Brainstem NTCP and Dose Constraints for Carbon Ion RT-Application and Translation From Japanese to European RBE-Weighted Dose.

BACKGROUND AND PURPOSE: The Italian National Center of Oncological Hadrontherapy (CNAO) has applied dose constraints for carbon ion RT (CIRT) as defined by Japan's National Institute of Radiological Sciences (NIRS). However, these institutions use different models to predict the relative biological effectiveness (RBE). CNAO applies the Local Effect Model I (LEM I), which in most clinical situations predicts higher RBE than NIRS's Microdosimetric Kinetic Model (MKM). Equal constraints therefore become more restrictive at CNAO. Tolerance doses for the brainstem have not been validated for LEM I-weighted dose (D LEM I). However, brainstem constraints and a Normal Tissue Complication Probability (NTCP) model were recently reported for MKM-weighted dose (D MKM), showing that a constraint relaxation to D MKM|0.7 cm3 <30 Gy (RBE) and D MKM|0.1 cm3 <40 Gy (RBE) was feasible. The aim of this work was to evaluate the brainstem NTCP associated with CNAO's current clinical practice and to propose new brainstem constraints for LEM I-optimized CIRT at CNAO. MATERIAL AND METHODS: We reproduced the absorbed dose of 30 representative patient treatment plans from CNAO. Subsequently, we calculated both D LEM I and D MKM, and the relationship between D MKM and D LEM I for various brainstem dose metrics was analyzed. Furthermore, the NTCP model developed for D MKM was applied to estimate the NTCPs of the delivered plans. RESULTS: The translation of CNAO treatment plans to D MKM confirmed that the former CNAO constraints were conservative compared with D MKM constraints. Estimated NTCPs were 0% for all but one case, in which the NTCP was 2%. The relationship D MKM/D LEM I could be described by a quadratic regression model which revealed that the validated D MKM constraints corresponded to D LEM I|0.7 cm3 <41 Gy (RBE) (95% CI, 38-44 Gy (RBE)) and D LEM I|0.1 cm3 <49 Gy (RBE) (95% CI, 46-52 Gy (RBE)). CONCLUSION: Our study demonstrates that RBE-weighted dose translation is of crucial importance in order to exchange experience and thus harmonize CIRT treatments globally. To mitigate uncertainties involved, we propose to use the lower bound of the 95% CI of the translation estimates, i.e., D LEM I|0.7 cm3 <38 Gy (RBE) and D LEM I|0.1 cm3 <46 Gy (RBE) as brainstem dose constraints for 16 fraction CIRT treatments optimized with LEM I.

Evaluation of the stage classification of anal cancer by the TNM 8th version versus the TNM 7th version.

Background: The UICC TNM 7th edition introduced stage groups for anal cancer which in 2019 has not yet come into general use. The new TNM 8th edition from 2016 defines 7 sub-stages. Background data for these changes are lacking. We aimed to investigate whether the new classification for anal cancer reliably predict the prognosis in the different stages.Patients and methods: The Nordic Anal Cancer Group (NOAC) conducted a large retrospective study of all anal cancers in Norway, Sweden and most of Denmark in 2000-2007. From the Nordic cohort 1151 anal cancer patients with follow-up data were classified by the TNM 4th edition which has identical T, N and M definitions as the TNM 7th edition, and therefore also can be classified by the TNM 7th stage groups. We used the Nordic cohort to translate the T, N and M stages into the TNM 8th stages and sub-stages. Overall survival for each stage was assessed.Results: Although the summary stage groups for TNM 8th edition discriminates patients with different prognosis reasonably well, the analyses of the seven sub-stages show overlapping overall survival: HR for stage IIA 1.30 (95%CI 0.80-2.12) is not significantly different from stage I (p = .30) and HR for stage IIB 2.35 (95%CI 1.40-3.95) and IIIA 2.48 (95%CI 1.43-4.31) are also similar as were HRs for stage IIIB 3.41 (95%CI 1.99-5.85) and IIIC 3.22 (95%CI 1.99-5.20). Similar overlapping was shown for local recurrence and distant spread.Conclusion: The results for the sub-stages calls for a revision of the staging system. We propose a modification of the TNM 8th edition for staging of anal cancer into four stages based on the T, N and M definitions of the TNM 8th classification.

