Consolidative active scanning proton therapy for mediastinal lymphoma: selection criteria, treatment implementation and clinical feasibility.

AIMS: Proton therapy (PT) represents an advanced form of radiotherapy with unique physical properties which could be of great advantage in reducing long-term radiation morbidity for cancer survivors. Here, we aim to describe the whole process leading to the clinical implementation of consolidative active scanning proton therapy treatment (PT) for mediastinal lymphoma. METHODS: The process included administrative, technical and clinical issues. Authorization of PT is required in all cases as mediastinal lymphoma is currently not on the list of diseases reimbursable by the Italian National Health Service. Technically, active scanning PT treatment for mediastinal lymphoma is complex, due to the interaction between actively scanned protons and the usually irregular and large volumes to be irradiated, the nearby healthy tissues and the target motion caused by breathing. A road map to implement the technical procedures was prepared. The clinical selection of patients was of utmost importance and took into account both patient and tumor characteristics. RESULTS: The first mediastinal lymphoma was treated at our PT center in 2018, four years after the start of the clinical activities. The treatment technique implementation included mechanical deep inspiration breath-hold simulation computed tomography (CT), clinical target volume (CTV)-based multifield optimization planning and plan robustness analysis. The ultimate authorization rate was 93%. In 4 cases a proton-photon plan comparison was required. Between May 2018 and February, 2021, 14 patients were treated with consolidative PT. The main clinical reasons for choosing PT over photons was a bulky disease in 8 patients (57%), patient's age in 11 patients (78%) and the proximity of the lymphoma to cardiac structures in 10 patients (71%). With a median follow-up of 15 months (range, 1-33 months) all patients but one (out-of-field relapse) are without evidence of disease, all are alive and no late toxicities were observed during the follow-up period. CONCLUSIONS: The clinical implementation of consolidative active scanning PT for mediastinal lymphoma required specific technical procedures and a prolonged experience with PT treatments. An accurate selection of patients for which PT could be of advantage in comparison with photons is mandatory.

Clinical results of proton therapy reirradiation for recurrent nasopharyngeal carcinoma.

Background and purpose: Recurrent nasopharyngeal carcinoma (NPC) has limited curative treatment options. Reirradiation is the only potential definitive treatment in advanced stages at a cost of substantial severe and often life-threatening toxicity. Proton therapy (PT) reduces irradiated volume compared with X-ray radiotherapy and could be advantageous in terms of safety and efficacy in a population of heavily pretreated patients. We report the retrospective results of PT reirradiation in recurrent NPC patients treated at our Institution Methods: All recurrent NPC patients treated since the beginning of clinical activity entered the present analysis. Clinical target volume consisted of Gross Tumor volume plus a patient-specific margin depending on disease behavior, tumor location, proximity of organs at risk, previous radiation dose. No elective nodal irradiation was performed. Active scanning technique with the use of Single Field Optimization (SFO) or Multifield Optimization (MFO) was adopted. Cumulative X-ray -PT doses were calculated for all patients using a dose accumulation tool since 2016. Treatment toxicity was retrospectively collected. Results: Between February 2015, and October 2018, 17 recurrent NPC patients were treated. Median follow-up (FUP) was 10 months (range 2-41). Median PT reirradiation dose was 60 Gy RBE (range 30.6-66). The majority of patients (53%) underwent concomitant chemotherapy. Acute toxicity was low with no ≥ G3 adverse events. Late events ≥ G3 occurred in 23.5% of patients. Most frequent late toxicity was hearing impairment (17,6%). G2 soft tissue necrosis occurred in two patients. Fatal bleeding of uncertain cause (either tumor recurrence or G5 carotid blowout) occurred in one patient. Kaplan-Meier 18 months Overall Survival (OS) and Local control (LC) rates were 54.4% and 66.6%, respectively. Conclusions: Our initial results with the use of modern PT for reirradiation of recurrent NPC patients are encouraging. Favorable LC and OS rates were obtained at the cost of acceptable severe late toxicity.

Axillary irradiation omitting axillary dissection in breast cancer: is there a role for shoulder-sparing proton therapy?

The recent EORTC 10981-22023 AMAROS trial showed that axillary radiotherapy and axillary lymph node dissection provide comparable local control and reduced lymphoedema in the irradiated group. However, no significant differences between the two groups in range of motion and quality of life were reported. It has been acknowledged that axillary irradiation could have induced some toxicity, particularly shoulder function impairment. In fact, conventional breast irradiation by tangential beams has to be modified to achieve full-dose coverage of the axillary nodes, including in the treatment field a larger portion of the shoulder structures. In this scenario, alternative irradiation techniques were discussed. Compared with modern photon techniques, axillary irradiation by proton therapy has the potential for sparing the shoulder without detrimental increase of the medium-to-low doses to the other normal tissues.

