPID). Because different collimator rota- Methods The technique of target splitting has been described in tions (0°, ± 90°) will be applied in clinical cases for opti- detail [3]. In an individually chosen transversal plane, the mal MLC coverage and/or to allow the insertion of a target is split into a cranial and a caudal part. For either motorized wedge, all combinations of possibly adjacent part completely independent beam arrangements are jaws (x1/x2, x1/y1, x1/y2, y1/x2 and y1/y2) have to be designed. Half collimated, coplanar asymmetric fields tested. On a monthly basis and after each head mainte- ('half beams'), in general each adjacent to the isocentric nance, five different sequences of beam segments are irra- Centrally located tumor Figure 1 Centrally located tumor. 83 years; central squamous cell carcinoma, 4 cm ∅, atelectasis upper lobe, paralysis phrenical nerve with elevated diaphragma; enlarged PET-positive ipsilateral mediastinal nodes. A. Scheme; position of junction plane and upper and lower borders, doses (Gy). B. Treatment plan single fraction. C. Overall treatment plan. D. DVHs. Page 2 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:30 http://www.ro-journal.com/content/4/1/30 Figure 2 Peripheral tumor, hilus/mediastinum to be treated not within the craniocaudal extension of the the primary tumor Peripheral tumor, hilus/mediastinum to be treated not within the craniocaudal extension of the the primary tumor. 53 years; squamous cell carcinoma peripheral lower lobe, 5,5 cm ∅; enlarged PET-positive hilar, subcarineal and bilat- eral mediastinal nodes. A. Scheme; position of junction plane and upper and lower borders, doses (Gy). B. Treatment plan sin- gle fraction. C. Overall treatment plan. D. DVHs. diated onto the panel: the first four sequences deliver each jaw and MLC-leaf penumbra measurements. However, in one quadrant field with four intersegmental collimator detail, the problem has some degree of complexity, since rotations (0°, 90°, 180°, -90°) to be summed up in one the relative position of a leaf to the closely following image per sequence. The last sequence keeps the collima- backup-jaw will influence the gradient of the penumbra as tor rotation at 0°, while irradiating the four quadrants by well as inter-leave-leakage in the junction plane. Addi- changing the jaw- (and leave) positions (Figure 7). tionally, different penumbra gradients of x and y jaws (due to their different distance to the focus of the This method inherently guarantees that all jaw-offsets will machine) will sum up to an unavoidable, slightly inhom- be aligned to the radiation field's central axis as defined by geneous dose distribution apparent as parallel regions of the mechanical axis of collimator rotation. If over- or over- and underdosage next to the junction plane (Figure underdosages are measured along the junction lines, a 7). Over- or underdosages in the range of up to 10% straight forward calibration of jaw and leave positions within a zone of less than ± 1 mm can be neglected. with sub-millimeter accuracy is possible, if the relation- Although this error might be increased in principal by ship between maldosage and field-shift is known. The lat- connecting two opposing beams (knowing that the ter can easily be determined once in advance from single machine's isocenter is a sphere or ellipsoid with radii in Page 3 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:30 http://www.ro-journal.com/content/4/1/30 Peripheral tumor, Figure 3 hilus/mediastinum to be treated partially within the craniocaudal extension of the the primary tumor Peripheral tumor, hilus/mediastinum to be treated partially within the craniocaudal extension of the the pri- mary tumor. 73 years; squamous cell carcinoma basal middle lobe, 4,2 cm ∅; enlarged PET-positive hilar and ipsilateral medi- astinal nodes. A. Scheme; position of junction plane and upper and lower borders, doses (Gy). B. Treatment plan single fraction. C. Overall treatment plan. D. DVHs. the range of 1 mm rather than a point), patient's daily position is performed as 'slow CT' from the apex to the setup deviations and intrafractional respiratory move- bases of the lung, patients freely breathing (non-spiral CT; ments will blur the overall maldosage in the junction 4 s/slice; slice thickness 7 mm formerly, more recently 5 plane as well as distributed gantry- and collimator angles, mm; couch movements 8 mm or 5 mm) [5]. In the case of which has been shown in a series of phantom-film meas- atelectasis 18-fluorodeoxyglucose positron emission tom- urements. ography (FDG-PET) is performed in treatment position and the slices are matched with the planning CT. Margins Patient set-up, planning procedure and treatment delivery from gross tumor volume (GTV) to planning target vol- Six exemplary treatment plans which cover different target ume (PTV) are 7 mm, regarding primary tumor, macro- volume constellations have been chosen among patients scopically involved lymph nodes and elective lymph node with advanced-stage NSCLC treated in the past three stations, defined as the region about 5 to 6 cm cranial to years. All six patients participate in a prospective study, in macroscopically involved nodes. In contouring of the which the dose to the primary tumor is correlated to its organs at risk, the GTV is excluded from the lung volume, size [4]. Two patients are staged T2N2 and T2N3, respec- the heart is contoured from about 1 cm below the level tively; one patient T3N2 and T4N2, respectively. where the lower edge of the pulmonary trunk crosses the median to the apex of the heart. Esophagus and spinal Patients are set up in vacuum cradles, usually supine with cord are contoured in their entire thoracic length. the hands above the head. A planning CT in treatment Page 4 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:30 http://www.ro-journal.com/content/4/1/30 Peripheral tumor locat Figure 4 ed lateral and distant to hilus/mediastinum Peripheral tumor located lateral and distant to hilus/mediastinum. 