Current practices of craniospinal irradiation techniques in Turkey: a comprehensive dosimetric analysis

Craniospinal irradiation (CSI) is a common treatment technique used for medulloblastoma, brain tumors at risk of leptomeningeal spread, and some rare hematological malignancies. The traditional method of delivering CSI involves lateral opposed fields that cover the entire brain and are matched to one or more posterior fields to treat the spine [1]. However, this approach results in dose inhomogeneity, particularly at beam junctions, and exposes non-target tissues anterior to the spinal target volume to a substantial radiation dose. In recent years, technological advancements in radiotherapy have led to the use of modern irradiation techniques such as Intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), and Tomotherapy, which provide better dose sparing and reduce the high radiation dose to healthy tissues.

While these modern techniques increase the volume of the whole body receiving low doses, they also decrease the toxicity of both acute and late side effects by sparing organs at risk (OAR). This reduction in the dose to the intestines and lungs can minimize the frequency and severity of acute side effects such as mucositis, nausea, vomiting, diarrhea, and pneumonia [2].

However, long term toxicity is more of a concern and studies such as the CCSS, CVSS, and RISK register have shown an increased prevalence of cardiovascular diseases, metabolic diseases, and radiation-induced secondary tumors and hypothyroidism as late sequelae of initial irradiation in childhood [3, 4].

To address these challenges, modern irradiation techniques are used to achieve better dose sparing in OARs and more 3D-CRT application of radiation [5, 6]. Several optimization methods have been developed to improve the capabilities of these techniques [7‐9]. However, the available evidence regarding the benefits of these techniques remains unclear [10].

In Turkey, both, the conventional 3D-CRT Radiotherapy technique and modern radiotherapy techniques are used for CSI.

The objective of this study was to compare the dosimetric characteristics of various craniospinal radiotherapy techniques currently employed in Turkey in order to assess their advantages, disadvantages, and potential superiority. Our objective was to offer recommendations for minimizing user-based variations among centers that employ the same technique, as well as enhancing the achievable optimal dose distribution using the available resources at radiotherapy centers. To accomplish these objectives, we conducted a comparative analysis of the dose distribution among four craniospinal irradiation (CSI) techniques commonly used throughout the country. Additionally, we examined the variations in dosimetric parameters by comparing them with the proton therapy technique, which is currently unavailable in our country. The primary aim of this study was to enhance the effectiveness and safety of CSI treatment and provide clinicians with valuable recommendations for optimizing treatment plans.

For this study, we utilized CT scans from both an adult and a pediatric patient who had received treatment at the Acıbadem Altunizade Radiation Oncology clinic. These scans were employed to identify the target volume and critical organs of the patients. To ensure privacy, the CT scans were anonymized before being distributed in DICOM format to 25 different centers across the country. Additionally, the CT structures were shared with the Emory Proton Therapy center, situated in Atlanta, GA, renowned for its expertise in proton therapy for craniospinal irradiation treatment.

For the purpose of radiotherapy, the adult and pediatric CSI patients were positioned in a supine orientation and immobilized using a thermoplastic head-neck mask and a vacuum bag manufactured by Civco Medical Solutions in Kalona, IA, USA. The CT scans were obtained with a slice thickness of 3 mm.

The contouring of target volumes and OAR was conducted by an experienced radiation oncologist using CT images registered with MRI. The CTV included the whole brain, cranial nerves, and meninges, and was divided into two parts: CTV_brain and CTV_spine. The CTV_spine consisted of the spinal canal from the cerebrospinal fluid to the spinal ganglia, with the lower border being delineated at the caudal extension of the thecal sac.

The planning target volume (PTV) was composed of PTV_brain, PTV_spine, and PTV_total. PTV_brain and PTV_spine were generated with a 5 mm uniform margin around the CTV_brain and CTV_spine, respectively. PTV_total was created as the sum of PTV_brain and PTV_spine. The latest SIOPE guidelines were used to determine the target volume [11].

The organs at risk (OAR) considered in this study included the left and right lenses, left and right eyes, left and right parotid glands, thyroid, larynx, heart, left and right lungs, total lungs, esophagus, left and right kidneys, intestines, and stomach. ART-Plan (Therapanacea) artificial intelligence automatic contouring software was used for automatic segmentation of normal tissues were performed under the control of the physician and dosimetrist. Additionally, the normal tissue volume (NTV) was defined as the external contour of the body excluding the planning target volume (PTV_total). The delineation of the NTV was carried out using the ART-Plan software, and all contours were carefully reviewed and verified by the physician and dosimetrist to ensure precision and consistency.

The study encompassed multiple participating centers, each employing their individual irradiation techniques for treatment planning. The prescription dose for all plans was 36 Gy delivered in 20 fractions of 1.8 Gy. The study requested that at least 95% of PTV_total received 95% of the prescribed dose, while also minimizing dose to critical organs.

The centers utilized a variety of radiation techniques, including 3D-CRT, IMRT, VMAT, and Tomotherapy. The overseas proton center created the plans with the pencil beam scanning technology (Intensity Modulated Proton Therapy or IMPT) method.

