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Conventionally-fractionated image-guided intensity modulated radiotherapy (IG-IMRT): a safe and effective treatment for cancer spinal metastasis

Conventionally-fractionated image-guided intensity modulated radiotherapy (IG-IMRT): a safe and... Background: Treatments for cancer spinal metastasis were always palliative. This study was conducted to investigate the safety and effectiveness of IG-IMRT for these patients. Methods: 10 metastatic lesions were treated with conventionally-fractionated IG-IMRT. Daily kilovoltage cone-beam computed tomography (kV-CBCT) scan was applied to ensure accurate positioning. Plans were evaluated by the dose-volume histogram (DVH) analysis. Results: Before set-up correction, the positioning errors in the left-right (LR), superior-inferior (SI) and anterior-posterior (AP) axes were 0.3 ± 3.2, 0.4 ± 4.5 and -0.2 ± 3.9 mm, respectively. After repositioning, those errors were 0.1 ± 0.7, 0 ± 0.8 and 0 ± 0.7 mm, respectively. The systematic/random uncertainties ranged 1.4–2.3/3.0–4.1 before and 0.1–0.2/0.7–0.8 mm after online set-up correction. In the original IMRT plans, the average dose of the planning target volume (PTV) was 61.9 Gy, with the spinal cord dose less than 49 Gy. Compared to the simulated PTVs based on the pre-correction CBCT, the average volume reduction of PTVs was 42.3% after online correction. Also, organ at risk (OAR) all benefited from CBCT-based set-up correction and had significant dose reduction with IGRT technique. Clinically, most patients had prompt pain relief within one month of treatment. There was no radiation-induced toxicity detected clinically during a median follow-up of 15.6 months. Conclusion: IG-IMRT provides a new approach to treat cancer spinal metastasis. The precise positioning ensures the implementation of optimal IMRT plan, satisfying both the dose escalation of tumor targets and the radiation tolerance of spinal cord. It might benefit the cancer patient with spinal metastasis. Page 1 of 10 (page number not for citation purposes) Radiation Oncology 2008, 3:11 http://www.ro-journal.com/content/3/1/11 treatment for cancer spinal metastasis. In this paper, we Background Spine is the most common place of cancer metastasis, report the preliminary results of the application with this especially for lung cancer and breast cancer. Each year, technique, giving details about the safety and effectiveness approximately 50,000 patients with cancer develop spinal of IMRT dose escalation with IGRT for metastatic tumors metastasis worldwide and the 5-year over-all survival rate of the spinal vertebra. of these patients was less than 5% [1,2]. All together, accompanying with the improvement of therapy for Methods malignant tumors, the overall survival time of cancer Patient selection patients prolonged and the incidence of spinal metastasis This study was carried out in Tumor Center at West China was increasing gradually. Radiotherapy is the standard Hospital, Sichuan University, PR. China. Between May treatment for vertebral metastasis of patients with cancer. and November 2006, 9 previously treated cancer patients Reviewing the literatures, three treatments/fractions were with confirmed diagnosis of ≤ 2 spinal metastases and no applied clinically worldwide: 30 Gy/10 fractions, 20 Gy/5 other distant metastasis were recruited in this study. The fractions and 8 Gy/1 fraction [3,4]. But all three treat- basic and clinical characteristics of these patients were ments were palliative, and recurrences in pre-irradiated shown in Table 1. Each diagnosis was confirmed by com- foci were frequent. Especially for those patients who only puted tomography (CT), magnetic resonance imaging had vertebral metastasis with primary lesion controlled, (MRI) or positron emission tomography-CT (PET-CT) higher dose may increase the local control and survival before the treatment. And KPS scores of the patients were possibility of such patients. ≥ 80 when admitted in our hospital, with life expectancy of more than 6 months. This study was carried out with To avoid radiation necrosis, the conventionally-fraction- the approval of West China Hospital's ethics committee. ated radiotherapy always prescribed no more than 50 Gy Treatment planning and evaluation on metastatic sites that were often insufficient to achieve acceptable local disease control and only inhibit tumor Each patient underwent spiral CT simulation with 3-mm growth. The more conformal dose distribution of inten- slice thickness with vacuum mattress (Stereotactic Body sity-modulated radiation therapy (IMRT) may provide Frame, Elekta, UK) immobilization. Target volumes and satisfactory dose coverage of tumor and avoid excessive normal structures were contoured by radiation physi- radiation of surrounding normal tissue, therefore with cians. The gross target volume (GTV) represented areas at potential advantage to achieve higher therapeutic ratio. cancer metastatic parts of vertebra based on pre-planning However the vertebral metastasis was often adjacent to CT, MRI or PET-CT imaging. If the whole vertebra was spinal cord and the sharp dose gradients between PTV and involved, the clinical tumor volume (CTV) was defined as spinal cord requires high precision of daily positioning to equal to GTV; otherwise a 10 mm margin around GTV was guarantee implementation of IMRT. Without special tech- added to generate CTV. For PTV, a 3 mm margin was niques that allow highly accurate set-up and dose escala- added isotropically to CTV, and the PTV was not allowed tion, some patients who might benefit from radiotherapy to overlap with the adjacent spinal cord but could touch may remain untreated or may be treated with doses it. The spinal canal was contoured as a critical structure unlikely to provide long-term local control. and to extend 2 cm length in SI direction beyond the level of PTV, with a median length of 11.6 cm (range of 8.1– So far, surgery is usually offered to patients with a reason- 13.4 cm) in planning. Depending on the metastatic sites, able life expectancy, whose spinal instability was present the lung, right/left kidney, and liver were delineated as and was causing symptoms [5,6]. Surgery also has been other OAR. All target delineations were reviewed by three used for more aggressive and relatively radio-resistant physicians and brought to the final consensus. The IMRT tumors. Also, the stereotactic radiosurgery is another plan was generated using 9–12 axial beam angles using choice for those patients. A few study reported that the aperture-based inverse planning system (PrecisePLAN single- or hypo-fractionated radiosurgery had the promis- Release 2.11, Electa, Sweden). A dose of 60–64 Gy was ing results in the treatment for cancer spinal metastasis [7- prescribed to PTV in 29–31 fractions, and the planning 10]. But in practice, the treatment failures were still com- was to deliver the prescribed dose to at least 95% of the mon [11,12]. PTV with a dose range not exceeding -10% and +15% of the prescribed dose. The dose to spinal cord was restricted To date, no ideal treatment could be prescribed for these within 50 Gy. The minimum segment size was 2 cm with cancer patients. The newly developed Elekta Synergy™ is a minimum of 4 monitor units (MU), a median of 43 an integrated image-guided radiotherapy (IGRT) system (35–55) segments were planned. Segments were manu- with the kV-CBCT system attached to