48 years; squamous cell carcinoma peripheral upper lobe, 4 cm ∅; enlarged PET-positive hilar and ipsilateral mediastinal nodes. A. Scheme; position of junction plane and upper and lower borders, doses (Gy). B. Treatment plan single fraction. C. Treatment plan single fraction of boost to primary tumor. D. Overall treatment plan. E. DVHs. Planning is performed with a 3D-planning system no additional time consuming dosimetric verifications (Oncentra Masterplan), inhomogeneities are taken into have to be accomplished. account by a pencil beam algorithm. Dose constraints for the spinal cord were set at 45 Gy, V20 (volume receiving For all 6 patients treatment plans with one single isocenter >20 Gy) for a single lung at 50%, V25 for both lungs con- can be provided. This enables a remote control of all treat- sidered as a single organ at 30%, the maximal dose to the ment steps by assisted setup functions. The daily set-up esophagus at 80 Gy (measured in the center of the esopha- time at the linac does not exceed the average time for any gus at its most exposed level). other patient. Treatments were delivered with 15 MV photons, fractional 1. Centrally located tumor (Figure 1) doses of 1,8 Gy (ICRU), twice daily, interval 11 h. The junction plane is chosen above the central tumor. The upper volume is treated by anterior-posterior (a-p) – right Since 2006, daily image guidance (IGRT) was performed oblique anterior and left oblique anterior, partially by MV cone beam CTs, since 2007 by orthogonal kV- wedged beams (290°, 0°, 70°), the lower volume by left imaging with adjustment to the esophageal and large air- oblique anterior, left lateral and left oblique posterior, ways' structures [6]. partially wedged beams (25°, 90°, 165°). After 45 Gy (elective dose for not macroscopically involved nodes) the upper jaws of the upper volume are closed asymmet- Results In contrast to our previous report about this technique, rically for a length of 5 cm. After 55,8 Gy (dose for macro- besides performing the regular QA program as described, scopically involved nodes) the primary tumor is boosted to 79,2 Gy (excluding the nodes by setting of MLCs). V20 Page 5 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:30 http://www.ro-journal.com/content/4/1/30 Peripheral tumor locat Figure 5 ed lateral, but close to hilus/mediastinum Peripheral tumor located lateral, but close to hilus/mediastinum. 67 years; adenocarcinoma peripheral upper lobe, 3,5 cm ∅; enlarged hilar nodes, mediastinoscopically proven bilateral mediastinal nodes. A. Scheme; position of junction plane and upper and lower borders, doses (Gy). B. Treatment plan single fraction. C. Treatment plan single fraction of boost to pri- mary tumor. D. Overall treatment plan. E. DVHs. of the right lung is 43%, of the left lung 32%, V25 for both lungs is 37%, 26% and 27%, respectively. V50 for the lungs 28%. In the upper volume the esophagus can be heart is 2%. spared very well; in the lower volume, because the pri- mary tumor is partially directly adherent to the esopha- 3. Peripheral tumor, hilus/mediastinum to be treated partially within the craniocaudal extension of the the gus, for about 3 cm it receives the full tumor dose at a major part of its circumference. primary tumor (Figure 3) The junction plane is chosen above the primary tumor. 2. Peripheral tumor, hilus/mediastinum to be treated not The upper volume (hilus and mediastinum) is treated by within the craniocaudal extension of the the primary three, partially wedged fields (20°, 80°, 150°) to 61,2 Gy. tumor (Figure 2) After 45,0 Gy the upper volume is reduced cranially for 6 The junction plane is chosen above the primary tumor, cm. In the lower volume, the primary tumor is treated by below the hilus. The upper volume is treated by 3 partially three, partially wedged fields (290°, 345°, 50°); only one wedged, left-sided beams (20°, 90°, 160°) to 59,4 Gy; of these fields (345°) meets also the PTV of the nodes, sit- after 45 Gy the upper jaws are retracted asymmetrically for uated only in the upper 2 cm of the caudal volume; the 5,5 cm. The lower volume (primary tumor) is treated with missing dose is supplied by two partially wedged fields three partially wedged right-sided beams (320°, 280°, (45°, 115°), which do not interfere grossly with the PTV 220°) to 84,6 Gy. V20 right and left lung and V25 both of the primary tumor. After 61,2 Gy these two fields are Page 6 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:30 http://www.ro-journal.com/content/4/1/30 Peripheral tumor, Figure 6 junction plane set within the primary tumor Peripheral tumor, junction plane set within the primary tumor. 62 years; squamous cell carcinoma dorsal upper lobe with infiltration of the chest wall, 6,5 cm ∅; enlarged PET-positive hilar and ipsilateral mediastinal nodes. A. Scheme; position of junction plane and upper and lower borders, doses (Gy). B. Treatment plan single fraction. C. Treatment plan single fraction of boost to primary tumor. D. Overall treatment plan. E. DVHs. withdrawn and the primary tumor alone is treated to 79,2 for the oblique beams (e.g. 285° and 75° instead of 305° Gy. V20 right and left lung and V25 both lungs is 49%, and 55°). However, as the whole upper volume is treated 22% and 26%, respectively. V50 for the heart is 2%. only with an elective dose (45 Gy), significant esophageal side effects have not been observed, and the beam angles 4. Peripheral tumor located lateral and distant to hilus/ were optimized with regard to sparing of lung tissues. In mediastinum (Figure 4) the lower volume the esophagus can be spared fairly. The junction plane is chosen above the primary tumor. D(max) for the heart is 3,5 Gy. The upper volume (elective nodes only) is treated by three, partially wedged beams (305°, 0°, 55°) to 45 Gy. 5. Peripheral tumor located lateral, but close to hilus/ mediastinum (Figure 5). Junction plane above the primary Within the lower volume, the primary tumor is treated by four, partially wedged fields (35°, 120°, 180°, 300°). tumor Two of these fields (120°, 300°) meet also the PTV of the The isocenter is set in the center of the primary tumor, nodes, the missing dose to the nodes is added by two which is treated by a rotational arc (345° to 180°) and a fields, which do not interfere with the primary tumor. right sided field (250°). The missing dose to the hilus and After 63,0 Gy the primary tumor alone is boosted to 79,2 mediastinum is added by two partially wedged fields Gy. V20 left