Ways to unravel the clinical potential of carbon ions for head and neck cancer reirradiation: dosimetric comparison and local failure pattern analysis as part of the prospective randomized CARE trial

Carbon ion radiotherapy (CIRT) yields well-known biophysical advantages [1] compared to photons yet what are key clinical benefits and potential pitfalls for patients with recurrent head and neck cancer? Although recent studies reported excellent outcomes with CIRT in various recurrent tumor sites [2], high-level evidence of clinical superiority is pending. Besides careful patient selection, the complex reirradiation setting requires a high-precision approach to enhance the balance of tumor control and toxicity. Therefore, the randomized controlled CARE trial [3], comparing CIRT with volumetric modulated arc therapy (VMAT) for reirradiation of head and neck cancer, was recently initiated.

Building on previous photon reirradiation studies [4, 5], modern conformal radiation techniques such as stereotactic body radiation therapy improved outcomes primarily in early-stage recurrent tumors [6]. In reality, most inoperable recurrences are locally advanced and target volume delineation is further impeded by tissue changes from previous treatments, making VMAT the standard of care [7]. Both proton [8] and in particular carbon ion reirradiation [9, 10] could further enhance dose escalation while reducing normal tissue complication probabilities. However, sophisticated radiobiological models [11] are required to calculate the relative biological effectiveness (RBE)-weighted dose of carbon ions for different tissues, treatment parameters and endpoints. Biological dose calculation based on the local effect model [12, 13] (LEM) I depends primarily on the clinical α/β value from the linear quadratic model, the absorbed dose and the underlying complex mixed radiation field of carbon ions to predict the local RBE. More recent RBE-models, in particular the modified microdosimetric kinetic model [14] (mMKM), revealed trends towards superior RBE prediction in low/midrange LET conditions [15] but outcome analysis in clinical trials is pending. Moreover, treatment delivery uncertainties of scanned carbon beams, mitigated by image-guidance and robust optimization, are crucial for treatment planning.

In the current project, dose-volume parameters of CIRT and VMAT were compared for target volumes and organs at risk (OAR) in different reirradiation scenarios. Further implications for target volume delineation and dose optimization were evaluated as part of a pattern of local failure analysis. Thereby, the aim of the current project was to unravel potential clinical benefits and pitfalls of CIRT compared to VMAT in patients with recurrent head and neck cancer.

The biophysical properties of CIRT translated into clinical dose-volume advantages both in the target volume and OAR across all reirradiation scenarios compared to VMAT. Local failure pattern analysis revealed further CIRT specific clinical benefits and potential pitfalls in patients with recurrent head and neck cancer.

Adding on to the complex reirradiation setting, the patient cohort included primarily unfavorable high-grade tumors (63%) with a mean GTV of 29 ccm. The target prescription dose was superior with CIRT compared to VMAT (CTV Dmean: 63.6 vs. 60.2 Gy EQD2; + 5.6%; p < 0.001). In general, reirradiation tumor control is dose-dependent and significantly inferior with a prescribed dose ≤ 60 Gy [24]. However, reirradiation with ≥ 68 Gy is associated with excessive toxicity, thereby resulting in decreased survival rates compared to 60 Gy [25]. In our study, most patients (n = 12; 75%) were treated within the recommended range of 60–66 Gy [7] prescription dose and some above (n = 4; 100% CIRT; Dmean 69.4 Gy EQD2). CIRT may enable further dose escalation without increasing side effects due to its biophysical advantages compared to VMAT, but outcome evaluation is pending. In comparison to squamous cell carcinoma (SCC), dose escalation effects may have more pronounced impact on tumor control in radioresistant tumors such as adenoid cystic carcinomas [26, 27]. Moreover, the previously described risk of severe soft-tissue necrosis [28] in the CIRT high-dose area of the previously irradiated target remains problematic. In recurrent SCC, the impact of moderate hypofractionated CIRT compared to normofractionated VMAT on tumor control and normal tissue complication probability (NTCP) has yet to be determined in randomized clinical trials.

Despite the increased target dose, CIRT resulted in significantly reduced OAR dose across all patients (− 8.7% Dmean) compared to VMAT. Reirradiation NTCPs have yet to be determined in clinical trials, considering previous sequelae, the radiation interval and cumulative dose-volume metrics. The toxicity profiles as the primary endpoint of the CARE trial will therefore be analyzed after completion of the study. Previous dosimetric comparisons of proton RT and VMAT have shown clinical benefits with similar mean dose reductions [29, 30] and NTCPs could be even more dose-dependent in the reirradiation setting. On the other hand, for OAR close to the target, EQD2 reduction by CIRT is attenuated due to hypofractionation compared to normofractionated VMAT.