Inter-patient variations in relative biological effectiveness for cranio-spinal irradiation with protons.

Cranio-spinal irradiation (CSI) using protons has dosimetric advantages compared to photons and is expected to reduce risk of adverse effects. The proton relative biological effectiveness (RBE) varies with linear energy transfer (LET), tissue type and dose, but a variable RBE has not replaced the constant RBE of 1.1 in clinical treatment planning. We examined inter-patient variations in RBE for ten proton CSI patients. Variable RBE models were used to obtain RBE and RBE-weighted doses. RBE was quantified in terms of dose weighted organ-mean RBE ([Formula: see text] = mean RBE-weighted dose/mean physical dose) and effective RBE of the near maximum dose (D2%), i.e. RBED2% = [Formula: see text], where subscripts RBE and phys indicate that the D2% is calculated based on an RBE model and the physical dose, respectively. Compared to the median [Formula: see text] of the patient population, differences up to 15% were observed for the individual [Formula: see text] values found for the thyroid, while more modest variations were seen for the heart (6%), lungs (2%) and brainstem (<1%). Large inter-patient variation in RBE could be correlated to large spread in LET and dose for these organs at risk (OARs). For OARs with small inter-patient variations, the results show that applying a population based RBE in treatment planning may be a step forward compared to using RBE of 1.1. OARs with large inter-patient RBE variations should ideally be selected for patient-specific biological or RBE robustness analysis if the physical doses are close to known dose thresholds.

Rectum Dose Constraints for Carbon Ion Therapy: Relative Biological Effectiveness Model Dependence in Relation to Clinical Outcomes.

The clinical application of different relative biological effectiveness (RBE) models for carbon ion RBE-weighted dose calculation hinders a global consensus in defining normal tissue constraints. This work aims to update the local effect model (LEM)-based constraints for the rectum using microdosimetric kinetic model (mMKM)-defined values, relying on RBE translation and the analysis of long-term clinical outcomes. LEM-optimized plans of treated patients, having suffered from prostate adenocarcinoma (n = 22) and sacral chordoma (n = 41), were recalculated with the mMKM using an in-house developed tool. The relation between rectum dose-volume points in the two RBE systems (DLEM|v and DMKM|v) was fitted to translate new LEM-based constraints. Normal tissue complication probability (NTCP) values, predicting late rectal toxicity, were obtained by applying published parameters. No late rectal toxicity events were reported within the patient cohort. The rectal toxicity outcome was confirmed using dosimetric analysis: DMKMVHs lay largely below original constraints; the translated DLEM|v values were 4.5%, 8.3%, 18.5%, and 35.4% higher than the nominal DMKM|v of the rectum volume, v-1%, 5%, 10% and 20%. The average NTCP value ranged from 5% for the prostate adenocarcinoma, to 0% for the sacral chordoma group. The redefined constraints, to be confirmed prospectively with clinical data, are DLEM|5cc ≤ 61 Gy(RBE) and DLEM|1cc ≤ 66 Gy(RBE).

RBE-weighted dose in carbon ion therapy for ACC patients: Impact of the RBE model translation on treatment outcomes.

PURPOSE/OBJECTIVE: The purpose of this study is to assess the impact of the conversion scheme for relative biological effectiveness (RBE)-weighted dose (DRBE), implemented at our center, on treatment outcomes of adenoid cystic carcinoma (ACC) patients. MATERIAL/METHODS: Treatment plans of 78 ACC patients, optimized with the Local Effect Model (LEM), were recalculated with the modified Microdosimetric Kinetic Model (mMKM). DRBE to 95%, 50% and 2% (DV%) of the clinical target volume (CTV), were selected as relevant parameters to compare LEM and mMKM DRBE. The pattern of failure of ACC treatments was analyzed in relation to uncertainties involved in the DRBE translation methodology. RESULTS: mMKM recalculations of LEM plans, optimized to a prescription dose of 68.8 Gy(RBE), showed a D50% 8% higher, on average, than the expected value (60.8 Gy(RBE)), closer to the most frequently used mMKM prescription DRBE (64 Gy(RBE)). D95% and D2% deviations, with respect to the optimization goals in the two RBE systems, increased of 0.5% and 14.2%, respectively, due to the steeper mMKM RBE variation along the beam path. Local recurrences were mainly (63%) reported in areas where CTV coverage was not satisfactory in the original LEM plan and the mMKM analysis showed that OARs constraints were too conservative. CONCLUSION: No case of local recurrence could be explained by inadequate mMKM target coverage that was not already present in the LEM plan. New constraints have been defined for optic pathways and brainstem to improve target coverage with no expected increase in tissue complications.