and right lung, V25 both lungs is 47%, 16% (335°, 170°). After the dose to the nodes is reached (59,4 and 26%, respectively. In the upper volume the esophagus Gy), the primary tumor is boosted by an arrangement of could have been better spared chosing a less steep angle six fields (25°, 85°, 145°, 205°, 265°, 325°) to 79,2 Gy. Page 7 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:30 http://www.ro-journal.com/content/4/1/30 survival seems to be proven [7,8]. Furthermore, in order to prevent accelerated repopulation of clonogenic tumor cells, a short overall treatment time is important [9,10]. In this study we present exemplary treatment plans of patients with different topographical realities, in which doses up to 90,0 Gy in 33 days have been safely applied. Thereby beam arrangements are shown, which to our knowledge have not been published previously. In 1979 Williamson first described the matching of orthogonal fields by an isocentric half-beam technique, Dosimetric MLC he Figure 7 ad verification of accuracy of field junctions of a using a large lead block positioned in the accessory tray at Dosimetric verification of accuracy of field junctions the beam axis [11]. He proposed this method for head of a MLC head. White and black levelled regions represent and neck, breast and craniospinal treatments. With the dose inhomogeneities below 10%. Left: One double half colli- availability of independently moving jaws asymmetric mated quadrant beam (45°) was irradiated 4 times with rela- collimators were used to split the beam for head and neck tive intersegmental collimator rotations of 0°(I), +90°(II), patients [12]. In 1999, in our previous report we proposed +180°(III), -90°(IV). Right: 4 segments, each irradiated in dif- this technique not only for matching orthogonal fields, ferent quadrants (I-IV) by changing the field aperture with a fixed collimator rotation (45°). but to perform completely independent planning and treatments on both sides of the junction plane, including rotational elements, static fields at arbitrary angles, wedge Due to histological proof of bilaterally positive nodes in filters, etc. [3]. We called this technique 'target splitting', the middle mediastinum, the whole upper mediastinum because the positioning of the junction plane depends on has been electively irradiated up to 45 Gy (by three par- shape and topographic parameters of the target and its tially wedged fields; 290°, 0°, 70°). V20 left and right surroundings. lung, V25 both lungs: 52%, 32% and 32%, respectively. D(max) to the heart: 5 Gy. The method was initially applied to lung cancer patients. With ongoing practice some 'rules' evolved, breaking 6. Peripheral tumor, junction plane set within the primary some former "taboos" in radiotherapy of lung cancer: tumor (Figure 6) In order to optimize the angles of the beam arrangements 1. Minimizing the dose to the ipsilateral (i.e. tumor the junction plane is set within the primary tumor. The bearing) lung. upper volume is treated by oblique opposing plus left oblique beams (25°, 125°, 205°), with good sparing of In many cases the ipsilateral lung will be the first organ spinal cord and esophagus, at the cost of some medial to reach the dose constraint. This can be avoided by parts of the right lung. In the caudal volume, the oblique setting beams via median structures (spine, anterior ventral beam can be taken less steep (40°, 125°, 200°), mediastinum), mostly angled to the contralateral lung resulting in a better sparing of the lung while maintaining (e.g. caudal volume of patient 1). The contralateral good sparing of myelon and esophagus,. This series is lung is irradiated if necessary to its tolerance limit. treated to 63,0 Gy; after 45 Gy the elective nodes of the upper mediastinum are withdrawn by setting of MLCs. In 2. If necessary, for optimizing beam arrangements a second series the primary tumor is boosted to 90,0 Gy junction planes can easily be set within the primary (130°, 180°, 250°). V20 right and left lung and V25 both tumor itself (e.g. patient 6) or within macroscopically lungs is 37%, 19% and 25%, respectively. D(max) for the involved nodes (e.g. patient 1, 4, 6) (comments heart is 6 Gy. below). The mean dose to the primary tumor of these six patients As to elective nodal irradiation, usually the region about 5 amounts to 81,9 Gy (79,2 – 90,0 Gy), to macroscopically – 6 cm above macroscopic nodal disease is included into involved nodes 61,2 Gy (55,8 – 63,0 Gy), and to elective the PTV. If the upper mediastinal nodes are involved, a nodes 45,0 Gy in an accelerated fractionation schedule. supraclavicular field is used. Most studies engaged in dose The median overall treatment time was 33 days (31 – 38 escalation of NSCLC disapprove elective nodal irradia- days). tion, in order to gain potential to raise the dose to the pri- mary tumor [8,13]. However, isolated elective nodal Discussion recurrence occurs. Rosenzweig et al describe an actuarial In primary radiation therapy of NSCLC a positive dose- elective nodal failure rate at 2 years in locally controlled response relationship with regard to tumor control and patients of 9% [14]. RTOG 9311, also omitting elective Page 8 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:30 http://www.ro-journal.com/content/4/1/30 nodal irradiation, reports 12/176 patients with isolated practice we don't see any problem. Summing up, we con- elective nodal recurrences [13]. Microscopic spread cra- sider slow planning CTs a simple, effective, non-expensive nial to macroscopically involved nodes must be assumed method, capable to depict the relevant positions of a mov- in a relevant portion of patients and a 'collateral' dose ing lung tumor. from the macroscopic PTVs in these sites is not applied. Because FDG-PET scans detect malignant tissue only at a The issue of setting the junction plane within macroscopic minimal size of about 0,5 cm, this mode has been disease has been discussed in our previous report [3]. In retained unchanged also with the availability of PET stag- the phantom a homogeneously irradiated volume is ing. In our experience of treating >100 patients with 45 Gy proven. Actually, with non-splitting techniques there is in 2,5 weeks, no isolated recurrence in electively