The distribution of techniques employed by the 25 participating centers in the study is as follows: Among them, 7 centers preferred the 3D-CRT technique for pediatric patients, whereas 6 centers utilized it for adult patients. IMRT was the preferred technique for 4 centers in pediatric patients and 3 centers in adult patients. VMAT was employed by 9 centers for pediatric patients and 11 centers for adult patients. Additionally, 5 centers utilizing Tomotherapy employed the helical IMRT technique for both pediatric and adult patients. The planning DVH comparison results for pediatric and adult patients, obtained using the Proknow software, are presented in two distinct groups.

In our study conducted in Turkey, we discovered that the 3D-CRT technique remains widely utilized, despite the availability of advanced LINACS and treatment planning systems capable of implementing IMRT and VMAT techniques. Clinics with advanced technology still preferred the 3D-CRT technique due to its minimal low-dose bath volume. However, this preference for the 3D-CRT technique resulted in less homogeneous and lower coverage in the target volume, especially in the spinal region. Further examination of the best dose distribution plans using the 3D-CRT technique revealed the utilization of divergence-compatible angles and the moving junction technique. Additionally, incorporating Field in Field helped achieve a more homogeneous dose distribution in high-dose regions. In comparison to the 3D-CRT technique, advanced techniques such as IMRT, VMAT, and Tomotherapy demonstrated superiority in reducing doses to critical organs, except for the lungs and kidneys in terms of OAR doses. There have been several studies comparing craniospinal irradiation technics [7, 12, 13]. Sun et al.'s comparison of Helical Tomotherapy, IMRT, and VMAT in the treatment of CSI, have found that HT offers superior outcomes in terms of PTV conformity, PTV homogeneity, and critical OAR sparing [14].

We also conducted a comparison of proton treatment plans for both adult and pediatric patients at the proton center included in our research with the treatment plans of the four techniques commonly employed in our country. The results highlighted the superiority of proton treatment in maintaining target volume coverage and reducing doses to OAR as well as low dose area. The findings of our study unequivocally highlight the significant value associated with establishing a proton center in our country, particularly for pediatric patients. The importance of offering these opportunities to our patients in the forthcoming years becomes evident.

Separate analyses for adult and pediatric patients were conducted due to the heightened risk of secondary cancer and potential side effects in pediatric cases, underscoring the need to minimize normal tissue dose.

We conducted a comparative analysis of techniques between adult and pediatric patients to determine the approach yielding the lowest healthy tissue dose and to investigate whether center preferences vary based on the patient's age. Among the 11 centers employing the VMAT technique for adults, one used IMRT for pediatric patients, and another used the 3D-CRT.

The distinction in planning requirements between age groups prompted the use of different methods, highlighting the impact of age-specific factors on optimal treatment strategies. Due to the length of the spinal area, pediatric patients can be treated with a single spinal area, whereas in adult patients, two adjacent areas are needed, necessitating various methods employed by centers (such as moving junction, etc.) to compensate for dose distribution at the area junction.

In a study conducted by Seravalli et al. comparing different CSI techniques applied in various European countries, modern photon techniques were found to have superior spinal PTV conformity and homogeneity indices, with lower doses for thyroid, heart, esophagus, and pancreas than 3D-CRT technique. When proton technique was used, there was a more than 10 Gy dose reduction in parotid glands, thyroid, and pancreas compared to photon techniques. However, the study also reported wide dosimetric differences between centers using the same technique in proton applications [9]. Our study found that the 3D-CRT technique, although widely used in Turkey, has limitations in achieving optimal target coverage and dose homogeneity, particularly in the spinal region; this finding is consistent with previous studies that have reported the same limitations [14]. We observed that advanced techniques such as IMRT, VMAT, Tomotherapy, and Proton Therapy offer superior target coverage and dose homogeneity compared to the 3D-CRT technique. This finding is in line with the study by Seravalli et al. which reported that modern photon techniques offer superior spinal PTV conformity and homogeneity indices compared to the 3D-CRT technique, and proton therapy provides a significant dose reduction in critical organs compared to photon techniques [9]. While the dosimetric outcomes of this study favor proton therapy and tomotherapy, it's noteworthy that 3D-CRT techniques were the most preferred. However, it's important to highlight that there was a notable variation in maximum doses observed among centers employing similar 3D-CRT techniques.

Pollul et al. conducted a study comparing different VMAT techniques, namely partial arc, full arc, and avoidance sector, with 3D-CRT plans. The objective was to assess their effectiveness in reducing dose exposure to OARs such as the heart, thyroid, or gonads to minimize the likelihood of late complications. The results demonstrated that the Short Partial Arc VMAT_AVD technique successfully reduced dose exposure to radiosensitive OARs when compared to the 3D-CRT method, resulting in a lower probability of late complications [10]. In our own study, all centers employing the VMAT technique utilized the avoidance sector. While the VMAT technique achieved comparable target volume coverage in dose distributions, particularly in pediatric patients, it notably outperformed the 3D-CRT technique in reducing doses to OARs.

Furthermore, our study revealed that proton therapy provides excellent target coverage and low OAR doses compared to all four techniques used in our country. This finding is consistent with previous studies that have reported the superior dosimetric properties of proton therapy in reducing the dose to critical organs [15].

