Benefit of dosimetry distribution for patients with multiple brain metastases from non-small cell lung cancer by a Cyberknife stereotactic radiosurgery (SRS) system

Abstract

Background: To achieve high precision in treating tumors and a steep dose fall-off in healthy tissues for brain metastasis stereotactic radiosurgery (SRS), this study investigated SRS planning optimization by comparing one multiple-lesions plan (MLP) with multiple single-lesion plans (SLPs) for patients with multiple brain metastases using the Cyberknife (CK) system.

Methods: Fifty non-small cell lung cancer (NSCLC) patients (28 males and 22 females) with 2-4 brain metastases, inter-tumour distances less than 3 cm, were retrospectively replanned with the original prescription dose (12-32 Gy) in the original fractions (1-3). Two different clinical CK SRS plans (SLPs and MLP) were generated for the same patients with the same collimator and prescription isodose line (62-68%) by the CK Multiplan System. Both SLPs and MLP were able to achieve >95% PTV volume covered prescription dose and met the Timmerman 2011 organs at risk (brainstem, optic nerve and pituitary) constraints.

Results: Compared with those in the SLPs, the maximum dose (D_max) and mean dose (D_mean) of brainstem in the MLP were reduced 0.22-3.13% (2.62%) and 2.71-12.56% (5.57%), respectively, all P<0.05. Meanwhile, the volumes of the whole brain minus the tumors that received a single dose equivalent of 8-16 Gy (V8Gy-V16Gy) were effectively reduced in the MLP. The treatment time parameters, the total number of beams and monitor units, of the MLP were reduced by 3.31% and 1.47% (P<0.05), respectively. Although there were a few differences in the conformity index (CI) and homogeneity index (HI) between the two treatment plans, the differences were not statistically significant (P = 2.94 and 1.08>0.05).

Conclusion: One multiple-lesions plan for brain metastases could achieve higher precision in the target and lower doses in healthy tissue while shortening the treatment time and improving the treatment efficiency over multiple single-lesion plans.

Background

Brain metastases develop in 20-40% of cancer patients, including 36-64% of patients with lung cancer, 15-25% of patients with breast cancer, and a few patients with melanoma, colorectal cancer and renal carcinoma [1, 2]. Clinical treatment options for patients with brain metastases include surgery, whole brain radiotherapy, and stereotactic radiosurgery (SRS) alone or in combination [3]. Although whole brain radiotherapy (WBRT) can improve the control rate of multiple brain metastases, it cannot prolong the overall survival of patients, and it increases the toxic side-effect risk in the patients’ nervous system [4-6]. However, SRS alone or combined with immunotherapy can guarantee a curative effect and avoid long-term adverse reactions to clinical treatment. Therefore, this combination has been recognized and accepted by an increasing number of clinical experts and patients, and it has gradually become the core protocol to treat multiple metastases.

The American National Comprehensive Cancer Network (NCCN) recommends SRS for patients with brain metastases that meet the following criteria: 1) tumour diameter <5 cm, 2) no more than 4 tumours, 3) co-application of surgery or WBRT, and 4) recurrence after SRS (6 months) [7]. Common SRS treatment equipment includes Gammaknife, Cyberknife (CK) and various kinds of linear accelerators [8, 9]. CK can be used to treat encephalic lesions by adapting orthogonal X-ray tubes to image the patient’s head in real time and performing radiotherapy of the lesions by positioning the CK after registering the patient’s skull images. Therefore, CK SRS can improve the dose delivered to the tumour and simultaneously reduce injury to the healthy brain tissue [10].

In addition to local control, remote control and overall survival rate, various nervous functional states and quality of life indicators should be the focus in brain metastasis treatment. CK SRS performs single large-segmentation radiotherapy for treating patients with multiple brain metastases. This easily results in a greater radiation dose absorbed by healthy brain tissue and organs at risk (OAR) adjacent to the tumours and increases the probability of clinical cerebral oedema, delayed intratumoral bleeding or brain necrosis [11, 12]. Therefore, effectively reducing the irradiation dose absorbed by normal brain tissue is essential for CK SRS treatment planning.