treated the same situation: to the patient is offered a homogene- sites until now has been observed. ously treated volume. Also, intensity modulated treat- ments use a multitude of single static and/or dynamic Regarding pulmonary doses, when we started to imple- elements resulting in homogeneously treated volumes. ment target splitting and to raise the dose, we set the con- straints as recommended for safe 3D-treatments some Our planning system facilitates a pencil beam algorithm. years ago: a dose of ≥ 20 Gy should not exceed 50% of the More advanced algorithms such as superposition-convo- volume of a single lung and ≥ 25 Gy should not exceed lution methods would compute the influence of inhomo- 30% of the volume of both lungs together [15-17]. geneities on dose distributions more accurately, but this Observing these limits resulted in a high tolerability using seems to be negligible for the aim of this report. the target splitting technique. However, patients with pre- existing lung fibrosis should be excluded from acceler- Target splitting has first enabled the secure application of ated, high dose therapies [4]. With regard to the doses up to 94,5 Gy with conventional fractionation for esophagus we limited the maximum dose in accelerated NSCLC patients [18]. After a phase I/II trial, showing good schedules to 80 Gy. Such a high dose rarely must be tolerability of accelerated, twice daily applied high dose applied because the esophageal dose mostly is deter- radiotherapy in 30 patients, currently a prospective accel- mined by the dose given to the nodes, not to the primary erated high dose trial is ongoing, relating the dose to the tumor and because target splitting has a capability also to size of the primary tumors (4 groups: <2,5 cm/73,8 Gy; spare the esophagus. In our experience of 15 years with 2,5–4,5 cm/79,2 Gy; 4,5–6,0 cm/84,6 Gy; >6,0 cm/90,0 high dose treatments of lung cancer patients we did not Gy; 1,8 Gy bid). The first results in 102 patients show an observe any severe late esophageal toxicity [4,18,19]. actuarial local tumor control at 2 years of 82% and an encouraging median overall survival time of 28,0 months To account for sufficient margins, a rim of 7 mm from [4,19]. Recently, sophisticated forms of intensity modu- GTV to PTV in patients freely breathing might appear lated techniques such as tomotherapy, intensity modu- rather tight. This issue has been described and discussed lated arc therapies or volumetric modulated arc therapies in detail previously [5]. Shortly, slow planning CTs depict have been described [1,2]. As results of treatments of lung the different relevant positions of the moving tumors cancer patients with these techniques are still missing, a individually, so that adding a general extra-margin for comparison of the efficacy of the different approaches is tumor motion (internal margin) is not necessary. Further- not yet possible. more, we consider a margin for microscopic spread from GTV to the clinical target volume (CTV) in high dose radi- Recently, a shift in the incidence from central to periph- otherapy dispensable. Giraud et al report 95% of micro- eral tumors in lung cancer patients has been observed scopic tumor spread within a distance of 8 and 6 mm [21]. With its ability to differentiate the beam arrange- from the gross tumor in adenocarcinomas and squamous ments, the technique of target splitting seems to be a use- cell carcinomas of the lung, respectively [20]. Applied to ful tool especially for peripheral tumors in advanced the presented six patients' gross tumor dose of 81,9 Gy a stages. sufficient dose to the rim of microscopic disease (about 45 Gy in 2,5 weeks) is delivered anyway. With growing incidence we use this technique also for extrathoracic tumor sites, such as thyroid, stomach, pel- It has been criticized that 4D planning CTs depict more vic/paraaortic, limbs etc. exactly the extreme positions of moving tumors and deliver sharper contours compared to slow CTs. Perhaps Summarizing, the technical developments of target split- this is also a question of institutional practice and habits. ting evolved since the first report enable secure dose esca- Not capturing extreme, short lasting positions of parts of lations above 90 Gy for patients with advanced NSCLC, the tumor can be advantageous, when a resulting smaller without heavy inroad on resources in term of staff and PTV enables raising the total dose. 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Publish with Bio Med Central and every 11. Williamson T: A technique for matching orthogonal megavolt- age fields. Int J Radiat Oncol Biol Phys 1979, 5:111-116. scientist can read your work free of charge 12. Sohn J, Suh J, Pohar S: A method for delivering accurate and uni- "BioMed Central will be the most significant development for form radiation dosages to the head and neck with asymmet- ric collimators and a single isocenter. Int J Radiat Oncol Biol Phys disseminating the results of biomedical researc h in our lifetime." 1995, 32:809-813. Sir Paul Nurse, Cancer Research UK 13. Bradley J, Graham M, Winter K, Purdy J, Komaki R, Roa W, Ryu J, Bosch W, Emami B: Toxicity and outcome results of RTOG Your research papers will be: 9311: A phase I-II dose escalation study using three-dimen- available free of charge to the entire biomedical community sional conformal radiotherapy in patients with inoperable peer reviewed and published immediately upon acceptance NSCLC. Int J Radiat Oncol Biol Phys 2005, 61:318-328. 14. Rosenzweig K, Sura S, Jackson A, Yorke E: Involved-field radiation cited in PubMed and archived on PubMed Central therapy for inoperable NSCLC. J Clin Oncol 2007, 25:5557-5561. yours — you keep the copyright 15. Armstrong J, Raben A, Zelefsky M, Burt M, Leibel S, Burman C, Kutcher G, Harrison L, Hahn C, Ginsberg R, Rusch V, Kris M: Prom- BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 10 of 10 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Target splitting in radiation therapy for lung cancer: further developments and exemplary treatment plans

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Springer Journals
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Copyright © 2009 by Wurstbauer et al; licensee BioMed Central Ltd.