a digitalized medical ally adjusted after aperture-based optimization to increase linear accelerator that can provide onboard CBCT imaging the dose gradient between target and OAR in 3 patients. of set-up errors. Thus, it had been stated as a potential Page 2 of 10 (page number not for citation purposes) Radiation Oncology 2008, 3:11 http://www.ro-journal.com/content/3/1/11 Table 1: Basic and clinical characteristics of the study population rection of translational error. Only the translational errors (n = 9) of the target which exceed the 2 mm action limit were con- verted to a respective shift of the treatment table by man- Age (years) ual adjustment. Rotational set-up errors were identified <45 4 ≥ 45 5 but unable to correct due to limitation of couch move- Gender ment. If the rotational set-up errors exceed 2°, patient Male 4 should be re-positioned immediately. CBCT re-scan Female 5 should be applied to ensure action level not exceeded. The Cancer type projection of isocenter was marked on the abdominal skin Lung cancer 2 of each patient to verify the maintenance of patient set-up Breast cancer 3 accuracy during treatment at the first fraction, and the Colorectal cancer 2 Other cancer types 2 patient set-up remained unmovable during the whole Spinal metastasis site(n = 10) treatment. Cervical 2 Thoracic 5 The positioning errors were analyzed as described previ- Lumbar 3 ously [14]: The mean of all displacements and the stand- Total volume of GTV (mm3) ard deviation (SD) of all displacements of the whole ≤ 20 2 group of patients were calculated. For each patient indi- 20 ~ 40 6 ≥ 40 2 vidually the mean (systematic error) and standard devia- tion (random error) of all errors were calculated. The systematic uncertainty Σ is defined as the standard devia- All plans were evaluated according to DVH analysis. The tion of the systematic errors. The root-mean-square of the homogeneity index (HI) was defined as D /D (mini- random errors was calculated as σ. Errors were calculated 5 95 mum dose in 5% of the PTV/minimum dose in 95% of separately for all three axes (LR, SI and AP). the PTV). The lower (closer to 1) the HI is, the better the dose homogeneity. Also, the conformity index (CI) was Simulation of observed patient set-up errors According to Yan et al [15], PTV margin can be designed calculated as follows: CI = CF (cover factor)·SF (spill fac- tor), where the CF was defined as the percentage of the based on a large confidence level (≥ 98%) with a simple PTV volume receiving the prescription dose and the SF as recipe of 2.27 × SD. The margins based on initial set-up the volume of the PTV receiving the prescription dose rel- errors and post-correction errors were thus calculated. ative to the total prescription dose-volume (see also Then the calculated PTV margin at initial setup was added RTOG protocol 9803). The closer the CI value to approach to CTV in three directions in each IMRT plans respectively, 1, the better the dose conformity is. to generate another PTV (PTV ) when no online correc- pre tion was applied. To simulate the impact of online correc- IMRT plan was delivered with step-and-shoot technique tion on dosimetry, the isocenter of the original IMRT plan utilizing the system's Beam Modulator™ that is an 80-leaf was shifted towards each OAR with a magnitude that was MLC with a leaf width of 4 mm (at the isocenter). equal to the difference between the calculated pre-correc- tion margin and actual applied margin (3 mm). The dose- KV-CBCT imaging volume parameters of OARs of the original and simulated Daily kV-CBCT images were acquired with the Vol- IMRT plans were then compared. umeView™ XVI function. The XVI allows acquiring a series of projected images at different gantry rotation that can be Follow-up reconstructed to 3-dimensional volumetric data, cut to Chemotherapy was prescribed after IG-IMRT. And sections and registered to input planning CT for matching. patients were seen 1 month, and every 3 months after The parameters for CBCT scan were 100–120 kV, scan treatment. The 100 mm Visual Analog Scale (VAS) meas- started from 182–260° and ended at 100–180° with the ure was used to evaluate the pain of these patients. The total imaging dose of 16 mGy per scanning [13], utilizing radiation-induced toxicities were assessed with RTOG cri- medium resolution reconstruction. Each acquisition pro- teria [16]. The median follow-up of the study patients was cedure (including image reconstruction) lasted 5 minutes. 15.6 months (range of 11–19 months). Daily CBCT images were registered with the planning CT using automatically bone matching (correlation coeffi- Results cient algorithm, Elekta XVI software) to calculate the tar- In treatment planning, the average dose which the PTVs get deviations on the LR, SI and AP axis. The ROI for received was 61.9 Gy, with the maximum dose of 64.6 Gy image registration was limited to the vertebrae on the level and the minimum dose of 58.7 Gy (Figure 1). The average of the PTV. An action level of 2 mm was set for online cor- level of the maximum dose which the adjacent cord Page 3 of 10 (page number not for citation purposes) Radiation Oncology 2008, 3:11 http://www.ro-journal.com/content/3/1/11 Th Figure 1 e maximum, minimum and mean dose of the 10 metastatic lesions (PTV) in treatment plans and the average level The maximum, minimum and mean dose of the 10 metastatic lesions (PTV) in treatment plans and the aver- age level. th Figure 3 The IMRT plans, resp e homogeneity index/dose conf ectively) ormity index and the average level in treatment plans (1, 2, 3..10 represented the number of The homogeneity index/dose conformity index and the average level in treatment plans (1, 2, 3..10 repre- sented the number of the IMRT plans, respectively). Page 4 of 10 (page number not for citation purposes) Radiation Oncology 2008, 3:11 http://www.ro-journal.com/content/3/1/11 spine the maximum dose and D (maximum dose in 5% volume of the spinal cord) of spinal cord, respectively. Clinically, grade 1/2 acute radiation-induced skin toxicity was observed during treatment, and the majority of patients had prompt pain relief within 4 weeks of treat- ment. According to their VAS score, the average level was 83 mm (range, 70–90 mm) at the baseline. 4 weeks after IG-IMRT, the average score decreased to 52 mm, with a range of 40–62 mm. And at the end of follow-up, the aver- age VAS score of these patients was 42 mm. 3 months after treatment, one patient developed progressive metastasis in the brain, and one developed liver metastasis, but the regions of the spine treated with IG-IMRT were clinically stable. No patient developed acute radiation-induced injury after the treatment. During follow-up, the lower extremity strength and ambulation of all patients Th th Figure 2 e a e maximu verage lm dose of the evel spinal cord in treatment plans and remained stable and no patients have experienced compli- The maximum dose of the spinal cord in treatment cations as a result of the procedure. plans and the average level. Discussion The irradiation tolerance of the spinal cord, the TD , is 5/5 received was 45.9 Gy, with a range of 44.5–49.0 Gy (Fig- considered to be in the range of 50 Gy for single daily frac- ure 2). Based on the DVH analysis, the average CI was tions of 1.8–2.0 Gy [17]. The dose required for cure of a 0.569, with a range of 0.567–0.572 (Figure 3). For HI, the cancer spinal metastasis should be analogous to that of