CyberKnife = Significantly Better Cervical Cancer Treatment

by | Jan 19, 2025 | Cervical Cancer Treatment

Stereotactic Body Radiotherapy Boost with the CyberKnife for Locally Advanced Cervical Cancer: Dosimetric Analysis and Potential Clinical Benefits:

This is a very scientific study. It’s hard to understand when reading it unless you are a scientist, or a doctor who can understand it. There is a link at the bottom of this blog which you can click on and see the full study, with graphics.

If you are diagnosed with cervical cancer talk to your doctor about CyberKnife therapy, or better yet, call a CyberKnife center near you to find out if you are a candidate for this effective, safe treatment, which causes the least disruption to your life.

Here is the Conclusion: Consistent with previous studies, CK-CTV plans can produce significantly better target coverage, OAR sparing, and radiobiological effects compared to BT plans. When the target volume is less than 56.50 cm3 , CK-PTV plans with a 5 mm PTV margin can achieve a dose distribution comparable to that of BT plans. CK-based SBRT could be an effective alternative to BT for patients with LACC. With improved precision of target localization, a reduced PTV margin might increase the eligibility of patients with large tumors. Further clinical investigation to provide a higher level of evidence of the efficacy of a CK-based SBRT boost is needed.

Simple Summary: The recommended treatment for locally advanced cervical cancer (LACC) consists of chemoradiotherapy (CRT) followed by brachytherapy (BT). Although BT is considered a minimally invasive procedure, patients still suffer severe discomfort from it and risk uterine perforation. Dosimetric uncertainties are often inevitable due to anatomical variations and inconsistencies in applicator loadings. These issues prompted us to explore the use of stereotactic body radiotherapy (SBRT) as a viable alternative. It has been well described that the CyberKnife (CK), a robotic image-guided SBRT delivery system, is capable of producing rapidly fall-off dose gradients with submillimeter accuracy. The aim of this study was to compare the dose distributions and radiobiological effects of a CK-based SBRT boost and a BT boost. We found a tumor volume threshold target, below which the CK-based SBRT plan could result in significantly better target coverage, OAR sparing and radiobiological effects compared to the BT plan. With improved precision of target localization, a reduced PTV margin might increase the eligibility of patients to receive a CK-based SBRT boost after CRT, rather than BT. CK-based SBRT could be an alternative option for patients who are not candidate for BT.

Abstract: (1) Aim: To compare the treatment plans of stereotactic body radiotherapy (SBRT) with CyberKnife (CK) and high-dose-rate (HDR) intracavitary/interstitial brachytherapy (IC/ISBT) and examine the feasibility of CK-SBRT as a viable alternative to BT in patients with locally advanced cervical cancer (LACC). (2) Methods: A BT plan of 28 Gy in four fractions delivered previously to 20 patients with LACC was compared with a CK plan based on the same CT images with structures delineation for BT. The SBRT treatment plan was further divided according to two different approaches, with the high-risk planning target volume (HR-PTV) defined by the high-risk clinical target volume (HR-CTV) without and with a 5 mm margin, which were named CK-CTV plan and CK-PTV plan, respectively. The dose distributions and dosimetric parameters of the target volumes and organs at risk (OARs) were recorded and compared for the three boost plans. Radiobiological metrics were calculated based on the EUD for the hybrid plans. Additionally, the relationship between tumor volume and tolerance doses for the OARs in the BT plan and CK-PTV plan was investigated. (3) Results: Target coverage was better with the CK plan than with the BT plan, as the D95%, D98%, HI and CI of the CK-CTV plan and CK-PTV plan were higher than those of the BT plan; an exception was the D50%. Similarly, the TCP of the target was also significantly in favor of the CK hybrid plans (p < 0.01). For the OARs, the CK-CTV plan was superior to the BT plan as regards the rectum D2cc, bladder D2cc and bladder Dmax. The CK-PTV plan could achieve dosimetric parameters comparable to those of the BT plan for OARs concerning the small residual tumor volume.

The NTCP of the rectum for the WPI+CK-CTV plans was significantly lower than that of the WPI+BT plans (p < 0.01). (4) Conclusions: CK-based SBRT can achieve better target coverage, dose sparing for the OARs and radiobiological effects compared with the BT plan for tumors that are not excessively large. CK-based SBRT could be an alternative option to administer a radiation boost for patients with LACC.