Bi-tangential hybrid IMRT for sparing the shoulder in whole breast irradiation.

BACKGROUND AND PURPOSE: A bi-tangential technique is proposed to reduce undesired doses to the shoulder produced by standard tangential irradiation. PATIENTS AND METHODS: A total of 6 patients affected by shoulder pain and reduced functional capacity after whole-breast irradiation were retrospectively analysed. The standard tangential plan used for treatment was compared with (1) a single bi-tangential plan where, to spare the shoulder, the lateral open tangent was split into two half-beams at isocentre, with the superior portion rotated by 10-20° medially with respect to the standard lateral beam; (2) a double bi-tangential plan, where both the tangential open beams were split. The planning target volume (PTV) coverage and the dose to the portion of muscles and axilla included in the standard tangential beams were compared. RESULTS: PTV95 % of standard plan (91.9 ± 3.8) was not significantly different from single bi-tangential plan (91.8 ± 3.4); a small but significant (p < 0.01) decrease was observed with the double bi-tangential plan (90.1 ± 3.7). A marked dose reduction to the muscle was produced by the single bi-tangential plan around 30-40 Gy. The application of the double bi-tangential technique further reduced the volume receiving around 20 Gy, but did not markedly affect the higher doses. The dose to the axilla was reduced both in the single and the double bi-tangential plans. CONCLUSION: The single bi-tangential technique would have been able to reduce the dose to shoulder and axilla, without compromising target coverage. This simple technique is valuable for irradiation after axillary lymph node dissection or in patients without dissection due to negative or low-volume sentinel lymph node disease.

Quasi-VMAT in high-grade glioma radiation therapy.

PURPOSE: To compare a quasi-volumetric modulated arc therapy (qVMAT) with three-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT) for the treatment of high-grade gliomas. The qVMAT technique is a fast method of radiation therapy in which multiple equispaced beams analogous to those in rotation therapy are radiated in succession. PATIENTS AND METHODS: This study included 12 patients with a planning target volume (PTV) that overlapped at least one organ at risk (OAR). 3D-CRT was planned using 2-3 non-coplanar beams, whereby the field-in-field technique (FIF) was used to divide each field into 1-3 subfields to shield the OAR. The qVMAT strategy was planned with 15 equispaced beams and IMRT was planned using 9 beams with a total of 80 segments. Inverse planning for qVMAT and IMRT was performed by direct machine parameter optimization (DMPO) to deliver a homogenous dose distribution of 60 Gy within the PTV and simultaneously limit the dose received by the OARs to the recommended values. Finally, the effect of introducing a maximum dose objective (max. dose < 54 Gy) for a virtual OAR in the form of a 0.5 cm ring around the PTV was investigated. RESULTS: The qVMAT method gave rise to significantly improved PTV95% and conformity index (CI) values in comparison to 3D-CRT (PTV95% = 90.7 % vs. 82.0 %; CI = 0.79 vs. 0.74, respectively). A further improvement was achieved by IMRT (PTV95% = 94.4 %, CI = 0.78). In qVMAT and IMRT, the addition of a 0.5 cm ring around the PTV produced a significant increase in CI (0.87 and 0.88, respectively), but dosage homogeneity within the PTV was considerably reduced (PTV95% = 88.5 % and 92.3 %, respectively). The time required for qVMAT dose delivery was similar to that required using 3D-CRT. CONCLUSION: These findings suggest that qVMAT should be preferred to 3D-CRT for the treatment of high-grade gliomas. The qVMAT method could be applied in hospitals, for example, which have limited departmental resources and are not equipped with systems capable of VMAT delivery.

Clinical target volume delineation in glioblastomas: pre-operative versus post-operative/pre-radiotherapy MRI.

OBJECTIVES: Delineation of clinical target volume (CTV) is still controversial in glioblastomas. In order to assess the differences in volume and shape of the radiotherapy target, the use of pre-operative vs post-operative/pre-radiotherapy T(1) and T(2) weighted MRI was compared. METHODS: 4 CTVs were delineated in 24 patients pre-operatively and post-operatively using T(1) contrast-enhanced (T1(PRE)CTV and T1(POST)CTV) and T(2) weighted images (T2(PRE)CTV and T2(POST)CTV). Pre-operative MRI examinations were performed the day before surgery, whereas post-operative examinations were acquired 1 month after surgery and before chemoradiation. A concordance index (CI) was defined as the ratio between the overlapping and composite volumes. RESULTS: The volumes of T1(PRE)CTV and T1(POST)CTV were not statistically different (248 ± 88 vs 254 ± 101), although volume differences >100 cm(3) were observed in 6 out of 24 patients. A marked increase due to tumour progression was shown in three patients. Three patients showed a decrease because of a reduced mass effect. A significant reduction occurred between pre-operative and post-operative T(2) volumes (139 ± 68 vs 78 ± 59). Lack of concordance was observed between T1(PRE)CTV and T1(POST)CTV (CI = 0.67 ± 0.09), T2(PRE)CTV and T2(POST)CTV (CI = 0.39 ± 0.20) and comparing the portion of the T1(PRE)CTV and T1(POST)CTV not covered by that defined on T2(PRE)CTV images (CI = 0.45 ± 0.16 and 0.44 ± 0.17, respectively). CONCLUSION: Using T(2) MRI, huge variations can be observed in peritumoural oedema, which are probably due to steroid treatment. Using T(1) MRI, brain shifts after surgery and possible progressive enhancing lesions produce substantial differences in CTVs. Our data support the use of post-operative/pre-radiotherapy T(1) weighted MRI for planning purposes.