The risk of second primary cancers, particularly associated with high or very high radiation doses, is attributed to the repopulation of heavily irradiated tissues by surviving stem cells, some of which may have undergone malignant transformation due to radiation exposure [16]. While the exact mechanism remains elusive, various models have been proposed. Understanding these mechanisms is critical, especially for evaluating the risks tied to advanced radiation treatment methods like IMRT and VMAT. These techniques deliver high doses to the target volume while exposing relatively large volumes of healthy tissue to low to moderate doses [17]. Additionally, treatments employing protons or heavy ions instead of photons offer precise targeting of treatment volumes, thereby reducing healthy tissue exposure [18]. However, they may introduce other concerns, such as the production of secondary neutrons during treatment [18, 19].

Assessing how the risk of second primary cancers changes with radiation dose is a complex undertaking, primarily due to the diverse treatment protocols used over the years, including variations in fractionation and concurrent chemotherapy [16]. Notably, Dörr and Herrmann [20] discovered that nearly 60% of second cancers developed within tissues corresponding to the 'penumbra' of the initial radiotherapy volume, receiving a dose less than 6 Gy, while about 35% developed at doses between 10 and 30 Gy. Additionally, research has explored the interaction between cancer treatment and genetic mutations in DNA repair genes, providing insights into the risks associated with specific radiation doses and genetic profiles [21]. Their findings indicated that mutations in homologous recombination genes were significantly associated with an increased rate of second primary female breast cancer, particularly among survivors who had received chest doses greater than or equal to 20 Gy. Mutations in nucleotide excision repair genes were associated with second primary thyroid cancer among survivors who had received neck doses greater than or equal to 30 Gy [21]. The risk of second primary cancers following cumulative high radiation doses varies depending on the exposed tissue. Aside from a reduction in the risk of thyroid gland cancer, the risk of second primary solid cancers generally appears to increase linearly with an escalating cumulative tissue dose, particularly within a dose range of tens of gray [20].

Proton therapy has shown promising results in reducing the risk of secondary malignancy compared to photon techniques. This is because protons have a characteristic depth-dose distribution that allows for more precise targeting of the tumor volume while sparing the surrounding healthy tissues [22]. However, the use of proton therapy also requires careful consideration of the risks associated with secondary neutrons, which can contribute to the risk of secondary malignancy [23]. While Mirabell et al. proposed that proton beam therapy might play a role in substantially reducing secondary cancers among children and adolescents undergoing treatment, it's important to note that Upadhyay et al. suggested that the risks associated with secondary cancers could be comparable with both techniques [19, 22].

There is limited information available regarding the use of specific techniques in craniospinal irradiation (CSI) in low-income countries. However, Abdel-Wahab et al. analyzed the availability and accessibility of radiotherapy services in low- and middle-income countries (LMICs), where resources and infrastructure may be limited. The study provided a comprehensive analysis of the radiotherapy landscape in LMICs, the use of more advanced techniques such as IMRT or VMAT was limited due to the lack of necessary equipment and human resources [24]. Although our country falls into the middle-income category, over the last decade it has made significant progress in terms of radiation therapy equipment, with several centers equipped with state-of-the-art technology. We believe concerns over secondary cancers prompted a preference for 3D-CRT treatment techniques in clinics, however considering current research, we recommend centers equipped with modern technologies like IMRT and VMAT to adopt these techniques. The Dutch 3D study, an ongoing endeavor, encompasses 126 patients who have undergone craniospinal RT for CNS tumors, with a predominant focus on medulloblastoma (90 patients), as well as other histologies and treatment sites. This study aims to compile and standardize digital radiotherapy records from various multi-center resources, with the ultimate objective of enabling the future calculation of organ-specific radiation doses for childhood cancer survivors who received treatment during the 3D era [25]. Therefore, while 3D-CRT technique may have advantages in terms of reducing the volume of low dose bath, the use of advanced techniques such as IMRT, VMAT, and proton therapy can also reduce the risk of secondary malignancy by minimizing the dose to the surrounding normal tissues [22]. However, the risks associated with secondary neutrons in proton therapy should also be carefully considered when selecting the appropriate treatment modality for craniospinal radiotherapy. Clinicians should weigh the potential benefits and risks of each treatment option on a case-by-case basis, taking into account the patient's medical history, age, and other individual factors. Despite limitations, our study provides valuable insights into the current practice of craniospinal radiotherapy in Turkey and highlights the need for centralization of RT services to more experienced centers using advanced techniques.

In conclusion, our study suggests that advanced techniques such as IMRT, VMAT, and proton therapy offer superior target coverage and dose homogeneity compared to the 3D-CRT technique. Therefore, we recommend leveraging advanced technology to overcome the challenges in organizing field overlap areas and reducing OAR doses when devices that apply IMRT and VMAT techniques are available. Furthermore, establishing a proton center in our country is highly valuable, especially for pediatric patients, and provides excellent opportunities for reducing the dose to critical organs. Centralization of radiation therapy services to centers using advanced techniques with more expertise should be considered especially for pediatric patients undergoing CSI.