Subject
Medicine & Public Health; Oncology; Radiotherapy
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1748-717X
DOI
10.1186/1748-717X-4-30
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19678961
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Abstract

Background: Reporting further developments evolved since the first report about this conformal technique. Methods: Technical progress focused on optimization of the quality assurance (QA) program, especially regarding the required work input; and on optimization of beam arrangements. Results: Besides performing the regular QA program, additional time consuming dosimetric measurements and verifications no longer have to be accomplished. 'Class solutions' of treatment plans for six patients with non-resected non-small cell lung cancer in locally advanced stages are presented. Target configurations comprise one central and five peripheral tumor sites with different topographic positions to hilus and mediastinum. The mean dose to the primary tumor is 81,9 Gy (range 79,2–90,0 Gy), to macroscopically involved nodes 61,2 Gy (range 55,8–63,0 Gy), to electively treated nodes 45,0 Gy. Treatments are performed twice daily, with fractional doses of 1,8 Gy at an interval of 11 hours. Median overall treatment time is 33 days. The set-up time at the linac does not exceed the average time for any other patient. Conclusion: Target splitting is a highly conformal and nonetheless non-expensive method with regard to linac and staff time. It enables secure accelerated high-dose treatments of patients with NSCLC. Background volumetric modulated arc therapies have been described In order to improve locoregional tumor control of lung recently and begin to be applied clinically [1,2]. Results of cancer patients by radiation therapy, raising of the tumor treatments of lung cancer patients with these latter tech- dose is mandatory. This constitutes a challenge to be over- niques are still missing. come only by the use of conformal, healthy tissue sparing techniques. Following rather simple 3D approaches, In 1999 our first report about the conformal technique of sophisticated forms of intensity modulated techniques target splitting in external radiotherapy of lung cancer has such as tomotherapy, intensity modulated arc therapies or been published [3]. Since then, we use this method rou- Page 1 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:30 http://www.ro-journal.com/content/4/1/30 tinely for lung cancer patients in all stages. During the past splitting (junction) plane, allow for set-up of highly con- years, this technique has continuously been evolved with formal treatment plans. regard to optimizing the procedures for quality assurance and raising conformity of the treatment plans. Progress in Quality Assurance (QA) since the first report In order to prevent over- or underdosages in or next to the This report gives an update about the technical innova- junction plane, special care has to be taken to ensure cor- tions and implications for workflow and demonstrates rect positioning of independent jaws at the central axis. As exemplary treatment solutions in 6 lung cancer patients an individual fine adjustment of MLC jaws for each with different tumor topographies (Figure 1, Figure 2, Fig- patient is time consuming, we developed and imple- ure 3, Figure 4, Figure 5 and Figure 6). mented a QA program which is periodically testing for over- or underdosages by means of amorphous silicon flat panel imaging (EPID). Because different collimator rota- Methods The technique of target splitting has been described in tions (0°, ± 90°) will be applied in clinical cases for opti- detail [3]. In an individually chosen transversal plane, the mal MLC coverage and/or to allow the insertion of a target is split into a cranial and a caudal part. For either motorized wedge, all combinations of possibly adjacent part completely independent beam arrangements are jaws (x1/x2, x1/y1, x1/y2, y1/x2 and y1/y2) have to be designed. Half collimated, coplanar asymmetric fields tested. On a monthly basis and after each head mainte- ('half beams'), in general each adjacent to the isocentric nance, five different sequences of beam segments are irra- Centrally located tumor Figure 1 Centrally located tumor. 83 years; central squamous cell carcinoma, 4 cm ∅, atelectasis upper lobe, paralysis phrenical nerve with elevated diaphragma; enlarged PET-positive ipsilateral mediastinal nodes. A. Scheme; position of junction plane and upper and lower borders, doses (Gy). B. Treatment plan single fraction. C. Overall treatment plan. D. DVHs. Page 2 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:30 http://www.ro-journal.com/content/4/1/30 Figure 2 Peripheral tumor, hilus/mediastinum to be treated not within the craniocaudal extension of the the primary tumor Peripheral tumor, hilus/mediastinum to be treated not within the craniocaudal extension of the the primary tumor. 53 years; squamous cell carcinoma peripheral lower lobe, 5,5 cm ∅; enlarged PET-positive hilar, subcarineal and bilat- eral mediastinal nodes. A. Scheme; position of junction plane and upper and lower borders, doses (Gy). B. Treatment plan sin- gle fraction. C. Overall treatment plan. D. DVHs. diated onto the panel: the first four sequences deliver each jaw and MLC-leaf penumbra measurements. However, in one quadrant field with four intersegmental collimator detail, the problem has some degree of complexity, since rotations (0°, 90°, 180°, -90°) to be summed up in one the relative position of a leaf to the closely following image per sequence. The last sequence keeps the collima- backup-jaw will influence the gradient of the penumbra as tor rotation at 0°, while irradiating the four quadrants by well as inter-leave-leakage in the junction plane. Addi- changing the jaw- (and leave) positions (Figure 7). tionally, different penumbra gradients of x and y jaws (due to their different distance to the focus of the This method inherently guarantees that all jaw-offsets will machine) will sum up to an unavoidable, slightly inhom- be aligned to the radiation field's central axis as defined by geneous dose distribution apparent as parallel regions of the mechanical axis of collimator rotation. If over- or over- and underdosage next to the junction plane (Figure underdosages are measured along the junction lines, a 7). Over- or underdosages in the range of up to 10% straight forward calibration of jaw and leave positions within a zone of less than ± 1 mm can be neglected. with sub-millimeter accuracy is possible, if the relation- Although this error might be increased in principal by ship between maldosage and field-shift is known. The lat- connecting two opposing beams (knowing that the ter can easily be determined once in advance from single machine's isocenter is a sphere or ellipsoid with radii in Page 3 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:30 http://www.ro-journal.com/content/4/1/30 Peripheral tumor, Figure 3 hilus/mediastinum to be treated partially within the craniocaudal extension of the the primary tumor Peripheral tumor, hilus/mediastinum to be treated partially within the craniocaudal extension of the the pri- mary tumor. 