DCE-MRI data analysis for cancer area classification.

OBJECTIVES: The paper aims at improving the support of medical researchers in the context of in-vivo cancer imaging. Morphological and functional parameters obtained by dynamic contrast-enhanced MRI (DCE-MRI) techniques are analyzed, which aim at investigating the development of tumor microvessels. The main contribution consists in proposing a machine learning methodology to segment automatically these MRI data, by isolating tumor areas with different meaning, in a histological sense. METHODS: The proposed approach is based on a three-step procedure: i) robust feature extraction from raw time-intensity curves, ii) voxel segmentation, and iii) voxel classification based on a learning-by-example approach. In the first step, few robust features that compactly represent the response of the tissue to the DCE-MRI analysis are computed. The second step provides a segmentation based on the mean shift (MS) paradigm, which has recently shown to be robust and useful for different and heterogeneous clustering tasks. Finally, in the third step, a support vector machine (SVM) is trained to classify voxels according to the labels obtained by the clustering phase (i.e., each class corresponds to a cluster). Indeed, the SVM is able to classify new unseen subjects with the same kind of tumor. RESULTS: Experiments on different subjects affected by the same kind of tumor evidence that the extracted regions by both the MS clustering and the SVM classifier exhibit a precise medical meaning, as carefully validated by the medical researchers. Moreover, our approach is more stable and robust than methods based on quantification of DCE-MRI data by means of pharmacokinetic models. CONCLUSIONS: The proposed method allows to analyze the DCE-MRI data more precisely and faster than previous automated or manual approaches.

Inhibition of tyrosine kinase receptors by SU6668 promotes abnormal stromal development at the periphery of carcinomas.

Dynamic contrast-enhanced (albumin-Gd-DTPA) magnetic resonance imaging, performed during 2 weeks of daily administration of an inhibitor of tyrosine kinase receptors (SU6668) in an HT-29 colon carcinoma model, revealed the onset of a hyper-enhancing rim, not observed in untreated tumours. To account for tissue heterogeneity in the quantitative analysis, we segmented tumours into three subunits automatically identified by cluster analysis of the enhancement curves using a k-means algorithm. Transendothelial permeability (Kps) and fractional plasma volume (fPV) were calculated in each subunit. An avascular and necrotic region, an intermediate zone and a well-vascularised periphery were reliably identified. During untreated tumour growth, the identified sub-regions did not substantially change their enhancement pattern. Treatment with SU6668 induced major changes at tumour periphery where a significant increase of Kps and fPV was observed with respect to control tumours. Histology revealed a sub-capsular layer composed of hyper-dense viable tumour cells in the periphery of untreated tumours. The rim of viable neoplastic cells was reduced in treated tumours, and replaced by loose connective tissue characterised by numerous vessels, which explains the observed hyper-enhancement. The present data show a peripheral abnormal development of cancer-associated stroma, indicative of an adaptive response to anti-angiogenic treatment.

Mesenchymal stem cells share molecular signature with mesenchymal tumor cells and favor early tumor growth in syngeneic mice.

Tumor microenvironment in carcinomas recruits mesenchymal cells with an abnormal proangiogenic and invasive phenotype. It is not clear whether mesenchymal tumor cells (MTCs) derive from the activation of mature fibroblasts or from their stem cell precursors. However, stromal cell activation in tumors resembles in several aspects the mesenchymal rearrangement which normally occurs during reparative processes such as wound healing. Mesenchymal stem cells (MSCs) play a crucial role in developmental and reparative processes and have extraordinary proangiogenic potential, on the basis of which they are thought to show great promise for the treatment of ischemic disorders. Here, we show that MTCs have proangiogenic potential and that they share the transcriptional expression of the best-known proangiogenic factors with MSCs. We also found that MTCs and MSCs have the same molecular signature for stemness-related genes, and that when co-implanted with cancer cells in syngeneic animals MSCs determine early tumor appearance, probably by favoring the angiogenic switch. Our data (1) reveal crucial aspects of the proangiogenic phenotype of MTCs, (2) strongly suggest their stem origin and (3) signal the risk of therapeutic use of MSCs in tumor-promoting conditions.