Introduction: Cervical cancer is the fourth frequent malignancy in women globally and remains a leading cause of cancer death in developing countries. Approximately 604,000 new cases of cervical carcinoma were diagnosed worldwide and 342,000 people died of the disease in 2020 [1]. External beam radiotherapy (EBRT) with concomitant chemotherapy followed by brachytherapy (BT) is the recommended treatment of choice for locally advanced cervical cancer (LACC) [2]. With the demonstrated improvement in clinical outcomes, BT is a crucial component in the management of LACC [3]. However, the use of BT has progressively declined since the early 2000s due to the rapid development of high-precision EBRT [4–6]. In certain circumstances, the practicability of BT is compromised because of unfavorable anatomy, medical comorbidities and patient refusal to receive the procedure. Furthermore, BT is operator-dependent, and radiation centers with a low treatment volume tend to pursue alternative EBRT boost modalities [5,6]. Previously published studies concluded that the clinical outcomes were adequately admissible to consider an EBRT boost if patients could not undergo brachytherapy [7,8]. With the advent of radiation delivery and image-guiding techniques, stereotactic body radiotherapy (SBRT) can now deliver a substantially higher dose to defined target volumes and effectively protect organs at risk (OARs). In addition, compared with other EBRT boost techniques, a higher biologically equivalent dose can be achieved by SBRT [9]. Earlier studies indicated that SBRT could be similar to BT in clinical outcomes and minimal toxicities for patients with cervical cancer [10–13]. In a propensity-matched analysis based on the National Cancer Database, those who underwent the SBRT boost had equal overall survival rates when compared with patients who received the BT one [14], which indicates that SBRT is a promising alternative for patients who are not candidates for BT. The CyberKnife (CK), a robotic-based SBRT delivery system, enables the target volumes to be irradiated preeminently and produces rapid fall-off dose gradients, with submillimeter accuracy. The prescribed doses for linac-based SBRT in LACC treatment mostly remained below the recommended biologically equivalent doses of 2 Gy per fraction (EQD2) of at least 85 Gy [7], whereas the CK-based therapy could closely mimic the dose distribution of BT [11,15]. Moreover, radiobiological metrics such as tumor control probability (TCP) and normal tissue complication probability (NTCP) can be assessed and provide a more robust comparison of the efficacy of different radiotherapy modalities. However, there is very little information in the current literature regarding plan quality and the radiobiological effects of a CK-based SBRT boost in LACC patients compared with BT. Given the challenges of administering BT and the benefits of CK-based SBRT, this study aimed to further investigate the dosimetric and radiobiological feasibility of SBRT with CK as an alternative to BT for patients with LACC.