73 years; squamous cell carcinoma basal middle lobe, 4,2 cm ∅; enlarged PET-positive hilar and ipsilateral medi- astinal nodes. A. Scheme; position of junction plane and upper and lower borders, doses (Gy). B. Treatment plan single fraction. C. Overall treatment plan. D. DVHs. the range of 1 mm rather than a point), patient's daily position is performed as 'slow CT' from the apex to the setup deviations and intrafractional respiratory move- bases of the lung, patients freely breathing (non-spiral CT; ments will blur the overall maldosage in the junction 4 s/slice; slice thickness 7 mm formerly, more recently 5 plane as well as distributed gantry- and collimator angles, mm; couch movements 8 mm or 5 mm) [5]. In the case of which has been shown in a series of phantom-film meas- atelectasis 18-fluorodeoxyglucose positron emission tom- urements. ography (FDG-PET) is performed in treatment position and the slices are matched with the planning CT. Margins Patient set-up, planning procedure and treatment delivery from gross tumor volume (GTV) to planning target vol- Six exemplary treatment plans which cover different target ume (PTV) are 7 mm, regarding primary tumor, macro- volume constellations have been chosen among patients scopically involved lymph nodes and elective lymph node with advanced-stage NSCLC treated in the past three stations, defined as the region about 5 to 6 cm cranial to years. All six patients participate in a prospective study, in macroscopically involved nodes. In contouring of the which the dose to the primary tumor is correlated to its organs at risk, the GTV is excluded from the lung volume, size [4]. Two patients are staged T2N2 and T2N3, respec- the heart is contoured from about 1 cm below the level tively; one patient T3N2 and T4N2, respectively. where the lower edge of the pulmonary trunk crosses the median to the apex of the heart. Esophagus and spinal Patients are set up in vacuum cradles, usually supine with cord are contoured in their entire thoracic length. the hands above the head. A planning CT in treatment Page 4 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:30 http://www.ro-journal.com/content/4/1/30 Peripheral tumor locat Figure 4 ed lateral and distant to hilus/mediastinum Peripheral tumor located lateral and distant to hilus/mediastinum. 48 years; squamous cell carcinoma peripheral upper lobe, 4 cm ∅; enlarged PET-positive hilar and ipsilateral mediastinal nodes. A. Scheme; position of junction plane and upper and lower borders, doses (Gy). B. Treatment plan single fraction. C. Treatment plan single fraction of boost to primary tumor. D. Overall treatment plan. E. DVHs. Planning is performed with a 3D-planning system no additional time consuming dosimetric verifications (Oncentra Masterplan), inhomogeneities are taken into have to be accomplished. account by a pencil beam algorithm. Dose constraints for the spinal cord were set at 45 Gy, V20 (volume receiving For all 6 patients treatment plans with one single isocenter >20 Gy) for a single lung at 50%, V25 for both lungs con- can be provided. This enables a remote control of all treat- sidered as a single organ at 30%, the maximal dose to the ment steps by assisted setup functions. The daily set-up esophagus at 80 Gy (measured in the center of the esopha- time at the linac does not exceed the average time for any gus at its most exposed level). other patient. Treatments were delivered with 15 MV photons, fractional 1. Centrally located tumor (Figure 1) doses of 1,8 Gy (ICRU), twice daily, interval 11 h. The junction plane is chosen above the central tumor. The upper volume is treated by anterior-posterior (a-p) – right Since 2006, daily image guidance (IGRT) was performed oblique anterior and left oblique anterior, partially by MV cone beam CTs, since 2007 by orthogonal kV- wedged beams (290°, 0°, 70°), the lower volume by left imaging with adjustment to the esophageal and large air- oblique anterior, left lateral and left oblique posterior, ways' structures [6]. partially wedged beams (25°, 90°, 165°). After 45 Gy (elective dose for not macroscopically involved nodes) the upper jaws of the upper volume are closed asymmet- Results In contrast to our previous report about this technique, rically for a length of 5 cm. After 55,8 Gy (dose for macro- besides performing the regular QA program as described, scopically involved nodes) the primary tumor is boosted to 79,2 Gy (excluding the nodes by setting of MLCs). V20 Page 5 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:30 http://www.ro-journal.com/content/4/1/30 Peripheral tumor locat Figure 5 ed lateral, but close to hilus/mediastinum Peripheral tumor located lateral, but close to hilus/mediastinum. 67 years; adenocarcinoma peripheral upper lobe, 3,5 cm ∅; enlarged hilar nodes, mediastinoscopically proven bilateral mediastinal nodes. A. Scheme; position of junction plane and upper and lower borders, doses (Gy). B. Treatment plan single fraction. C. Treatment plan single fraction of boost to pri- mary tumor. D. Overall treatment plan. E. DVHs. of the right lung is 43%, of the left lung 32%, V25 for both lungs is 37%, 26% and 27%, respectively. V50 for the lungs 28%. In the upper volume the esophagus can be heart is 2%. spared very well; in the lower volume, because the pri- mary tumor is partially directly adherent to the esopha- 3. Peripheral tumor, hilus/mediastinum to be treated partially within the craniocaudal extension of the the gus, for about 3 cm it receives the full tumor dose at a major part of its circumference. primary tumor (Figure 3) The junction plane is chosen above the primary tumor. 2. Peripheral tumor, hilus/mediastinum to be treated not The upper volume (hilus and mediastinum) is treated by within the craniocaudal extension of the the primary three, partially wedged fields (20°, 80°, 150°) to 61,2 Gy. tumor (Figure 2) After 45,0 Gy the upper volume is reduced cranially for 6 The junction plane is chosen above the primary tumor, cm. In the lower volume, the primary tumor is treated by below the hilus. The upper volume is treated by 3 partially three, partially wedged fields (290°, 345°, 50°); only one wedged, left-sided beams (20°, 90°, 160°) to 59,4 Gy; of these fields (345°) meets also the PTV of the nodes, sit- after 45 Gy the upper jaws are retracted asymmetrically for uated only in the upper 2 cm of the caudal volume; the 5,5 cm. The lower volume (primary tumor) is treated with missing dose is supplied by two partially wedged fields three partially wedged right-sided beams (320°, 280°, (45°, 115°), which do not interfere grossly with the PTV 220°) to 84,6 Gy. V20 right and left lung and V25 both of the primary tumor. After 61,2 Gy these two fields are Page 6 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:30 http://www.ro-journal.com/content/4/1/30 Peripheral tumor, Figure 6 junction plane set within the primary tumor Peripheral tumor, junction plane set within the primary tumor. 