Single-lesion plans (SLPs), which are one-on-one treatments for SRS plans and tumours, are often used during CK SRS planning for patients with multiple metastases. Brain tissue around the gross tumour volume (GTV) receives high radiation dose in a short time, because CK SRS uses higher single dose and less fraction. Therefore, when the tumours are very close together (outer contour distance < 3 cm), the radiation dose delivered to the healthy brain tissue between tumours may be larger than the prescription dose and must be refocused in multiple plan composition. In this paper, we aimed to develop a multiple-lesions plan (MLP) that used only one plan for the treatment of multiple brain metastases. Retrospective analysis and evaluation were performed on the quality, efficiency and differences of dose distribution between CK SRS SLPs and MLP for 50 non-small cell lung cancer (NSCLC) patients with multiple metastases in the CK centre of Tianjin Medical University Cancer Hospital to provide a reference basis for the clinical design of CK SRS treatment plans.

Methods

Patients and simulation

Table 1. 50 Patient characteristics

From January 2016 to June 2019, 50 patients with 2-4 brain metastases, inter-tumour distances less than 3 cm, received the same prescription dose in the same fractions as image-guided SRS using the CK system (Cyberknife III, Accuray Inc., Sunnyvale, CA) for brain metastasis at Tianjin Medical University Cancer Institute and Hospital. All patients participating in this study had no metastases to other organs and did not undergo pre-CK SRS metastasectomy or pre- or concurrent-to-CK SRS WBRT. Twenty-six patients had KPS<70, and all patients were in RTOG-RPA class 2 or 3. This report performed a head-to-head, quantitative comparison of dosimetry profiles between the different treatment plans for 114 brain metastases lesions developed by the Multiplan system (Accuray, Sunnyvale, CA, USA) software program. The outlines of the lesions were based on computed tomography (CT) and enhanced T1-weighted magnetic resonance imaging (MRI) fusion. Table 1 shows the patient characteristics.

An overall skull CT scan for the patients was performed by a Philips Brilliance Big Bore CT device (16 rows) with a scan layer thickness of 1.5 mm. The images obtained from T1-weighted magnetic resonance imaging scans obtained with a Siemens 1.5 T device were registered to the CT images. CT and MR images were used to delineate the gross tumour volume (GTV) and organs at risk (OARs), including the brainstem, eyes, lenses, optic nerves, optic chiasm, and pituitary gland. The targeting error of the brain CK SRS under skull tracking is 0.956 mm, and a 1.6-mm margin was added to the GTV to create the plan tumour volume (PTV), except for patients with brainstem metastasis.

CK SRS treatment planning

Brain metastases that were close to each other and required the same prescription radiation dose and fractions could be planned together. Five dose-limiting shells (2 mm, 3 mm, 5 mm, 7 mm, 9 mm) were placed away from each PTV to optimize the dose distribution to the healthy brain tissues. Based on the delineation results and requirements, the planner conducted the design and optimization of the CK SRS plans by adapting the existing plans through the CK Multiplan system. Two different treatment plans were designed for every patient, including multiple SLPs (one plan to one PTV) and MLP (one plan for all PTVs). When SLPs were used to treat the patients, the different treatment plans for the different lesions were executed by sequential single-plan therapy. The same collimator and prescription isodose (65-70%) were adopted during plan designing for the same patient without the iris or MLC system to ensure consistency of the beam data in the plans. A high-resolution calculation was performed in the evaluation step to finalize the CK SRS plans. All the plans were able to meet >95% coverage of the PTV with the prescription dose and the Timmerman 2011 OAR (brainstem, optic nerves and pituitary) constraints [13]. The radiotherapy path was forbidden to pass through the patient’s lens in the CK SRS plans so the maximum dose for the lens was <1 Gy.