Discussion: Cervical cancer is one of the most prevalent cancers among females worldwide [23]. A combination of chemoradiotherapy and a BT boost is the standard of care for patients with LACC [24]. Although BT is considered a minimally invasive procedure, patients may suffer from vaginal pain, uterine perforation and anesthesia-associated risks [25]. Conversely, if patients are treated with SBRT, these risks could in principle be eliminated, with the added benefits of comfort and a shorter treatment time. Meanwhile, the SBRT allows a higher degree of dose control and a precise dose delivery to the cervical tumor volume, sparing the normal organs, compared to conventional radiation delivery methods. Therefore, many studies attempted to use SBRT to achieve a boost dose distribution similar to that of BT plans. Previously published results showed that SBRT could provide a potential alternative to boost cervical carcinomas when BT is not performed [15,26,27]. Moreover, Guerrero et al. suggested that SIB-IMRT was radiobiologically feasible for LACC patients who cannot undergo BT [28]. Unlike their study, our study not only presents a dosimetric comparison but also shows the achievement of the expected clinical outcome based on TCP and NTCP. Earlier research demonstrated that a poor target coverage during radiation therapy is closely related to an increased risk of local and probably distant recurrence [29,30]. Our study indicates a consistent superiority of CK-based SBRT as a boost compared with BT in regard to target volume coverage and OAR sparing, and these results are similar to those previously published [11,26,31]. D90% is considered the essential parameter for HRCTV [32], but D98% seems to be a better predictor of local control rates [33]. In our study, the CK-CTV plan showed statistically significant differences in the D98% and D95% when compared to the BT plan. D98% and D95% in the CK-CTV plan were higher than in the BT plan, while D50% was on average 22.8% less than in the BT plan. That is to say that the results regarding the higher isodose volume outperformed those for the lower isodose volume. These findings are in line with the results of Malhotra et al. [34]. A study by Morgenthaler et al. [15] reported that the D90% and V100 in the target volume were almost optimal when the boost was delivered by robotic radiosurgery. We also found that the EUD and TCP of the target volume for the WPI+CK-CTV plans were higher than those of the WPI+BT plans (p < 0.001). Additionally, the target volume coverage in the CK-PTV plan was superior compares to that of the BT plan in our study. With regard to plan quality, CK improved the dose homogeneity in the target volume. Our study showed that the HI and CI were also better with the CK-CTV plan and CK-PTV plan compared to the BT plan. The reason might be the geometrical variation and uncertainty of implantation in BT and, especially, the nature of the radiation from the BT source, resulting in a hot spot, a heterogeneous distribution and a suboptimal conformation of the prescribed dose. The position of the cervix changes appreciably during the course of radiotherapy for cervical cancer. Previous studies examined the mean maximal inter-fractional movement of the cervix in the superior–inferior, anterior–posterior and right–left lateral dimensions and reported values of 2.1, 1.6 and 0.82 cm, respectively [35]. Moreover, cervix displacements Cancers 2022, 14, 5166 11 of 14 greater than 1.5 cm occurred in intra-fractional radiation treatments [36]. Given organ motion and the uncertainties of the setup, HR-PTV was obtained from HR-CTV by a 5 mm margin in the CK-PTV plan in our study. It is notable that the CK-CTV plan was superior to the BT plan as regards rectum D2cc (p = 0.019), bladder D2cc (p = 0.007) and bladder Dmax (p = 0.003) in our study. In addition, the EUD and NTCP values for the rectum were significantly lower in the WPI+CK-CTV plans (p < 0.001). For the bladder, the EUD and NTCP were comparable between the WPI+CK-CTV and WPI+BT plans. Cengiz et al. [11] compared the dose distribution characteristics in SBRT plans generated by a CK and in HDR BT plans for 11 patients with cervical cancer. No margin was added around the CTV to construct the PTV in the SBRT plans. Their study revealed distinct advantages in terms of target coverage and dose distributions to the surrounding normal tissues in SBRT plans, except for the bone marrow. The results are similar to ours with the CK-CTV plans. When the range of tumor motion is large, the internal target volume may be large, and this could cause increased the treatment toxicity [37]. However, the CK can achieve a submillimeter dose delivery with high precision, as tumor motion is tracked in real time using image guidance with different tracking system [38,39]. Hadi et al. assessed the feasibility of an MR-guided SBRT boost modality in patients who were ineligible for BT. Online-adaptive treatment planning was conducted to adjust the tumor volumes derived from daily anatomy [17]. If cervix motion is monitored or modified, it means that the margin of HR-PTV can be reduced. Hence, in order to minimize the margin of HR-PTV, it is suggested that adaptive radiotherapy planning be generated for each SBRT fraction, and real-time tracking and correction of cervix and tumor displacement be implemented. Such approach may result in a decrease in the volume of normal tissues exposed to the low-dose region, thereby reducing the late toxicity. Accordingly, dose distributions to the adjacent organs in a CK plan may be better than in a BT plan. As has been previously revealed, the cervical tumor size is a critical independent prognostic factor for local control and pelvic recurrences after irradiation [40,41]. Promising clinical outcomes were reported by Mantz et al. [42], using a stereotactic ablative radiotherapy (SABR) boost in gross tumor volume (GTV) in 55 patients with FIGO stage IB–IIB cervical cancer. No grade 3 or greater late toxicities were observed, but this GTV-only modality needs to be further investigated. Albuquerque et al. [43] carried out a phase II trial of SABR as a boost for LACC, but the trial was closed due to severe toxicity concerns. The high rate of toxicity may be associated with the fact that large tumors were treated in this study. What accounts for late high-grade toxicity is the increased radiation exposure to OARs in the presence of bulky tumors. If the OARs are close to the PTV, the doses to the OARs may increase with a rise in the PTV [44]. Gultekin et al. retrospectively evaluated the oncological outcomes of an SBRT boost in 21 patients with cervical cancer. They found that while the 2-year LC rate was 75% in patients with residual tumor size < 4 cm, it was 50% when there was ≥4 cm residual tumor after definitive chemoradiotherapy (p < 0.001) [45]. It is suggested that a certain threshold of tumor size in patients with cervical cancer should be considered for eligibility to receive an SBRT boost. According to the size of the patient’s tumor, we arranged all dosimetric parameters in regard to the OARs and investigated the relationship between the tumor volume and OARs tolerance in the BT and CK-PTV plans. For the cohort of our study, when the tumor volume was less than 56.50 cm3 , there was no statistical difference between the BT and the CK-PTV plans in all dosimetric parameters in relation to the OARs. This indicated that for patients with a target volume less than 56.50 cm3 , lower OARs toxicity might be achieved with a CK boost. Systemic clinical trials are necessary for to provide a rigorous proof. The main limitation of this study is that CT images with applicators were used to generate the CK plans, which is not in line with the actual treatment situation by CK. The applicators are not expected to be used in clinical treatments using the CK. The shape and location of the tumor will be affected during the implantation of the applicators. In a proposed future prospective study, a CT simulation without applicators will be performed after patients have received the last EBRT fraction. However, by the principle of physics, it Cancers 2022, 14, 5166 12 of 14 is anticipated that the results of this study should hold true when no implanted applicators are in use.

Conclusions: Consistent with previous studies, CK-CTV plans can produce significantly better target coverage, OAR sparing, and radiobiological effects compared to BT plans. When the target volume is less than 56.50 cm3 , CK-PTV plans with a 5 mm PTV margin can achieve a dose distribution comparable to that of BT plans. CK-based SBRT could be an effective alternative to BT for patients with LACC. With improved precision of target localization, a reduced PTV margin might increase the eligibility of patients with large tumors.  Further clinical investigation to provide a higher level of evidence of the efficacy of a CK-based SBRT boost is needed.

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