Optic nerve constraints for carbon ion RT at CNAO - Reporting and relating outcome to European and Japanese RBE.

BACKGROUND AND PURPOSE: Until now, carbon ion RT (CIRT) dose constraints for the optic nerve (ON) have only been validated and reported in the NIRS RBE-weighted dose (DNIRS). The aim of this work is to improve CNAO's RBE-weighted dose (DLEM) constraints by analyzing institutional toxicity data and by relating it to DNIRS. MATERIAL AND METHODS: A total of 65 ONs from 38 patients treated with CIRT to the head and neck region in the period 2013-14 were analyzed. The absorbed dose (DAbs) of the treatment plans was reproduced and subsequently both DLEM and DNIRS were applied, thus relating CNAO clinical toxicity to DNIRS. RESULTS: Median FU was 47 (26-67) months. Visual acuity was preserved for the 56 ONs in which the old constraints were respected. Three ONs developed visual decline at DLEM|1% ≥71 Gy(RBE)/DLEM|20% ≥68 Gy(RBE), corresponding to DNIRS|1% ≥68 Gy(RBE)/DNIRS|20% ≥62 Gy(RBE). Dose recalculation revealed that NIRS constraints of DNIRS|1% ≤40 Gy(RBE)/DNIRS|20% ≤28 Gy(RBE) corresponded to DLEM|1% ≤50 Gy(RBE)/DLEM|20% ≤40 Gy(RBE). Reoptimization of treatment plans with these new DLEM constraints showed that the dose distribution still complied with NIRS constraints when evaluated in DNIRS. However, due to uncertainties in the method, and to comply with the EQD2-based constraints used at GSI/HIT, a more moderate constraint relaxation to DLEM|1% ≤45 Gy(RBE)/DLEM|20% ≤37 Gy(RBE) has been implemented in CNAO clinical routine since October 2018. CONCLUSION: New DLEM constraints for the ON were derived by analyzing CNAO toxicity data and by linking our results to the experience of NIRS and GSI/HIT. This work demonstrates the value of recalculating and reporting results in both DLEM and DNIRS.

Rationale for combination of radiation therapy and immune checkpoint blockers to improve cancer treatment.

Radiation therapy for cancer is considered to be immunosuppressive. However, the cellular response after radiation therapy may stimulate or suppress an immune response. The effect may vary with the tumor type and occasionally tumor regressions have been observed outside the irradiated volume, both in animal studies and in the clinic. A renewed interest in the role of immunity for the observed effect of radiation came with the current recognized role of immune checkpoint blockers (ICBs) for control of selected cancer types. We therefore here review preclinical studies and clinical reports on the interaction of ICBs and radiation as a basis for further clinical trials. Some tumor types where the combination of these modalities seems especially promising are also proposed.

Exploration and application of phenomenological RBE models for proton therapy.