Data analysis

The same patient’s SLPs, with the same prescription dose and the same fractions, were fused and evaluated by the plan QA functional component (Reference Plan) in the Cyberknife Multiplan system. The dosimetry distribution in the metastatic tumours, normal brain tissue and OAR were compared between MLP and SLPs for each patient. The conformity index (CI) represents an objective measure of how well the distribution of radiation follows the shape of the PTV and is calculated as follows:

CI = PIV/TIV (1)

where PIV is the volume included by the prescription isodose, and TIV is the tumour volume covered by the prescription isodose. This definition of CI is different than the radiation therapy oncology group (RTOG) definition, which is PIV divided by total tumour volume [14]. The closer the value of the CI is to 1, the better the plan.

To quantify the difference in the dose parameter, the values of the minimum dose (D_min), maximum dose (D_max) and covering mean dose (D_mean) for the healthy brain tissue and OAR were expressed as a percentage of the global maximum dose in the plans. Their reduction is calculated as follows:

R = (Data_SLP - Data_MLP)/Data_MLP (2)

where Data_SLP and Data_MLP represent the values in the SLPs and MLP, respectively.

Furthermore, the volumes of the whole brain minus the PTVs received a single dose equivalent of 4 to 16 Gy (V4Gy-V16Gy) and were evaluated by assuming an α/β ratio of 2.0 to the brain tissue with iLQ (V4.0) [15]. The total number of beam and monitor units (MUs) were compared.

All statistical analyses were performed with SPSS (Statistical Product and Service Solutions for Statistical Computing, IBM, USA, version 19.0). Data from different plans were compared with a two-sided paired t test. A P-value <0.05 was considered statistically significant.

Results

Figure 1 shown the dosimetry distribution of the MLP versus the SLPs for the same patient with two brain metastases. The results indicate that the radiation around the PTV was more widespread or the SLPs; for example, the 40% isodose (purple line) was included in the PTV+6 contour in the MLP (as shown in Figure 1(B)) but not in the SLPs (as shown in Figure 1(C)). While the OAR (brainstem) were very well protected and were characterized as less irradiated areas, the 10% isodose did not appear in the brainstem from the MLP. These results indicate that using an MLP for patients with multiple brain metastases could significantly reduce the dose distribution in healthy brain tissue and OAR.

To quantify the difference in dosimetry distribution between the two plans, statistical analysis was carried out on the CK SRS plans for the 50 patients, as shown in Table 2. The values of D_min, D_max and D_mean are expressed as percentages of the global maximum dose in the plans. Compared with those in the SLPs, in the MLP, the dose in PTV+6 significantly decreased, the D_max value dropped 0.29-1.91%, the D_mean value decreased 1.89-2.58%, and the D_min value dropped 4.35-8.98%. The dose parameters of the OAR are shown in Table 2. MLP decreased the radiation dose in the OAR with respect to the dose from the SLPs; specifically, the D_max, and D_mean value of the brainstem decreased by 0.22-3.13% and 2.71-12.56%, respectively. Thus, using an MLP for treating patients with multiple brain metastases could reduce the risk of symptomatic radiation-induced injury in healthy brain tissue and OAR.

Table 2 Dosimetric distribution of PTV+6 and OAR in CK SRS SLP and MLP for 50 patient

*PTV+6 was 6-mm-thick zones of healthy brain tissue adjacent the PTVs, D_Max, D_mean and D_Min were maximum dose, mean dose and minimum dose, expressed as percent of the global maximum dose in plans. 

Table 3. Indexes of 50 patient CK SRS plans

The statistical results for V4Gy-V16Gy were shown in Figure 2. Although there was no obvious difference for V4Gy and V6Gy, compared with those in the SLPs, the V8Gy-V16Gy values showed a marked decrease in the MLP. This finding provides more evidence for the theory that using an MLP could protect healthy brain tissue better than multiple SLPs while satisfying the need for clinical treatment.

Table 3 compares the CK SRS plan parameters. The conformity index (CI) and homogeneity index (HI) values of the two different plans were similar, showing no significant difference. This result indicated that either the SLPs or the MLP could yield desirable curative effects for the PTV getting prescription dose homogeneously of the patients clinically. However, the total number of beam and monitor units (MUs) were lower in the MLP, with average decreases of 4.63% and 0.56%, respectively. Radiotherapy linear accelerator is carried to different beam paths by the manipulator and outputs prescription dose (through MUs). Therefore, the execution time (including moving time and output time) of the MLP was apparently less than that of the SLPs during multiple brain metastases patients treatment by CK SRS.