62 years; squamous cell carcinoma dorsal upper lobe with infiltration of the chest wall, 6,5 cm ∅; enlarged PET-positive hilar and ipsilateral mediastinal nodes. A. Scheme; position of junction plane and upper and lower borders, doses (Gy). B. Treatment plan single fraction. C. Treatment plan single fraction of boost to primary tumor. D. Overall treatment plan. E. DVHs. withdrawn and the primary tumor alone is treated to 79,2 for the oblique beams (e.g. 285° and 75° instead of 305° Gy. V20 right and left lung and V25 both lungs is 49%, and 55°). However, as the whole upper volume is treated 22% and 26%, respectively. V50 for the heart is 2%. only with an elective dose (45 Gy), significant esophageal side effects have not been observed, and the beam angles 4. Peripheral tumor located lateral and distant to hilus/ were optimized with regard to sparing of lung tissues. In mediastinum (Figure 4) the lower volume the esophagus can be spared fairly. The junction plane is chosen above the primary tumor. D(max) for the heart is 3,5 Gy. The upper volume (elective nodes only) is treated by three, partially wedged beams (305°, 0°, 55°) to 45 Gy. 5. Peripheral tumor located lateral, but close to hilus/ mediastinum (Figure 5). Junction plane above the primary Within the lower volume, the primary tumor is treated by four, partially wedged fields (35°, 120°, 180°, 300°). tumor Two of these fields (120°, 300°) meet also the PTV of the The isocenter is set in the center of the primary tumor, nodes, the missing dose to the nodes is added by two which is treated by a rotational arc (345° to 180°) and a fields, which do not interfere with the primary tumor. right sided field (250°). The missing dose to the hilus and After 63,0 Gy the primary tumor alone is boosted to 79,2 mediastinum is added by two partially wedged fields Gy. V20 left and right lung, V25 both lungs is 47%, 16% (335°, 170°). After the dose to the nodes is reached (59,4 and 26%, respectively. In the upper volume the esophagus Gy), the primary tumor is boosted by an arrangement of could have been better spared chosing a less steep angle six fields (25°, 85°, 145°, 205°, 265°, 325°) to 79,2 Gy. Page 7 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:30 http://www.ro-journal.com/content/4/1/30 survival seems to be proven [7,8]. Furthermore, in order to prevent accelerated repopulation of clonogenic tumor cells, a short overall treatment time is important [9,10]. In this study we present exemplary treatment plans of patients with different topographical realities, in which doses up to 90,0 Gy in 33 days have been safely applied. Thereby beam arrangements are shown, which to our knowledge have not been published previously. In 1979 Williamson first described the matching of orthogonal fields by an isocentric half-beam technique, Dosimetric MLC he Figure 7 ad verification of accuracy of field junctions of a using a large lead block positioned in the accessory tray at Dosimetric verification of accuracy of field junctions the beam axis [11]. He proposed this method for head of a MLC head. White and black levelled regions represent and neck, breast and craniospinal treatments. With the dose inhomogeneities below 10%. Left: One double half colli- availability of independently moving jaws asymmetric mated quadrant beam (45°) was irradiated 4 times with rela- collimators were used to split the beam for head and neck tive intersegmental collimator rotations of 0°(I), +90°(II), patients [12]. In 1999, in our previous report we proposed +180°(III), -90°(IV). Right: 4 segments, each irradiated in dif- this technique not only for matching orthogonal fields, ferent quadrants (I-IV) by changing the field aperture with a fixed collimator rotation (45°). but to perform completely independent planning and treatments on both sides of the junction plane, including rotational elements, static fields at arbitrary angles, wedge Due to histological proof of bilaterally positive nodes in filters, etc. [3]. We called this technique 'target splitting', the middle mediastinum, the whole upper mediastinum because the positioning of the junction plane depends on has been electively irradiated up to 45 Gy (by three par- shape and topographic parameters of the target and its tially wedged fields; 290°, 0°, 70°). V20 left and right surroundings. lung, V25 both lungs: 52%, 32% and 32%, respectively. D(max) to the heart: 5 Gy. The method was initially applied to lung cancer patients. With ongoing practice some 'rules' evolved, breaking 6. Peripheral tumor, junction plane set within the primary some former "taboos" in radiotherapy of lung cancer: tumor (Figure 6) In order to optimize the angles of the beam arrangements 1. Minimizing the dose to the ipsilateral (i.e. tumor the junction plane is set within the primary tumor. The bearing) lung. upper volume is treated by oblique opposing plus left oblique beams (25°, 125°, 205°), with good sparing of In many cases the ipsilateral lung will be the first organ spinal cord and esophagus, at the cost of some medial to reach the dose constraint. This can be avoided by parts of the right lung. In the caudal volume, the oblique setting beams via median structures (spine, anterior ventral beam can be taken less steep (40°, 125°, 200°), mediastinum), mostly angled to the contralateral lung resulting in a better sparing of the lung while maintaining (e.g. caudal volume of patient 1). The contralateral good sparing of myelon and esophagus,. This series is lung is irradiated if necessary to its tolerance limit. treated to 63,0 Gy; after 45 Gy the elective nodes of the upper mediastinum are withdrawn by setting of MLCs. In 2. If necessary, for optimizing beam arrangements a second series the primary tumor is boosted to 90,0 Gy junction planes can easily be set within the primary (130°, 180°, 250°). V20 right and left lung and V25 both tumor itself (e.g. patient 6) or within macroscopically lungs is 37%, 19% and 25%, respectively. D(max) for the involved nodes (e.g. patient 1, 4, 6) (comments heart is 6 Gy. below). The mean dose to the primary tumor of these six patients As to elective nodal irradiation, usually the region about 5 amounts to 81,9 Gy (79,2 – 90,0 Gy), to macroscopically – 6 cm above macroscopic nodal disease is included into involved nodes 61,2 Gy (55,8 – 63,0 Gy), and to elective the PTV. If the upper mediastinal nodes are involved, a nodes 45,0 Gy in an accelerated fractionation schedule. supraclavicular field is used. Most studies engaged in dose The median overall treatment time was 33 days (31 – 38 escalation of NSCLC disapprove elective nodal irradia- days). tion, in order to gain potential to raise the dose to the pri- mary tumor [8,13]. However, isolated elective nodal Discussion recurrence occurs. Rosenzweig et al describe an actuarial In primary radiation therapy of NSCLC a positive dose- elective nodal failure rate at 2 years in locally controlled response relationship with regard to tumor control and patients of 9% [14]. RTOG 9311, also omitting elective Page 8 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:30 http://www.ro-journal.com/content/4/1/30 nodal irradiation, reports 12/176 patients with isolated practice we don't see any problem. Summing up, we con- elective nodal recurrences [13]. Microscopic spread cra- sider slow planning CTs a simple, effective, non-expensive nial to macroscopically involved nodes must be assumed method, capable to depict the relevant positions of a mov- in a relevant portion of patients and a 'collateral' dose ing lung tumor. from the macroscopic PTVs in these sites is not applied. Because FDG-PET scans detect malignant tissue only at a The issue of setting the junction plane within macroscopic minimal size of about 0,5 cm, this mode has been disease has