maximum and the minimum values were 1.122 and the primary site, which generally should not be less than 1.117 respectively, with an average value of 1.12 (Figure 60 Gy (1.8–2.0 Gy/fraction) for solid tumors. Obviously 3). A representative IMRT plan with radiation isodose the standard conventionally-fractionated 30–40 Gy was curves was shown in Figure 4. The PTV (red region) was insufficient for long-last control of the spinal metastasis, covered by the 95% curve (58.5 Gy, the green line) of the resulted in the infield failure to be 26% or more [18]. Sev- prescription dose (60 Gy), and the curve of 47 Gy touched eral studies had been reported using single/hypo-fraction- the adjacent cord. ated radiosurgery for cancer spinal metastases [7-12]. According to the linear quadratic formula [19], the bio- As shown in Table 2, both systematic (Σ) and random (σ) logical-effective-dose (BED) of the metastatic lesions uncertainties were markedly reduced after online correc- received in these studies was between 60–153 Gy . The tion which ranged 0.1–0.2/0.7–0.8 mm after correction clinical outcome indicated that radiosurgery was effective compared to 1.4–2.3/3.0–4.1 mm before correction. And in the treatment of these patients, improving long-term the group mean (M) of the setup errors were small both palliation. However, the efficacy and safety of radiosur- before and after correction. gery is limited by tumor volume and the closeness of tar- gets to the critical organs, for larger tumors the dose is According to the calculated pre-correction margins (2.27 often reduced to avoid radiation-induced necrosis. × SD) shown in Table 2, the volume of the actual PTV Another limitation inherent of radiosurgery is that it (PTV ) in the applied IMRT plans and simulated PTV delivers radiation over a single session and thus does not real pre were shown in Table 3 in details. The average volume of encounter multiple mitotic phases, which may spare the PTV and PTV was 77.1 and 133.7 cm respectively; cells staying in the radioresistant phases and increases risk real pre with an average reduction of 42.3% after online correc- of recurrence especially with reduced dose [20]. Recently, tion. The impact of translational shift of treatment iso- improvement in radiation technique provides potential center towards each OAR on the dose-volume parameters means of IMRT dose escalation for spinal metastasis can- was shown in Table 4. More notably, the average reduc- cer. Thus for the first time, conventionally-fractionated tion in dose-volume parameters of OAR from PTV to radiotherapy with daily CBCT online correction was pre PTV were 14.8%, 10.7% and 14.5% in the mean dose, applied for cancer spinal metastasis in this study: the BED real V and V of the lungs; 19.9%, 33.3%, 29.6% and was in a range of 97–107 Gy for the metastatic lesions 20 12.5 10 21.1% in the mean dose, V , V and V of the liver; and the irradiation dose of the spinal cord was less than 30 20 10 21.9%, 42.9%, 23.8% and 20.5% in the mean dose, V , 49 Gy in 29–31 fractions. Comparing to the data from V and V of the right/left kidney; 28.2% and 16.7% in radiosurgery, a therapeutic dose was prescribed for tumor 20 10 Page 5 of 10 (page number not for citation purposes) Radiation Oncology 2008, 3:11 http://www.ro-journal.com/content/3/1/11 A representati Figure 4 ve IMRT plan with radiation isodose curves A representative IMRT plan with radiation isodose curves. The PTV (red region) was covered by the 95% curve of the prescription dose (the green line), and the dose of the adjacent cord was less than 49 Gy. (a: transverse section and b: sagittal section). target with IMRT plan, guaranteeing the irradiation toler- Due to the steep dose gradients between metastatic ance of the spinal cord. Follow-up showed no patient suf- lesions and spinal cord of the IMRT plan, very precise set- fering from the radiation-induced necrosis as a result of up procedure before radiotherapy is necessary. With the the treatment and all patients had varying degrees of pain application of IGRT technique, patient set-up accuracy relief. The average VAS scores of these patients were 83, 52 was verified by in-room CT scanner, helical tomotherapy, and 42 mm before, 4 weeks after IG-IMRT and at the end orthogonal X-ray cameras, and CT on rail in radiotherapy of follow-up, respectively. Complete pain relief was for spinal or paraspinal cancer [12,21-24]. Basically, sim- observed in 3 patients, and the remaining 6 patients were ply applying the patient immobilizing technique with able to reduce pain medication. The result was similar wall laser marks on the body surface still can not fulfill the with those from radiosurgery and more superior to the stringent target position requirement of high precision palliative radiotherapy in such patient. Clinically, the radiotherapy. In this study, daily CBCT with online cor- treatment was effective in the studied population. rection of set-up errors before treatment was practiced to Table 2: The positioning errors before/after (without/with) online set-up correction in the LR, SI and AP axes in this study (mm) LR SI AP Before After Before After Before After mean 0.3 0.1 0.4 0.0 -0.2 0.0 SD 3.2 0.7 4.5 0.8 3.9 0.7 Range -12.0 ~ 13.5 -2.6 ~ 1.4 -17.2 ~ 16.3 -2.5 ~ 1.5 -12.9 ~ 10.9 -1.9 ~ 1.5 Σ 1.4 0.2 2.1 0.2 2.3 0.1 σ 3.0 0.8 4.1 0.7 3.2 0.7 Theoretic margin 7.4 1.7 10.2 1.6 8.8 1.7 Translational shift 4.4 7.2 5.8 Before: before online set-up correction; After: after online set-up correction; Theoretic margin: calculated by 2.27 × SD based on a pre-selected confidence level of 98%; Translational shift: translational shift of the treatment isocenter in simulated IMRT plan to cover the theoretic margin without online set-up correction in three axes, and calculated as "theoretic margin before online set-up correction-3" mm. Page 6 of 10 (page number not for citation purposes) Radiation Oncology 2008, 3:11 http://www.ro-journal.com/content/3/1/11 Table 3: The volumes of original and simulated PTVs in this study (cm ) Target number PTVreal PTVpre Volume reduction from PTVpre to PTVreal (%) 1 15.6 26.4 40.9% 2 94.7 168.6 43.8% 3 82.5 126.2 34.6% 4 89.3 150.6 40.7% 5 72.6 116.4 37.6% 6 18.9 37.2 49.2% 7 108.4 204.3 46.9% 8 91.2 155.8 41.4% 9 112.3 221.2 49.2% 10 85.9 130.6 34.2% Average 77.1 133.7 42.3% PTVreal: actual PTV in the original IMRT plans; PTVpre: simulated PTV based on the theoretic margins in three axes without online set-up correction. achieve the maximum accuracy and safety for the patient. Based on the margin-calculating recipe, a 1.7, 1.6 and 1.7 The systematic/random errors at initial set-up were 1.4/ mm margin should be added to the CTV for generating 3.0, 2.1/4.1 and 2.3/3.2 mm in the LR, SI and AP axes, PTV in the LR, SI and AP axes respectively with CBCT respectively. After set-up correction, those errors were 0.2/ online correction, confirming that the 3 mm region 0.8, 0.2/0.7 and 0.1/0.7 mm in the three axes respectively, around the GTV/CTV was enough and acceptable with indicating the role of online correction on improving CBCT-based guidance. Without online correction, the cal- positioning precision for radiotherapy of spinal meta- culated margins in the three axes were 7.4, 10.2 and 8.8 static cancer, thus may potentially reduce the adverse mm, respectively. In each IMRT plan, we simulated the effect of set-up errors on tumor control probability and hypothetic effects of the pre-correction