Discussion

With the improvement of medical technology and increasingly prolonged lifespans of cancer patients, brain metastasis has become an important clinical manifestation for late cancer patients. Some researchers have shown that approximately 80% of patients with brain metastases could have 1-3 metastatic tumours simultaneously [16]. At present, treatment methods for brain metastatic tumours mainly include surgery, WBRT, SRS, etc. [17]. Chang et al. believe that compared with WBRT, SRS could increase the local control rate of intracranial tumours, avoid the occurrence of long-term nerve cognitive disorder and improve patients’ quality of life [18]. Rades Dirk et al. performed a retrospective comparison and analysis on patients with brain metastases treated by SRS or WBRT (number of tumours<3 and tumour diameter<4 cm), and the results showed that the median survival and one-year

local control rate in the SRS group were superior to those in the WBRT group [19, 20]. Chung C et al. indicated that 68% of radiation oncologists believed 1-3 brain metastases were ideal quantities to be treated with stereotactic radioactive surgery (SRS) [21]. Murovic Judith et al. performed a comparison and analysis on patients with 1-3 brain metastases and on the curative effect for patients with more than 4 brain metastases who only received CK SRS. The results showed that the mean overall survival (OS) for both was 13 months, with no significant difference; therefore, CK radiosurgery could effectively control patients with brain metastases [22].

For the treatment of multiple brain metastases, CK SRS can effectively shorten the treatment cycle and duration. As a result, severe radiation damage in the clinic can be avoided. Additionally, the local control rate of patients’ lesions can be improved. In this study, analytical research was performed on 50 patients with multiple brain metastases treated by SLPs and an MLP from the CK SRS system. The results showed that the MLP could ensure that the prescription dose covered the PTV, effectively reducing the dose distribution to healthy brain tissue and OAR. The CI and HI value of the SLPs and MLP for the same patient were similar, showing no significant differences. Thus, these two different plans could lead to a relatively ideal dose distribution for the PTV. Radiotherapy with an MLP for patients with multiple brain metastases can reduce the radiation doses delivered to the healthy brain tissue between tumors, especially functional areas. This was an effective way to improve the well-being and overall health of patients after radiotherapy. Furthermore, because the robot arm controlling in CK system must move to each beam during radiotherapy, when the exposure interval for the target location was set, the number of total beam number and total monitor units would determine the treatment time in the Cyberknife G3 system. Compared with the SLPs, the MLP with fewer treatment beam and total monitor units could effectively shorten the treatment time. Therefore, the MLP, shortened treatment time and lower treatment costs, could be used for good clinical treatment of patients with multiple brain metastases by CK SRS.

It is worth noting that a multiple collimator ( ≤ 3 collimators) combination is needed to realize the MLP for CK SRS treatment when the patient has different sizes and volumes of metastatic lesions. However, a technician is needed to change the collimators when a third generation or lower version of the CK system (G3) is used to implement clinical treatment, which can cause certain complications and extend the treatment time. Therefore, both the convenience and safety of clinical operation should be comprehensively considered during CK SRS planning.

In summary, when CK SRS is used for the clinical treatment of patients with multiple brain metastases, adopting an MLP can ensure dose distributions and curative effects, effectively reducing radiation injury to the patient’s normal brain tissue and OAR and shortening the duration of clinical treatment. CK SRS plans are designed for patients with multiple brain metastases, and dose distributions and clinical treatment time should be fully considered. However, the clinical curative effects for both plan designs must be further discussed by collecting and tracing more cases to establish a reliable clinical database, providing a more significant reference for the implementation of treatment.