The dose-volume benefits were most pronounced in the brainstem (− 20.7% Dmax) and the optic chiasma (− 13.0% Dmax) with CIRT compared to VMAT. The mean dose to the ipsilateral and contralateral inner ear (− 11.3%/− 13.7%), eye (− 9.8%/− 4.2%) and optic nerve (− 8.8%/− 9.0%) was also advantageous with CIRT. These dose-limiting OAR are decisive for the treatment option of reirradiation but with exception of the brainstem and spinal cord, a risk–benefit-tradeoff is frequently inevitable [17]. In the current study, the clinical goal of the ipsilateral optic nerve (81.3% vs. 75.0%) was reached slightly more often with CIRT. In line with previous studies on particle therapy [31], the dose reduction was particularly noticeable for the contralateral side with regard to paired OAR (Additional file 1: Tab. S3). The difference in maximum dose did not reach significance for the ipsilateral optic nerve, mandible, brain and ipsilateral eye, due to proximity to the target volume. Other dose-volume metrics (e.g. D1cc) could be more relevant for CIRT in certain clinical scenarios where the high-LET target region is very close to vital OAR.

The pattern of local failure analysis revealed primarily extraneous dose failures (50%), mostly caused by possible aberrant areas of recurrence. Tissue changes from previous local therapies strongly impede target volume delineation in recurrent head and neck cancer. Combining multi-modality imaging including CT, diffusion-weighted MRI and positron emission tomography (PET)/CT can be crucial to mitigate uncertainties in contouring [32, 33]. One patient with type E local failure developed tumor recurrence within 5 mm of the CTV. Due to concerns regarding toxicity, the CTV margin was kept at 3 mm instead of 5 mm, as recommended in the consensus guidelines [7], thereby possibly causing local failure. In patients with type B local failure, the rate of overgrown recurrence could be reduced by improved image-guidance [34], in particular for CIRT. Since the start, ion beam image-guidance was based on daily orthogonal X-rays and weekly CT scans only in selected patients, possibly detecting aggressive tumor growth too late. Current and future perspectives in image-guided adaptive particle therapy, focused on CT/MR imaging [35], can eliminate type B failures caused by overgrown recurrence and provide functional response assessment. In addition, robustness of CIRT can be improved by state-of-the-art image-guidance, mitigating range uncertainties caused by anatomical changes. One type B local failure after VMAT was caused by dosimetric failure, due to proximity to the brainstem. The CIRT treatment plan was non-superior in this scenario, due to the direct spatial relationship of target volume and OAR.

Type A local failure occurred twice after CIRT, potentially caused by dosimetric and/or biological failure in both patients. In one patient the rGTV was located adjacent to a lower jaw metal implant, which potentially caused range uncertainties. In the other patient with hypopharyngeal recurrence, organ motion with changing air/tissue interface possibly deteriorated the dose distribution in the target volume. Moreover, α/β value of 2 Gy may lead to relative underdosage in the target, in particular for patients with SCC (α/β ~ 10 Gy) [36]. Nonetheless, mMKM dose recalculation revealed significantly reduced Dmean and D95% in the rGTV, compared to LEM I, in one patient. These findings advocate further comparisons of RBE-models for CIRT to mitigate RBE uncertainties in the target volume and OAR within the ongoing CARE study. The clinical potential of CIRT is not reached yet. Several further research endeavors, e.g. multi-ion RT [37], hadron arc RT [38], and ultra-high dose rate CIRT [39], aim to further optimize biological effects for the best of the patient.

The current study had several limitations. First, the sample size was rather small, requiring further investigations as part of the CARE study. Second, the PTV is defined slightly different and dose fractionation schemes varied according to treatment group. Third, according to the clinical standard for CIRT at our institution, the α/β value was equal for the tumor and OAR, thereby underestimating radiobiological factors. Furthermore, the conversion of CIRT biological dose in EQD2 using the α/β used as input is an approximation not considering the local α and β values originating from the mixed radiation field of CIRT [40]. Nonetheless, the current study is the first to compare CIRT to VMAT as part of a randomized prospective trial, thereby increasing the body of evidence with relevant clinical data.

Both VMAT and CIRT are feasible techniques for reirradiation of recurrent head and neck cancer. CIRT resulted in highly improved critical OAR sparing compared to VMAT across all head and neck cancer reirradiation scenarios despite an increased prescription dose. Pattern of local failure analysis revealed potential clinical pitfalls with regard to image-guidance and biological dose-optimization. Therefore, continued investigations within the CARE study will consider novel imaging and dose recalculation strategies for treatment planning.