been discussed in our previous report [3]. In retained unchanged also with the availability of PET stag- the phantom a homogeneously irradiated volume is ing. In our experience of treating >100 patients with 45 Gy proven. Actually, with non-splitting techniques there is in 2,5 weeks, no isolated recurrence in electively treated the same situation: to the patient is offered a homogene- sites until now has been observed. ously treated volume. Also, intensity modulated treat- ments use a multitude of single static and/or dynamic Regarding pulmonary doses, when we started to imple- elements resulting in homogeneously treated volumes. ment target splitting and to raise the dose, we set the con- straints as recommended for safe 3D-treatments some Our planning system facilitates a pencil beam algorithm. years ago: a dose of ≥ 20 Gy should not exceed 50% of the More advanced algorithms such as superposition-convo- volume of a single lung and ≥ 25 Gy should not exceed lution methods would compute the influence of inhomo- 30% of the volume of both lungs together [15-17]. geneities on dose distributions more accurately, but this Observing these limits resulted in a high tolerability using seems to be negligible for the aim of this report. the target splitting technique. However, patients with pre- existing lung fibrosis should be excluded from acceler- Target splitting has first enabled the secure application of ated, high dose therapies [4]. With regard to the doses up to 94,5 Gy with conventional fractionation for esophagus we limited the maximum dose in accelerated NSCLC patients [18]. After a phase I/II trial, showing good schedules to 80 Gy. Such a high dose rarely must be tolerability of accelerated, twice daily applied high dose applied because the esophageal dose mostly is deter- radiotherapy in 30 patients, currently a prospective accel- mined by the dose given to the nodes, not to the primary erated high dose trial is ongoing, relating the dose to the tumor and because target splitting has a capability also to size of the primary tumors (4 groups: <2,5 cm/73,8 Gy; spare the esophagus. In our experience of 15 years with 2,5–4,5 cm/79,2 Gy; 4,5–6,0 cm/84,6 Gy; >6,0 cm/90,0 high dose treatments of lung cancer patients we did not Gy; 1,8 Gy bid). The first results in 102 patients show an observe any severe late esophageal toxicity [4,18,19]. actuarial local tumor control at 2 years of 82% and an encouraging median overall survival time of 28,0 months To account for sufficient margins, a rim of 7 mm from [4,19]. Recently, sophisticated forms of intensity modu- GTV to PTV in patients freely breathing might appear lated techniques such as tomotherapy, intensity modu- rather tight. This issue has been described and discussed lated arc therapies or volumetric modulated arc therapies in detail previously [5]. Shortly, slow planning CTs depict have been described [1,2]. As results of treatments of lung the different relevant positions of the moving tumors cancer patients with these techniques are still missing, a individually, so that adding a general extra-margin for comparison of the efficacy of the different approaches is tumor motion (internal margin) is not necessary. Further- not yet possible. more, we consider a margin for microscopic spread from GTV to the clinical target volume (CTV) in high dose radi- Recently, a shift in the incidence from central to periph- otherapy dispensable. Giraud et al report 95% of micro- eral tumors in lung cancer patients has been observed scopic tumor spread within a distance of 8 and 6 mm [21]. With its ability to differentiate the beam arrange- from the gross tumor in adenocarcinomas and squamous ments, the technique of target splitting seems to be a use- cell carcinomas of the lung, respectively [20]. Applied to ful tool especially for peripheral tumors in advanced the presented six patients' gross tumor dose of 81,9 Gy a stages. sufficient dose to the rim of microscopic disease (about 45 Gy in 2,5 weeks) is delivered anyway. With growing incidence we use this technique also for extrathoracic tumor sites, such as thyroid, stomach, pel- It has been criticized that 4D planning CTs depict more vic/paraaortic, limbs etc. exactly the extreme positions of moving tumors and deliver sharper contours compared to slow CTs. Perhaps Summarizing, the technical developments of target split- this is also a question of institutional practice and habits. ting evolved since the first report enable secure dose esca- Not capturing extreme, short lasting positions of parts of lations above 90 Gy for patients with advanced NSCLC, the tumor can be advantageous, when a resulting smaller without heavy inroad on resources in term of staff and PTV enables raising the total dose. Also, in handling with linac time. somewhat blurred contours drawing the PTV, with some Page 9 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:30 http://www.ro-journal.com/content/4/1/30 ising survival with three-dimensional conformal radiation Competing interests therapy for NSCLC. Radiother Oncol 1997, 44:17-22. The authors declare that they have no competing interests. 16. Graham M, Purdy J, Emami B, Matthews J, Harms W: Preliminary results of a prospectve trial using three-dimensional radio- therapy for lung cancer. Int J Radiat Oncol Biol Phys 1995, Authors' contributions 33:993-1000. KW mainly conceived and drafted the manuscript, partic- 17. Leibel S, Armstrong J, Kutcher G, Zelefsky M, Burman C, Mohan R, Ling C, Fuks Z: 3-D conformal radiation therapy for NSCLC. ipated in the conception of target splitting; HD conceived In 3-D conformal radiotherapy Volume 29. 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Publish with Bio Med Central and every 11. Williamson T: A technique for matching orthogonal megavolt- age fields. Int J Radiat Oncol Biol Phys 1979, 5:111-116. scientist can read your work free of charge 12. Sohn J, Suh J, Pohar S: A method for delivering accurate and uni- "BioMed Central will be the most significant development for form radiation dosages to the head and neck with asymmet- ric collimators and a single isocenter. Int J Radiat Oncol Biol Phys disseminating the results of biomedical researc h in our lifetime." 1995, 32:809-813. Sir Paul Nurse, Cancer Research UK 13. Bradley J, Graham M, Winter K, Purdy J, Komaki R, Roa W, Ryu J, Bosch W, Emami B: Toxicity and outcome results of RTOG Your research papers will be: 9311: A phase I-II dose escalation study using three-dimen- available free of charge to the entire biomedical community sional conformal radiotherapy in patients with inoperable peer reviewed and published immediately upon acceptance NSCLC. Int J Radiat Oncol Biol Phys 2005, 61:318-328. 14. Rosenzweig K, Sura S, Jackson A, Yorke E: Involved-field radiation cited in PubMed and archived on PubMed Central therapy for inoperable NSCLC. J Clin Oncol 2007, 25:5557-5561. yours — you keep the copyright 15. Armstrong J, Raben A, Zelefsky M, Burt M, Leibel S, Burman C, Kutcher G, Harrison L, Hahn C, Ginsberg R, Rusch V, Kris M: Prom- BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 10 of 10 (page number not for citation purposes)

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Radiation OncologySpringer Journals

Published: Aug 14, 2009

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