Conclusion

The results of this study demonstrated that the multiple-lesions-plan (MLP), with a lower total number of beam and monitor units, significantly reduced radiation injury outside the tumours relative to the SLPs. The resultant maximum dose (D_max) and mean dose (D_mean) value of the OAR (brainstem) in the MLP were significantly lowered. Only one multiple-lesions plan is needed to meet the needs of SRS treatment for multiple brain metastases, deliver a large dose to the tumour and minimize the amount of radiation delivered to healthy tissues.

Declarations

Ethics approval and consent to participate Patients gave verbal informed consent to participate at time of diagnosis and the ethics committee at Tianjin Tumor Hospital approved this procedure (Ek2019037). Patients were informed that they had the opportunity to opt-out if they were not willing to participate in the study.

Consent for publication

Not applicable.

Availability of data and materials

The data-sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

Postdoctoral Research Foundation of China (CN) (No.2019M661039) and Research Project of Tianjin Medical University Cancer Institute and Hospital (No.1903) provided financial support for this study and participated in the design, study conduct, analysis, and interpretation of the data as well as the writing, review, and approval of this manuscript.

Authors’ contributions

Study concept and design: YXY, WP. Acquisition, analysis, or interpretation of data: WYW. Drafting of the manuscript: YXY, YH. Critical revision of the manuscript for important intellectual content: ZLJ, YZY. Statistical analysis: WYW SYC. Obtained funding: YXY, WP. Administrative, technical, or material support: YZY. Study supervision: ZLJ. All authors read and approved the final manuscript.

Acknowledgments

The authors acknowledge the American Journal Experts (AJE) company for the English polishing service of this paper

Abbreviations

References

[1] Casanova N, Mazouni Z, Bieri S, Combescure C, Pica A and Weber DC. Whole brain radiotherapy with a conformational external beam radiation boost for lung cancer patients with 1-3 brain metastasis: a multi institutional study. Radiation Oncology 2010; 5: 13-13.

[2] Nieder C, Spanne O, Mehta MP, Grosu AL and Geinitz H. Presentation, patterns of care, and survival in patients with brain metastases: what has changed in the last 20 years? Cancer 2011; 117: 2505-2512.

[3] Moore A, Cohen-Naftaly M, Tobar A, Kundel Y, Benjaminov O, Braun M, Issachar A, Mor E, Sarfaty M and Bragilovski D. Stereotactic body radiation therapy (SBRT) for definitive treatment and as a bridge to liver transplantation in early stage inoperable Hepatocellular carcinoma. Radiation Oncology 2017; 12: 163.

[4] Tian J, Luo Y, Xiang J and Tang J. Combined treatment for non-small cell lung cancer and breast cancer patients with brain metastases with whole brain radiotherapy and temozolomide: a systematic review and meta-analysis. J Neurooncol 2017; 1-11.

[5] Khan M, Lin J, Liao G, Li R, Wang B, Xie G, Zheng J and Yuan Y. Comparison of WBRT alone, SRS alone, and their combination in the treatment of one or more brain metastases: Review and meta-analysis. Tumour Biol 2017; 39: 1010428317702903.

[6] Lamba N, Muskens IS, Dirisio AC, Meijer L, Briceno V, Edrees H, Aslam B, Minhas S, Verhoeff JJC and Kleynen CE. Stereotactic radiosurgery versus whole-brain radiotherapy after intracranial metastasis resection: a systematic review and meta-analysis. Radiation Oncology 2017; 12: 106.

[7] Schulten HJ, Bangash M, Karim S, Dallol A, Hussein D, Merdad A, Al-Thoubaity FK, Al-Maghrabi J, Jamal A and Al-Ghamdi F. Comprehensive molecular biomarker identification in breast cancer brain metastases. Journal of Translational Medicine 2017; 15: 269.

[8] Zhang I, Antone J, Li J, Saha S, Riegel AC, Vijeh L, Lauritano J, Marrero M, Salas S and Schulder M. Hippocampal-sparing and target volume coverage in treating 3 to 10 brain metastases: A comparison of Gamma Knife, single-isocenter VMAT, CyberKnife, and TomoTherapy stereotactic radiosurgery. Practical Radiation Oncology 2017; 7: 183.