The relative biological effectiveness (RBE) of protons varies with multiple physical and biological factors. Phenomenological RBE models have been developed to include such factors in the estimation of a variable RBE, in contrast to the clinically applied constant RBE of 1.1. In this study, eleven published phenomenological RBE models and two plan-based models were explored and applied to simulated patient cases. All models were analysed with respect to the distribution and range of linear energy transfer (LET) and reference radiation fractionation sensitivity ((α/ß) x ) of their respective experimental databases. Proton therapy plans for a spread-out Bragg peak in water and three patient cases (prostate adenocarcinoma, pituitary adenoma and thoracic sarcoma) were optimised using an RBE of 1.1 in the Eclipse™ treatment planning system prior to recalculation and modelling in the FLUKA Monte Carlo code. Model estimated dose-volume parameters for the planning target volumes (PTVs) and organs at risk (OAR) were compared. The experimental in vitro databases for the various models differed greatly in the range of (α/ß) x values and dose-averaged LET (LETd). There were significant variations between the model estimations, which arose from fundamental differences in the database definitions and model assumptions. The greatest variations appeared in organs with low (α/ß) x and high LETd, e.g. biological doses given to late responding OARs located distal to the target in the treatment field. In general, the variation in maximum dose (D2%) was larger than the variation in mean dose and other dose metrics, with D2% of the left optic nerve ((α/ß) x = 2.1 Gy) in the pituitary adenoma case showing the greatest discrepancies between models: 28-52 Gy(RBE), while D2% for RBE1.1 was 30 Gy(RBE). For all patient cases, the estimated mean RBE to the PTV was in the range 1.09-1.29 ((α/ß) x = 1.5/3.1/10.6 Gy). There were considerable variations between the estimations of RBE and RBE-weighted doses from the different models. These variations were a consequence of fundamental differences in experimental databases, model assumptions and regression techniques. The results from the implementation of RBE models in dose planning studies should be evaluated in light of these deviations.

Risk of carotid blowout after reirradiation with particle therapy.

PURPOSE: Carotid blowout (CB) is a serious complication in retreatment of neoplasms in the head and neck (H&N) region. Rates seem to increase in hypofractionated or accelerated hyperfractionated regimens. In this study, we investigate the CB rate and the cumulative doses received by the carotid artery (CA) in a cohort of patients who were reirradiated at CNAO with particle therapy in the H&N region. METHODS AND MATERIALS: The dosimetric information, medical records, and tumor characteristics of 96 patients were analyzed. For 49 of these patients, the quality of dosimetric information was sufficient to calculate the cumulative doses to the CA. The corresponding biological equivalent dose in 2 Gy fractions (EQD2) was calculated with an α/ß-ratio of 3. RESULTS: In the final reirradiation at CNAO, 17 patients (18%) had been treated with protons and 79 (82%) with carbon ions. Two patients experienced profuse oronasal bleeding, of which one case was confirmed to be caused by CB. If attributing both cases to CB, we found an actuarial CB rate of 2.7%. Interestingly, there were no CB cases in the carbon ion group even though this was the large majority of patients and they generally were treated more aggressively in terms of larger fraction doses and higher cumulative EQD2. CONCLUSIONS: The current practice of particle reirradiation at CNAO for recurrent neoplasms in the H&N region results in acceptable rates of CB.

Multimodal therapy is feasible in elderly anal cancer patients.

BACKGROUND: Many patients are diagnosed with an anal cancer in high ages. We here present the outcome after oncological therapy for patients above 80 years compared with younger patients. MATERIALS AND METHODS: A series of 213 consecutive patients was diagnosed and treated at a single institution from 1984 to 2009. The patients received similar radiation doses but with different techniques, thus progressively sparing more normal tissues. The majority of patients also had simultaneous [5-fluorouracil (5FU) and mitomycin C] or induction chemotherapy (cisplatin and 5FU). The patients were stratified by age above or below 80 years. Despite that the goal was to offer standard chemoradiation treatment to all, the octo- and nonagenarians could not always be given chemotherapy. RESULTS: In our series 35 of 213 anal cancer patients were above 80 years. After initial therapy similar complete response was observed, 80% above and 87% below 80 years. Local recurrence rate was also similar in both groups, 21% versus 26% (p = .187). Cancer-specific survival and relative survival were significantly lower in patients above 80 years, 60% and 50% versus 83% and 80%, (p = .015 and p = .027), respectively. CONCLUSION: Patients older than 80 years develop anal cancer, but more often marginal tumors. Even in the oldest age group half of the patients can tolerate standard treatment by a combination of radiation and chemotherapy, and obtain a relative survival of 50% after five years. Fragile patients not considered candidates for chemoradiation may be offered radiation or resection to control local disease.