positioning errors normal tissue complication probability (NTCP) in radio- on PTV and dose-volume parameters of OAR. As shown in therapy treatment [25]. Table 3, the reduction of volume from the pre-correction PTV to the PTV with online correction was considera- pre real Table 4: Average normal tissue dose-volume parameters based on PTVpre and PTVreal in each original and simulated IMRT plans Normal tissue parameter Average parameters based on PTVpre Average parameters based on Average parameters reductions from PTVreal PTVpre to PTVreal (%) Lung (n = 4) Maximum dose 57.3 Gy 55.2 Gy 3.7 Average dose 10.8 Gy 9.2 Gy 14.8 V20 12.2% 10.9% 10.7 V12.5 23.5% 20.1% 14.5 Liver (n = 4) Maximum dose 58.6 Gy 56.1 Gy 4.3 Average dose 14.6 Gy 11.7 Gy 19.9 V30 12% 8% 33.3 V20 27% 19% 29.6 V10 38% 30% 21.1 kidney (n = 4) Maximum dose 60.2 Gy 57.8 Gy 4.0 Average dose 14.6 Gy 11.4 Gy 21.9 V30 7% 4% 42.9 V20 21% 16% 23.8 V10 39% 31% 20.5 Cord (n = 10) Maximum dose 68.4 Gy 49.1 Gy 28.2 Average dose 34.3 Gy 31.2 Gy 9.1 D5spine 54.4 Gy 45.3 Gy 16.7 PTVpre: simulated PTV based on the theoretic margins in the three axes without online set-up correction; PTVreal: actual PTV in the original IMRT plans; D5spine: maximum dose in 5% volume of the spinal cord. Page 7 of 10 (page number not for citation purposes) Radiation Oncology 2008, 3:11 http://www.ro-journal.com/content/3/1/11 and AP axes Figure 5 Comparison of the simulate L riR or/po axis, ye steri llor in AP axi ow on the irrad and deep s, i resp g atio red effects of the positionin en n l ec ditive o ne se s:ly of is ; an oce the d th n spinal tee g r movi r e co enrd with the ng su li g errors ne wa pers the ac iowith/withou r/actua infertual DVH io l plan ( r in SI t CBCT-ba r ed and orange line: isocenter m a of the cord) xis, blue and sed onli purple ne set-up c lines: isocenter moving orrection in oving left/rig the LR, SI ht i ante- n Comparison of the simulated effects of the positioning errors with/without CBCT-based online set-up correc- tion in the LR, SI and AP axes on the irradiation dose of the spinal cord with the actual plan (red and orange line: isocenter moving left/right in LR axis, yellow and deep green lines: isocenter moving superior/inferior in SI axis, blue and purple lines: isocenter moving anterior/posterior in AP axis, respectively; and the green line was the actual DVH of the cord). (a: the simulated and actual DVHs of the cord and b: the simulated and actual maximum dose of 5% volume of the cord). ble, with an average level of 42.3%. Also, the translational The dose reductions could translate clinically into a lower shift of isocenter towards each OAR had significant probability of treatment toxicity, as well as a potential impact on the dose-volume parameters of these organs. increase in the number of patients that might be eligible Depending on the target location, there were 4 targets for IG-IMRT or concurrent chemoradiotherapy. related to lung, 4 targets related liver and right/left kidney, and 10 targets related to spinal cord. The dose-volume The spinal cord was the key OAR in this study. The iso- parameters of each OAR were reduced to varying degrees. center was shifted in the six directions (moving left/right, Page 8 of 10 (page number not for citation purposes) Radiation Oncology 2008, 3:11 http://www.ro-journal.com/content/3/1/11 inferior/superior, and anterior/posterior in LR, SI and AP of the treatment couch, patient in our study should be re- axes) respectively to simulate the impact of pre-correction positioned if the rotational set-up errors exceeded 2°. So, margin on the dose-volume parameters of the spinal cord. the rotational set-up errors and their impact on IMRT dose Figure 5 showed the simulated and original DVH of the delivery had not been evaluated in this study. spinal cord in one IMRT plan (the same patient as Figure 4 represented). The position errors in SI axes had little Conclusion impact on the irradiation dose of the cord. As well, it indi- Therefore, this study presented the preliminary data to spine cated that the D changed significantly, if position demonstrate the safety and effectiveness of this technique errors occurred towards the cord in LR and AP axis, respec- in treatment of patients with cancer spinal metastasis. tively. Most significantly, the posterior shift towards the These results are encouraging. Although the studied sam- cord resulted in a maximum dose of 68 Gy to the cord. ple size was somewhat small and with the limitation men- Comparing to the results reported by Guckenberger et al tioned above, it still was a hopeful progress in radiation [26], our study suggested that without the CBCT online therapy for patient with cancer. As a result, the application guidance, the IMRT plan could not be applied successfully of conventionally-fractionated IG-IMRT has the potential in such patients. to improve the clinical outcome of the patients with can- cer spinal metastasis. Although only the inter-fractional setup errors was taken into account as the major source of uncertainties to affect Competing interests the accuracy of IMRT dose delivery in this study, there was The authors declare that they have no competing interests. another important factor which also contribute to the dose delivery accuracy: movement of the target and spinal Authors' contributions cord during treatment (intra-fraction variation). First, CTV YG and JW contributed equally in design of the study, col- for the paraspinal lesions was assumed to be fixed to the lection of data and drafting the manuscript; SB and XJ vertebrae and the intra-treatment motion of the target worked on analysis of data; FX provided the conception of would be equivalent to the motion of the spinal column. this study and the final approval of the version to be pub- Data from literatures have confirmed that in conformal lished. And all authors read and approved the final man- radiotherapy, intra-fraction organ/target motion can be uscript. achieved in the range of 1 mm with proper immobiliza- tion [21,27]. Second, Cai et al found that the spinal cord Acknowledgements We thank Dr. Xin Wang and technicians Renming Zhong, Xiaoyu Li and motion during normal breathing was typically within 0.5 Yinbo He for their assistance in data collection. mm by dynamic MRI (dMRI), and partly stated that the spinal cord was almost immovable during breathing [28]. Financial supports Third, studies in Massachusetts General Hospital and Memorial Sloan-Kettering Cancer Center indicated that This study was supported in part by Science and Technology Key Project of the effects of intra-fraction organ motion on IMRT dose Sichuan Province, PR. China (Project 03SG022-008 to J.W. and 04SG022- delivery were ignorable in a typical treatment with 30 frac- 007 to F.X.). tions in breast and pulmonary radiotherapy [29,30]. 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Guckenberger M, Meyer J, Wilbert J, Baier K, Sauer O, Flentje M: Precision of image-guided radiotherapy (IGRT) in six Your research papers will be: degrees of freedom and limitations in clinical practice. Strahl- available free of charge to the entire biomedical community enther Onkol 2007, 183:307-313. 28. Cai J, Sheng K, Sheehan JP, Benedict SH, Larner JM, Read PW: Eval- peer reviewed and published immediately upon acceptance uation of thoracic spinal cord motion using dynamic MRI. cited in PubMed and archived on PubMed Central Radiother Oncol 2007, 84:279-282. 29. Bortfeld T, Jokivarsi K, Goitein M, Kung J, Jiang SB: Effects of intra- yours — you keep the copyright fraction motion on IMRT dose delivery: statistical analysis BioMedcentral and simulation. Phys Med Biol 2002, 47:2203-2220. 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

Conventionally-fractionated image-guided intensity modulated radiotherapy (IG-IMRT): a safe and effective treatment for cancer spinal metastasis

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Springer Journals
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Copyright © 2008 by Gong 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-3-11
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18426607
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Abstract

Background: Treatments for cancer spinal metastasis were always palliative. This study was conducted to investigate the safety and effectiveness of IG-IMRT for these patients. Methods: 10 metastatic lesions were treated with conventionally-fractionated IG-IMRT. Daily kilovoltage cone-beam computed tomography (kV-CBCT) scan was applied to ensure accurate positioning. Plans were evaluated by the dose-volume histogram (DVH) analysis. Results: Before set-up correction, the positioning errors in the left-right (LR), superior-inferior (SI) and anterior-posterior (AP) axes were 0.3 ± 3.2, 0.4 ± 4.5 and -0.2 ± 3.9 mm, respectively. After repositioning, those errors were 0.1 ± 0.7, 0 ± 0.8 and 0 ± 0.7 mm, respectively. The systematic/random uncertainties ranged 1.4–2.3/3.0–4.1 before and 0.1–0.2/0.7–0.8 mm after online set-up correction. In the original IMRT plans, the average dose of the planning target volume (PTV) was 61.9 Gy, with the spinal cord dose less than 49 Gy. Compared to the simulated PTVs based on the pre-correction CBCT, the average volume reduction of PTVs was 42.3% after online correction. Also, organ at risk (OAR) all benefited from CBCT-based set-up correction and had significant dose reduction with IGRT technique. Clinically, most patients had prompt pain relief within one month of treatment. There was no radiation-induced toxicity detected clinically during a median follow-up of 15.6 months. Conclusion: IG-IMRT provides a new approach to treat cancer spinal metastasis. The precise positioning ensures the implementation of optimal IMRT plan, satisfying both the dose escalation of tumor targets and the radiation tolerance of spinal cord. It might benefit the cancer patient with spinal metastasis. Page 1 of 10 (page number not for citation purposes) Radiation Oncology 2008, 3:11 http://www.ro-journal.com/content/3/1/11 treatment for cancer spinal metastasis. In this paper, we Background Spine is the most common place of cancer metastasis, report the preliminary results of the application with this especially for lung cancer and breast cancer. Each year, technique, giving details about the safety and effectiveness approximately 50,000 patients with cancer develop spinal of IMRT dose escalation with IGRT for metastatic tumors metastasis worldwide and the 5-year over-all survival rate of the spinal vertebra. of these patients was less than 5% [1,2]. All together, accompanying with the improvement of therapy for Methods malignant tumors, the overall survival time of cancer Patient selection patients prolonged and the incidence of spinal metastasis This study was carried out in Tumor Center at West China was increasing gradually. Radiotherapy is the standard Hospital, Sichuan University, PR. China. Between May treatment for vertebral metastasis of patients with cancer. and November 2006, 9 previously treated cancer patients Reviewing the literatures, three treatments/fractions were with confirmed diagnosis of ≤ 2 spinal metastases and no applied clinically worldwide: 30 Gy/10 fractions, 20 Gy/5 other distant metastasis were recruited in this study. The fractions and 8 Gy/1 fraction [3,4]. But all three treat- basic and clinical characteristics of these patients were ments were palliative, and recurrences in pre-irradiated shown in Table 1. Each diagnosis was confirmed by com- foci were frequent. Especially for those patients who only puted tomography (CT), magnetic resonance imaging had vertebral metastasis with primary lesion controlled, (MRI) or positron emission tomography-CT (PET-CT) higher dose may increase the local control and survival before the treatment. And KPS scores of the patients were possibility of such patients. ≥ 80 when admitted in our hospital, with life expectancy of more than 6 months. This study was carried out with To avoid radiation necrosis, the conventionally-fraction- the approval of West China Hospital's ethics committee. ated radiotherapy always prescribed no more than 50 Gy Treatment planning and evaluation on metastatic sites that were often insufficient to achieve acceptable local disease control and only inhibit tumor Each patient underwent spiral CT simulation with 3-mm growth. The more conformal dose distribution of inten- slice thickness with vacuum mattress (Stereotactic Body sity-modulated radiation therapy (IMRT) may provide Frame, Elekta, UK) immobilization. Target volumes and satisfactory dose coverage of tumor and avoid excessive normal structures were contoured by radiation physi- radiation of surrounding normal tissue, therefore with cians. The gross target volume (GTV) represented areas at potential advantage to achieve higher therapeutic ratio. cancer metastatic parts of vertebra based on pre-planning However the vertebral metastasis was often adjacent to CT, MRI or PET-CT imaging. If the whole vertebra was spinal cord and the sharp dose gradients between PTV and involved, the clinical tumor volume (CTV) was defined as spinal cord requires high precision of daily positioning to equal to GTV; otherwise a 10 mm margin around GTV was guarantee implementation of IMRT. Without special tech- added to generate CTV. For PTV, a 3 mm margin was niques that allow highly accurate set-up and dose escala- added isotropically to CTV, and the PTV was not allowed tion, some patients who might benefit from radiotherapy to overlap with the adjacent spinal cord but could touch may remain untreated or may be treated with doses it. The spinal canal was contoured as a critical structure unlikely to provide long-term local control. and to extend 2 cm length in SI direction beyond the level of PTV, with a median length of 11.6 cm (range of 8.1– So far, surgery is usually offered to patients with a reason- 13.4 cm) in planning. Depending on the metastatic sites, able life expectancy, whose spinal instability was present the lung, right/left kidney, and liver were delineated as and was causing symptoms [5,6]. Surgery also has been other OAR. All target delineations were reviewed by three used for more aggressive and relatively radio-resistant physicians and brought to the final consensus. The IMRT tumors. Also, the stereotactic radiosurgery is another plan was generated using 9–12 axial beam angles using choice for those patients. A few study reported that the aperture-based inverse planning system (PrecisePLAN single- or hypo-fractionated radiosurgery had the promis- Release 2.11, Electa, Sweden). A dose of 60–64 Gy was ing results in the treatment for cancer spinal metastasis [7- prescribed to PTV in 29–31 fractions, and the planning 10]. But in practice, the treatment failures were still com- was to deliver the prescribed dose to at least 95% of the mon [11,12]. PTV with a dose range not exceeding -10% and +15% of the prescribed dose. The dose to spinal cord was restricted To date, no ideal treatment could be prescribed for these within 50 Gy. The minimum segment size was 2 cm with cancer patients. The newly developed Elekta Synergy™ is a minimum of 4 monitor units (MU), a median of 43 an integrated image-guided radiotherapy (IGRT) system (35–55) segments were planned. Segments were manu- with the kV-CBCT system attached to a digitalized medical ally adjusted after aperture-based optimization to increase linear accelerator that can provide onboard CBCT imaging the dose gradient between target and OAR in 3 patients. of set-up errors. Thus, it had been stated as a potential Page 2 of 10 (page number not for citation purposes) Radiation Oncology 2008, 3:11 http://www.ro-journal.com/content/3/1/11 Table 1: Basic and clinical characteristics of the study population rection of translational error. Only the translational errors (n = 9) of the target which exceed the 2 mm action limit were con- verted to a respective shift of the treatment table by man- Age (years) ual adjustment. Rotational set-up errors were identified <45 4 ≥ 45 5 but unable to correct due to limitation of couch move- Gender ment. If the rotational set-up errors exceed 2°, patient Male 4 should be re-positioned immediately. CBCT re-scan Female 5 should be applied to ensure action level not exceeded. The Cancer type projection of isocenter was marked on the abdominal skin Lung cancer 2 of each patient to verify the maintenance of patient set-up Breast cancer 3 accuracy during treatment at the first fraction, and the Colorectal cancer 2 Other cancer types 2 patient set-up remained unmovable during the whole Spinal metastasis site(n = 10) treatment. Cervical 2 Thoracic 5 The positioning errors were analyzed as described previ- Lumbar 3 ously [14]: The mean of all displacements and the stand- Total volume of GTV (mm3) ard deviation (SD) of all displacements of the whole ≤ 20 2 group of patients were calculated. For each patient indi- 20 ~ 40 6 ≥ 40 2 vidually the mean (systematic error) and standard devia- tion (random error) of all errors were calculated. The systematic uncertainty Σ is defined as the standard devia- All plans were evaluated according to DVH analysis. The tion of the systematic errors. The root-mean-square of the homogeneity index (HI) was defined as D /D (mini- random errors was calculated as σ. Errors were calculated 5 95 mum dose in 5% of the PTV/minimum dose in 95% of separately for all three axes (LR, SI and AP). the PTV). The lower (closer to 1) the HI is, the better the dose homogeneity. Also, the conformity index (CI) was Simulation of observed patient set-up errors According to Yan et al [15], PTV margin can be designed calculated as follows: CI = CF (cover factor)·SF (spill fac- tor), where the CF was defined as the percentage of the based on a large confidence level (≥ 98%) with a simple PTV volume receiving the prescription dose and the SF as recipe of 2.27 × SD. The margins based on initial set-up the volume of the PTV receiving the prescription dose rel- errors and post-correction errors were thus calculated. ative to the total prescription dose-volume (see also Then the calculated PTV margin at initial setup was added RTOG protocol 9803). The closer the CI value to approach to CTV in three directions in each IMRT plans respectively, 1, the better the dose conformity is. to generate another PTV (PTV ) when no online correc- pre tion was applied. To simulate the impact of online correc- IMRT plan was delivered with step-and-shoot technique tion on dosimetry, the isocenter of the original IMRT plan utilizing the system's Beam Modulator™ that is an 80-leaf was shifted towards each OAR with a magnitude that was MLC with a leaf width of 4 mm (at the isocenter). equal to the difference between the calculated pre-correc- tion margin and actual applied margin (3 mm). The dose- KV-CBCT imaging volume parameters of OARs of the original and simulated Daily kV-CBCT images were acquired with the Vol- IMRT plans were then compared. umeView™ XVI function. The XVI allows acquiring a series of projected images at different gantry rotation that can be Follow-up reconstructed to 3-dimensional volumetric data, cut to Chemotherapy was prescribed after IG-IMRT. And sections and registered to input planning CT for matching. patients were seen 1 month, and every 3 months after The parameters for CBCT scan were 100–120 kV, scan treatment. The 100 mm Visual Analog Scale (VAS) meas- started from 182–260° and ended at 100–180° with the ure was used to evaluate the pain of these patients. The total imaging dose of 16 mGy per scanning [13], utilizing radiation-induced toxicities were assessed with RTOG cri- medium resolution reconstruction. Each acquisition pro- teria [16]. The median follow-up of the study patients was cedure (including image reconstruction) lasted 5 minutes. 15.6 months (range of 11–19 months). Daily CBCT images were registered with the planning CT using automatically bone matching (correlation coeffi- Results cient algorithm, Elekta XVI software) to calculate the tar- In treatment planning, the average dose which the PTVs get deviations on the LR, SI and AP axis. The ROI for received was 61.9 Gy, with the maximum dose of 64.6 Gy image registration was limited to the vertebrae on the level and the minimum dose of 58.7 Gy (Figure 1). The average of the PTV. An action level of 2 mm was set for online cor- level of the maximum dose which the adjacent cord Page 3 of 10 (page number not for citation purposes) Radiation Oncology 2008, 3:11 http://www.ro-journal.com/content/3/1/11 Th Figure 1 e maximum, minimum and mean dose of the 10 metastatic lesions (PTV) in treatment plans and the average level The maximum, minimum and mean dose of the 10 metastatic lesions (PTV) in treatment plans and the aver- age level. th Figure 3 The IMRT plans, resp e homogeneity index/dose conf ectively) ormity index and the average level in treatment plans (1, 2, 3..10 represented the number of The homogeneity index/dose conformity index and the average level in treatment plans (1, 2, 3..10 repre- sented the number of the IMRT plans, respectively). Page 4 of 10 (page number not for citation purposes) Radiation Oncology 2008, 3:11 http://www.ro-journal.com/content/3/1/11 spine the maximum dose and D (maximum dose in 5% volume of the spinal cord) of spinal cord, respectively. Clinically, grade 1/2 acute radiation-induced skin toxicity was observed during treatment, and the majority of patients had prompt pain relief within 4 weeks of treat- ment. According to their VAS score, the average level was 83 mm (range, 70–90 mm) at the baseline. 4 weeks after IG-IMRT, the average score decreased to 52 mm, with a range of 40–62 mm. And at the end of follow-up, the aver- age VAS score of these patients was 42 mm. 3 months after treatment, one patient developed progressive metastasis in the brain, and one developed liver metastasis, but the regions of the spine treated with IG-IMRT were clinically stable. No patient developed acute radiation-induced injury after the treatment. During follow-up, the lower extremity strength and ambulation of all patients Th th Figure 2 e a e maximu verage lm dose of the evel spinal cord in treatment plans and remained stable and no patients have experienced compli- The maximum dose of the spinal cord in treatment cations as a result of the procedure. plans and the average level. Discussion The irradiation tolerance of the spinal cord, the TD , is 5/5 received was 45.9 Gy, with a range of 44.5–49.0 Gy (Fig- considered to be in the range of 50 Gy for single daily frac- ure 2). Based on the DVH analysis, the average CI was tions of 1.8–2.0 Gy [17]. The dose required for cure of a 0.569, with a range of 0.567–0.572 (Figure 3). For HI, the cancer spinal metastasis should be analogous to that of maximum and the minimum values were 1.122 and the primary site, which generally should not be less than 1.117 respectively, with an average value of 1.12 (Figure 60 Gy (1.8–2.0 Gy/fraction) for solid tumors. Obviously 3). A representative IMRT plan with radiation isodose the standard conventionally-fractionated 30–40 Gy was curves was shown in Figure 4. The PTV (red region) was insufficient for long-last control of the spinal metastasis, covered by the 95% curve (58.5 Gy, the green line) of the resulted in the infield failure to be 26% or more [18]. Sev- prescription dose (60 Gy), and the curve of 47 Gy touched eral studies had been reported using single/hypo-fraction- the adjacent cord. ated radiosurgery for cancer spinal metastases [7-12]. According to the linear quadratic formula [19], the bio- As shown in Table 2, both systematic (Σ) and random (σ) logical-effective-dose (BED) of the metastatic lesions uncertainties were markedly reduced after online correc- received in these studies was between 60–153 Gy . The tion which ranged 0.1–0.2/0.7–0.8 mm after correction clinical outcome indicated that radiosurgery was effective compared to 1.4–2.3/3.0–4.1 mm before correction. And in the treatment of these patients, improving long-term the group mean (M) of the setup errors were small both palliation. However, the efficacy and safety of radiosur- before and after correction. gery is limited by tumor volume and the closeness of tar- gets to the critical organs, for larger tumors the dose is According to the calculated pre-correction margins (2.27 often reduced to avoid radiation-induced necrosis. × SD) shown in Table 2, the volume of the actual PTV Another limitation inherent of radiosurgery is that it (PTV ) in the applied IMRT plans and simulated PTV delivers radiation over a single session and thus does not real pre were shown in Table 3 in details. The average volume of encounter multiple mitotic phases, which may spare the PTV and PTV was 77.1 and 133.7 cm respectively; cells staying in the radioresistant phases and increases risk real pre with an average reduction of 42.3% after online correc- of recurrence especially with reduced dose [20]. Recently, tion. The impact of translational shift of treatment iso- improvement in radiation technique provides potential center towards each OAR on the dose-volume parameters means of IMRT dose escalation for spinal metastasis can- was shown in Table 4. More notably, the average reduc- cer. Thus for the first time, conventionally-fractionated tion in dose-volume parameters of OAR from PTV to radiotherapy with daily CBCT online correction was pre PTV were 14.8%, 10.7% and 14.5% in the mean dose, applied for cancer spinal metastasis in this study: the BED real V and V of the lungs; 19.9%, 33.3%, 29.6% and was in a range of 97–107 Gy for the metastatic lesions 20 12.5 10 21.1% in the mean dose, V , V and V of the liver; and the irradiation dose of the spinal cord was less than 30 20 10 21.9%, 42.9%, 23.8% and 20.5% in the mean dose, V , 49 Gy in 29–31 fractions. Comparing to the data from V and V of the right/left kidney; 28.2% and 16.7% in radiosurgery, a therapeutic dose was prescribed for tumor 20 10 Page 5 of 10 (page number not for citation purposes) Radiation Oncology 2008, 3:11 http://www.ro-journal.com/content/3/1/11 A representati Figure 4 ve IMRT plan with radiation isodose curves A representative IMRT plan with radiation isodose curves. The PTV (red region) was covered by the 95% curve of the prescription dose (the green line), and the dose of the adjacent cord was less than 49 Gy. (a: transverse section and b: sagittal section). target with IMRT plan, guaranteeing the irradiation toler- Due to the steep dose gradients between metastatic ance of the spinal cord. Follow-up showed no patient suf- lesions and spinal cord of the IMRT plan, very precise set- fering from the radiation-induced necrosis as a result of up procedure before radiotherapy is necessary. With the the treatment and all patients had varying degrees of pain application of IGRT technique, patient set-up accuracy relief. The average VAS scores of these patients were 83, 52 was verified by in-room CT scanner, helical tomotherapy, and 42 mm before, 4 weeks after IG-IMRT and at the end orthogonal X-ray cameras, and CT on rail in radiotherapy of follow-up, respectively. Complete pain relief was for spinal or paraspinal cancer [12,21-24]. Basically, sim- observed in 3 patients, and the remaining 6 patients were ply applying the patient immobilizing technique with able to reduce pain medication. The result was similar wall laser marks on the body surface still can not fulfill the with those from radiosurgery and more superior to the stringent target position requirement of high precision palliative radiotherapy in such patient. Clinically, the radiotherapy. In this study, daily CBCT with online cor- treatment was effective in the studied population. rection of set-up errors before treatment was practiced to Table 2: The positioning errors before/after (without/with) online set-up correction in the LR, SI and AP axes in this study (mm) LR SI AP Before After Before After Before After mean 0.3 0.1 0.4 0.0 -0.2 0.0 SD 3.2 0.7 4.5 0.8 3.9 0.7 Range -12.0 ~ 13.5 -2.6 ~ 1.4 -17.2 ~ 16.3 -2.5 ~ 1.5 -12.9 ~ 10.9 -1.9 ~ 1.5 Σ 1.4 0.2 2.1 0.2 2.3 0.1 σ 3.0 0.8 4.1 0.7 3.2 0.7 Theoretic margin 7.4 1.7 10.2 1.6 8.8 1.7 Translational shift 4.4 7.2 5.8 Before: before online set-up correction; After: after online set-up correction; Theoretic margin: calculated by 2.27 × SD based on a pre-selected confidence level of 98%; Translational shift: translational shift of the treatment isocenter in simulated IMRT plan to cover the theoretic margin without online set-up correction in three axes, and calculated as "theoretic margin before online set-up correction-3" mm. Page 6 of 10 (page number not for citation purposes) Radiation Oncology 2008, 3:11 http://www.ro-journal.com/content/3/1/11 Table 3: The volumes of original and simulated PTVs in this study (cm ) Target number PTVreal PTVpre Volume reduction from PTVpre to PTVreal (%) 1 15.6 26.4 40.9% 2 94.7 168.6 43.8% 3 82.5 126.2 34.6% 4 89.3 150.6 40.7% 5 72.6 116.4 37.6% 6 18.9 37.2 49.2% 7 108.4 204.3 46.9% 8 91.2 155.8 41.4% 9 112.3 221.2 49.2% 10 85.9 130.6 34.2% Average 77.1 133.7 42.3% PTVreal: actual PTV in the original IMRT plans; PTVpre: simulated PTV based on the theoretic margins in three axes without online set-up correction. achieve the maximum accuracy and safety for the patient. Based on the margin-calculating recipe, a 1.7, 1.6 and 1.7 The systematic/random errors at initial set-up were 1.4/ mm margin should be added to the CTV for generating 3.0, 2.1/4.1 and 2.3/3.2 mm in the LR, SI and AP axes, PTV in the LR, SI and AP axes respectively with CBCT respectively. After set-up correction, those errors were 0.2/ online correction, confirming that the 3 mm region 0.8, 0.2/0.7 and 0.1/0.7 mm in the three axes respectively, around the GTV/CTV was enough and acceptable with indicating the role of online correction on improving CBCT-based guidance. Without online correction, the cal- positioning precision for radiotherapy of spinal meta- culated margins in the three axes were 7.4, 10.2 and 8.8 static cancer, thus may potentially reduce the adverse mm, respectively. In each IMRT plan, we simulated the effect of set-up errors on tumor control probability and hypothetic effects of the pre-correction positioning errors normal tissue complication probability (NTCP) in radio- on PTV and dose-volume parameters of OAR. As shown in therapy treatment [25]. Table 3, the reduction of volume from the pre-correction PTV to the PTV with online correction was considera- pre real Table 4: Average normal tissue dose-volume parameters based on PTVpre and PTVreal in each original and simulated IMRT plans Normal tissue parameter Average parameters based on PTVpre Average parameters based on Average parameters reductions from PTVreal PTVpre to PTVreal (%) Lung (n = 4) Maximum dose 57.3 Gy 55.2 Gy 3.7 Average dose 10.8 Gy 9.2 Gy 14.8 V20 12.2% 10.9% 10.7 V12.5 23.5% 20.1% 14.5 Liver (n = 4) Maximum dose 58.6 Gy 56.1 Gy 4.3 Average dose 14.6 Gy 11.7 Gy 19.9 V30 12% 8% 33.3 V20 27% 19% 29.6 V10 38% 30% 21.1 kidney (n = 4) Maximum dose 60.2 Gy 57.8 Gy 4.0 Average dose 14.6 Gy 11.4 Gy 21.9 V30 7% 4% 42.9 V20 21% 16% 23.8 V10 39% 31% 20.5 Cord (n = 10) Maximum dose 68.4 Gy 49.1 Gy 28.2 Average dose 34.3 Gy 31.2 Gy 9.1 D5spine 54.4 Gy 45.3 Gy 16.7 PTVpre: simulated PTV based on the theoretic margins in the three axes without online set-up correction; PTVreal: actual PTV in the original IMRT plans; D5spine: maximum dose in 5% volume of the spinal cord. Page 7 of 10 (page number not for citation purposes) Radiation Oncology 2008, 3:11 http://www.ro-journal.com/content/3/1/11 and AP axes Figure 5 Comparison of the simulate L riR or/po axis, ye steri llor in AP axi ow on the irrad and deep s, i resp g atio red effects of the positionin en n l ec ditive o ne se s:ly of is ; an oce the d th n spinal tee g r movi r e co enrd with the ng su li g errors ne wa pers the ac iowith/withou r/actua infertual DVH io l plan ( r in SI t CBCT-ba r ed and orange line: isocenter m a of the cord) xis, blue and sed onli purple ne set-up c lines: isocenter moving orrection in oving left/rig the LR, SI ht i ante- n Comparison of the simulated effects of the positioning errors with/without CBCT-based online set-up correc- tion in the LR, SI and AP axes on the irradiation dose of the spinal cord with the actual plan (red and orange line: isocenter moving left/right in LR axis, yellow and deep green lines: isocenter moving superior/inferior in SI axis, blue and purple lines: isocenter moving anterior/posterior in AP axis, respectively; and the green line was the actual DVH of the cord). (a: the simulated and actual DVHs of the cord and b: the simulated and actual maximum dose of 5% volume of the cord). ble, with an average level of 42.3%. Also, the translational The dose reductions could translate clinically into a lower shift of isocenter towards each OAR had significant probability of treatment toxicity, as well as a potential impact on the dose-volume parameters of these organs. increase in the number of patients that might be eligible Depending on the target location, there were 4 targets for IG-IMRT or concurrent chemoradiotherapy. related to lung, 4 targets related liver and right/left kidney, and 10 targets related to spinal cord. The dose-volume The spinal cord was the key OAR in this study. The iso- parameters of each OAR were reduced to varying degrees. center was shifted in the six directions (moving left/right, Page 8 of 10 (page number not for citation purposes) Radiation Oncology 2008, 3:11 http://www.ro-journal.com/content/3/1/11 inferior/superior, and anterior/posterior in LR, SI and AP of the treatment couch, patient in our study should be re- axes) respectively to simulate the impact of pre-correction positioned if the rotational set-up errors exceeded 2°. So, margin on the dose-volume parameters of the spinal cord. the rotational set-up errors and their impact on IMRT dose Figure 5 showed the simulated and original DVH of the delivery had not been evaluated in this study. spinal cord in one IMRT plan (the same patient as Figure 4 represented). The position errors in SI axes had little Conclusion impact on the irradiation dose of the cord. As well, it indi- Therefore, this study presented the preliminary data to spine cated that the D changed significantly, if position demonstrate the safety and effectiveness of this technique errors occurred towards the cord in LR and AP axis, respec- in treatment of patients with cancer spinal metastasis. tively. Most significantly, the posterior shift towards the These results are encouraging. Although the studied sam- cord resulted in a maximum dose of 68 Gy to the cord. ple size was somewhat small and with the limitation men- Comparing to the results reported by Guckenberger et al tioned above, it still was a hopeful progress in radiation [26], our study suggested that without the CBCT online therapy for patient with cancer. As a result, the application guidance, the IMRT plan could not be applied successfully of conventionally-fractionated IG-IMRT has the potential in such patients. to improve the clinical outcome of the patients with can- cer spinal metastasis. Although only the inter-fractional setup errors was taken into account as the major source of uncertainties to affect Competing interests the accuracy of IMRT dose delivery in this study, there was The authors declare that they have no competing interests. another important factor which also contribute to the dose delivery accuracy: movement of the target and spinal Authors' contributions cord during treatment (intra-fraction variation). First, CTV YG and JW contributed equally in design of the study, col- for the paraspinal lesions was assumed to be fixed to the lection of data and drafting the manuscript; SB and XJ vertebrae and the intra-treatment motion of the target worked on analysis of data; FX provided the conception of would be equivalent to the motion of the spinal column. this study and the final approval of the version to be pub- Data from literatures have confirmed that in conformal lished. And all authors read and approved the final man- radiotherapy, intra-fraction organ/target motion can be uscript. achieved in the range of 1 mm with proper immobiliza- tion [21,27]. Second, Cai et al found that the spinal cord Acknowledgements We thank Dr. Xin Wang and technicians Renming Zhong, Xiaoyu Li and motion during normal breathing was typically within 0.5 Yinbo He for their assistance in data collection. mm by dynamic MRI (dMRI), and partly stated that the spinal cord was almost immovable during breathing [28]. Financial supports Third, studies in Massachusetts General Hospital and Memorial Sloan-Kettering Cancer Center indicated that This study was supported in part by Science and Technology Key Project of the effects of intra-fraction organ motion on IMRT dose Sichuan Province, PR. China (Project 03SG022-008 to J.W. and 04SG022- delivery were ignorable in a typical treatment with 30 frac- 007 to F.X.). tions in breast and pulmonary radiotherapy [29,30]. 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Radiation Oncology – Springer Journals

Published: Apr 22, 2008

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