[9] Murovic J, Ding V, Han SS, Adler JR and Chang SD. Impact of CyberKnife Radiosurgery on Overall Survival and Various Parameters of Patients with 1-3 versus ≥ 4 Brain Metastases. Cureus 2017; 9:

[10] Eriksson EA, Barletta JF, Figueroa BE, Bonnell BW, Sloffer CA, Vanderkolk WE, Mcallen KJ and Mickey O. The first 72 hours of brain tissue oxygenation predicts patient survival with traumatic brain injury. Journal of Trauma & Acute Care Surgery 2012; 72: 1345-1349.

[11] Inoue HK, Ken-Ichi S, Akihiko N, Kota T, Yoshiyuki S, Jun-Ichi S, Shin-Ei N and Takashi N. Three-fraction CyberKnife radiotherapy for brain metastases in critical areas: referring to the risk evaluating radiation necrosis and the surrounding brain volumes circumscribed with a single dose equivalence of 14 Gy (V14). Journal of Radiation Research,54,4(2013-2-11) 2013; 54: 727-735.

[12] Greto D, Pallotta S, Masi L, Talamonti C, Marrazzo L, Doro R, Saieva C, Scoccianti S, Desideri I and Livi L. A dosimetric comparison between CyberKnife and tomotherapy treatment plans for single brain metastasis. La Radiologia Medica 2017; 122: 392-397.

[13] Mchaffie DR, Pierre C, Anne D, Suh JH, Marie-Andrée F, Eric C, Robert T, Luis S, John G and Abdenour N. Safety and feasibility of motexafin gadolinium administration with whole brain radiation therapy and stereotactic radiosurgery boost in the treatment of ≤ 6 brain metastases: a multi-institutional phase II trial. Journal of Neuro-Oncology 2011; 105: 301-308.

[14] Treuer H, Hoevels M, Luyken K, Visservandewalle V, Wirths J, Kocher M and Ruge M. Intracranial stereotactic radiosurgery with an adapted linear accelerator vs. robotic radiosurgery : Comparison of dosimetric treatment plan quality. Strahlentherapie und Onkologie 2015; 191: 470-476.

[15] Gharib A, ., Balende C, ., Sarda N, ., Weissmann D, ., Plenevaux A, ., Luxen A, ., Bobillier P, . and Pujol JF. Biochemical and autoradiographic measurements of brain serotonin synthesis rate in the freely moving rat: a reexamination of the alpha-methyl-L-tryptophan method. Journal of Neurochemistry 2010; 72: 2593-2600.

[16] Rodrigues G, Warner A, Bauman G, Senan S and Lagerwaard F. Systematic review of fractionated brain metastases radiotherapy. Journal of Radiation Oncology 2012; 3: 29-41.

[17] Soffietti R, Abacioglu U, Baumert B, Combs SE, Kinhult S, Kros JM, Marosi C, Metellus P, Radbruch A and Villa Freixa SS. Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO). Neuro Oncol 2017; 19: 162-174.

[18] Chang JE, H Ian R and Mehta MP. Therapeutic advances in the treatment of brain metastases. Clinical Advances in Hematology & Oncology H & O 2007; 5: 54.

[19] Robins HI, O'Neill A, Mehta M and Grossman S. A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT & SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320: in regard to Sperduto e. International Journal of Radiation Oncology Biology Physics 2013; 86: 809-810.

[20] Rades D, Kueter JD, Hornung D, Veninga T, Hanssens P, Schild SE and Dunst J. Comparison of stereotactic radiosurgery (SRS) alone and whole brain radiotherapy (WBRT) plus a stereotactic boost (WBRT + SRS) for one to three brain metastases. Strahlentherapie Und Onkologie 2008; 184: 655-662.

[21] Chung C and Lutz S. Conventional radiation therapy for brain metastases. Journal of Radiation Oncology 2012; 1: 211-219.

[22] Murovic J, Ding V, Han SS, Adler JR and Chang SD. Impact of CyberKnife Radiosurgery on Median Overall Survival of Various Parameters in Patients with 1-12 Brain Metastases. Cureus 2017; 9: