Publications by authors named "Francesca Valvo"

72 Publications

Immunotherapy in Xeroderma Pigmentosum: a case of advanced cutaneous squamous cell carcinoma treated with cemiplimab and a literature review.

Oncotarget 2021 May 25;12(11):1116-1121. Epub 2021 May 25.

Department of Medical Sciences, Section of Dermatology, University of Turin, Turin, Italy.

Xeroderma Pigmentosum (XP) is a rare genetic disorder with a poor prognosis due to high photosensitivity in affected patients. Herein, we describe the first case of the use of cemiplimab in a patient with XP, a 19-year-old girl presented with locally advanced squamous cell carcinoma of the right periorbital and nasal region. This treatment has been undertaken after a cycle of proton beam radiotherapy. Besides, it is reported a description of the few cases in the literature describing the effectiveness of immunotherapy on skin cancers in XP-patients. This case is in line with those reported, underlining how anti-PD1 monoclonal antibodies may be a promising treatment in this genodermatosis.
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http://dx.doi.org/10.18632/oncotarget.27966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169062PMC
May 2021

Radiotherapy with Intensity-Modulated (IMRT) Techniques in the Treatment of Anal Carcinoma (RAINSTORM): A Multicenter Study on Behalf of AIRO (Italian Association of Radiotherapy and Clinical Oncology) Gastrointestinal Study Group.

Cancers (Basel) 2021 Apr 15;13(8). Epub 2021 Apr 15.

Laboratory of Biostatistics, Department of Medical, Oral and Biotechnological Sciences, "G. D'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy.

A multi-institutional retrospective study was conducted to evaluate the pattern of care and clinical outcomes of anal cancer patients treated with intensity-modulated radiotherapy (IMRT) techniques. In a cohort of 987 patients, the clinical complete response (CR) rate (beyond 6 months) was 90.6%. The 3-year local control (LC) rate was 85.8% (95% CI: 84.4-87.2), and the 3-year colostomy-free survival (CFS) rate was 77.9% (95% CI: 76.1-79.8). Three-year progression-free survival (PFS) and overall survival (OS) rates were 80.2% and 88.1% (95% CI: 78.8-89.4) (95% CI: 78.5-81.9), respectively. Histological grade 3 and nodal involvement were associated with lower CR ( = 0.030 and = 0.004, respectively). A statistically significant association was found between advanced stage and nodal involvement, and LC, CFS, PFS, OS and event-free survival (EFS). Overall treatment time (OTT) ≥45 days showed a trend for a lower PFS ( = 0.050) and was significantly associated with lower EFS ( = 0.030) and histological grade 3 with a lower LC ( = 0.025). No statistically significant association was found between total dose, dose/fraction and/or boost modality and clinical outcomes. This analysis reports excellent clinical results and a mild toxicity profile, confirming IMRT techniques as standard of care for the curative treatment of anal cancer patients. Lymph node involvement and histological grade have been confirmed as the most important negative prognostic factors.
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http://dx.doi.org/10.3390/cancers13081902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071256PMC
April 2021

Radiomics and Dosiomics for Predicting Local Control after Carbon-Ion Radiotherapy in Skull-Base Chordoma.

Cancers (Basel) 2021 Jan 18;13(2). Epub 2021 Jan 18.

Department of Electronics, Information and Bioengineering, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milan, Italy.

Skull-base chordoma (SBC) can be treated with carbon ion radiotherapy (CIRT) to improve local control (LC). The study aimed to explore the role of multi-parametric radiomic, dosiomic and clinical features as prognostic factors for LC in SBC patients undergoing CIRT. Before CIRT, 57 patients underwent MR and CT imaging, from which tumour contours and dose maps were obtained. MRI and CT-based radiomic, and dosiomic features were selected and fed to two survival models, singularly or by combining them with clinical factors. Adverse LC was given by in-field recurrence or tumour progression. The dataset was split in development and test sets and the models' performance evaluated using the concordance index (C-index). Patients were then assigned a low- or high-risk score. Survival curves were estimated, and risk groups compared through log-rank tests (after Bonferroni correction α = 0.0083). The best performing models were built on features describing tumour shape and dosiomic heterogeneity (median/interquartile range validation C-index: 0.80/024 and 0.79/0.26), followed by combined (0.73/0.30 and 0.75/0.27) and CT-based models (0.77/0.24 and 0.64/0.28). Dosiomic and combined models could consistently stratify patients in two significantly different groups. Dosiomic and multi-parametric radiomic features showed to be promising prognostic factors for LC in SBC treated with CIRT.
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http://dx.doi.org/10.3390/cancers13020339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832399PMC
January 2021

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

Front Oncol 2020 24;10:531344. Epub 2020 Nov 24.

National Center of Oncological Hadrontherapy, Pavia, Italy.

Background And Purpose: The Italian (CNAO) has applied dose constraints for carbon ion RT (CIRT) as defined by Japan's (NIRS). However, these institutions use different models to predict the (RBE). CNAO applies the (LEM I), which in most clinical situations predicts higher RBE than NIRS's (MKM). Equal constraints therefore become more restrictive at CNAO. Tolerance doses for the brainstem have not been validated for LEM I-weighted dose ( ). However, brainstem constraints and a (NTCP) model were recently reported for MKM-weighted dose ( ), showing that a constraint relaxation to <30 Gy (RBE) and <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 and , and the relationship between and for various brainstem dose metrics was analyzed. Furthermore, the NTCP model developed for was applied to estimate the NTCPs of the delivered plans.

Results: The translation of CNAO treatment plans to confirmed that the former CNAO constraints were conservative compared with constraints. Estimated NTCPs were 0% for all but one case, in which the NTCP was 2%. The relationship / could be described by a quadratic regression model which revealed that the validated constraints corresponded to <41 Gy (RBE) (95% CI, 38-44 Gy (RBE)) and <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, , <38 Gy (RBE) and <46 Gy (RBE) as brainstem dose constraints for 16 fraction CIRT treatments optimized with LEM I.
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http://dx.doi.org/10.3389/fonc.2020.531344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735105PMC
November 2020

Investigating the use of virtual 4DCT from 4DMRI in gated carbon ion radiation therapy of abdominal tumors.

Z Med Phys 2020 Oct 14. Epub 2020 Oct 14.

Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milano 20133, Italy; Centro Nazionale di Adroterapia Oncologica, Pavia 27100, Italy.

Purpose: To generate virtual 4DCT from 4DMRI with field of view (FOV) extended to the entire involved patient anatomy, in order to evaluate its use in carbon ion radiation therapy (CIRT) of the abdominal site in a clinical scenario.

Materials And Methods: The virtual 4DCT was generated by deforming a reference CT in order to (1) match the anatomy depicted in the 4DMRI within its FOV, by calculating deformation fields with deformable image registration to describe inter-fractional and breathing motion, and (2) obtain physically plausible deformation outside of the 4DMRI FOV, by propagating and modulating the previously obtained deformation fields. The implemented method was validated on a digital anthropomorphic phantom, for which a ground truth (GT) 4DCT was available. A CIRT treatment plan was optimized at the end-exhale reference CT and the RBE-weighted dose distribution was recalculated on both the virtual and GT 4DCTs. The method estimation error was quantified by comparing the virtual and GT 4DCTs and the corresponding recomputed doses. The method was then evaluated on 8 patients with pancreas or liver tumors treated with CIRT using respiratory gating at end-exhale. The clinical treatment plans adopted at the National Center for Oncological Hadrontherapy (CNAO, Pavia, Italy) were considered and the dose distribution was recomputed on all respiratory phases of the planning and virtual 4DCTs. By comparing the two datasets and the corresponding dose distributions, the geometrical and dosimetric impact of organ motion was assessed.

Results: For the phantom, the error outside of the 4DMRI FOV was up to 4.5mm, but it remained sub-millimetric in correspondence to the target within the 4DMRI FOV. Although the impact of motion on the target D resulted in variations ranging from 22% to 90% between the planned dose and the doses recomputed on the GT 4DCT phases, the corresponding estimation error was ≤2.2%. In the patient cases, the variation of the baseline tumor position between the planning and the virtual end-exhale CTs presented a median (interquartile range) value of 6.0 (4.9) mm. For baseline variations larger than 5mm, the tumor D variation between the plan and the dose recomputed on the end-exhale virtual CT resulted larger than 10%. Median variations higher than 10% in the target D and gastro-intestinal OARs D were quantified at the end-inhale, whereas close to the end-exhale phase, limited variations of relevant dose metrics were found for both tumor and OARs.

Conclusions: The negligible impact of the geometrical inaccuracy in the estimated anatomy outside of the 4DMRI FOV on the overall dosimetric accuracy suggests the feasibility of virtual 4DCT with extended FOV in CIRT of the abdominal site. In the analyzed patient group, inter-fractional variations such as baseline variation and breathing variability were quantified, demonstrating the method capability to support treatment planning in gated CIRT of the abdominal site.
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http://dx.doi.org/10.1016/j.zemedi.2020.08.005DOI Listing
October 2020

Endometrial Cancer: When Upfront Surgery Is Not an Option.

Oncology 2021 8;99(2):65-71. Epub 2020 Oct 8.

Department of Clinical and Experimental Medicine, Division of Gynecology and Obstetrics, University of Pisa, Pisa, Italy.

Background and Summary: The management of endometrial cancer, in an ever-older population with considerable comorbidity, remains a challenge for gynecological and radiation oncologists. Key Message: The present paper reviews literature data on treatment options for endometrial cancer patients unfit for surgery.
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http://dx.doi.org/10.1159/000510690DOI Listing
February 2021

Neoadjuvant (re)chemoradiation for locally recurrent rectal cancer: Impact of anatomical site of pelvic recurrence on long-term results.

Surg Oncol 2020 Dec 20;35:89-96. Epub 2020 Aug 20.

Colorectal Surgery Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.

Background: Selection criteria to propose neoadjuvant (re)chemoradiation (CHRT) in locally recurrent rectal cancer (LRRC) are required, since re-irradiation is sometimes associated to severe adverse effects. Aim of the present study was to compare chances of R0 surgery and disease-free survival (DFS) in LRRC patients (pts) treated by neoadjuvant (re)CHRT followed by surgery vs. upfront surgery, stratifying pts by each localization of LRRC.

Methods: LRRC pts treated at the National Cancer Institute of Milan (Italy) were retrospectively divided into two groups: neoadjuvant (re)CHRT vs. upfront surgery. According to our Milan classification, LRRC were categorized as S1, if located centrally (S1a-b) or anteriorly (S1c) within the pelvis; S2, in case of sacral involvement; S3, in case of lateral pelvic wall infiltration.

Results: 152 pts were candidate for multimodal treatment: 49 (32.2%) by neoadjuvant (re)CHRT and surgery, including 33 re-irradiations, vs. 103 (67.8%) by upfront surgery. No difference was observed in R0 resection rates (respectively 47.6% vs. 51.0%). However, neoadjuvant (re)CHRT followed by surgery improved the DFS (p = 0.028), also in R1 procedures (p = 0.013), compared with upfront surgery. At multivariate analysis, the R+ surgery (p < 0.0001) strongly predicted unfavorable DFS, while neoadjuvant (re)CHRT followed by surgery was independently associated to better DFS (p = 0.0197). Stratifying by LRRC localization, the combined approach significantly improved DFS in the S1c (p = 0.029) and S2 (p = 0.004) subgroups compared to upfront surgery, but not in S1a-b and S3 pts.

Conclusion: Anterior (S1c) and sacral-invasive (S2) pelvic recurrences significantly benefit in terms of DFS by combination of neoadjuvant (re)CHRT and radical surgery, also after R1 resection.
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http://dx.doi.org/10.1016/j.suronc.2020.08.017DOI Listing
December 2020

Mixed-beam approach for high-risk prostate cancer: Carbon-ion boost followed by photon intensity-modulated radiotherapy. Dosimetric and geometric evaluations (AIRC IG-14300).

Phys Med 2020 Aug 2;76:327-336. Epub 2020 Aug 2.

Scientific Directorate, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy.

Background And Purpose: The aim was to evaluate dosimetric uncertainties of a mixed beam approach for patients with high-risk prostate cancer (PCa). The treatment consists of a carbon ion radiotherapy (CIRT) boost followed by whole-pelvis intensity-modulated RT (IMRT).

Materials And Methods: Patients were treated with a CIRT boost of 16.6 Gy/4 fractions followed by whole-pelvis IMRT of 50 Gy/25 fractions, with consequent long term androgen deprivation therapy. Deformable computed tomography image registration (DIR) was performed and corresponding doses were used for plan sum. A comparative IMRT photon plan was obtained as whole-pelvis IMRT of 50 Gy/25 fractions followed by a boost of 28 Gy/14 fractions. DIR performances were evaluated through structure-related and image characteristics parameters.

Results: Until now, five patients out of ten total enrolled ended the treatment. Dosimetric parameters were lower in CIRT + IMRT than IMRT-only plans for all organs at risk (OARs) except femoral heads. Regarding DIR evaluation, femoral heads were the less deformed OAR. Penile bulb, bladder and anal canal showed intermediate deformation. Rectum was the most deformed. DIR algorithms were patient (P)-dependent, as performances were the highest for P3 and P4, intermediate for P2 and P5, and the lowest for P1.

Conclusions: CIRT allows better OARs sparing while increasing the efficacy due to the higher radio-biological effect of carbon ions. However, a mixed beam approach could introduce DIR problems in multi-centric treatments with different operative protocols. The development of this prospective trial will lead to more mature data concerning the clinical impact of implementing DIR procedures in dose accumulation applications for high-risk PCa treatments.
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http://dx.doi.org/10.1016/j.ejmp.2020.07.012DOI Listing
August 2020

Multi-parametric qualitative and quantitative MRI assessment as predictor of histological grading in previously treated meningiomas.

Neuroradiology 2020 Nov 24;62(11):1441-1449. Epub 2020 Jun 24.

Department of Clinical Surgical Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.

Purpose: Meningiomas are mainly benign tumors, though a considerable proportion shows aggressive behaviors histologically consistent with atypia/anaplasia. Histopathological grading is usually assessed through invasive procedures, which is not always feasible due to the inaccessibility of the lesion or to treatment contraindications. Therefore, we propose a multi-parametric MRI assessment as a predictor of meningioma histopathological grading.

Methods: Seventy-three patients with 74 histologically proven and previously treated meningiomas were retrospectively enrolled (42 WHO I, 24 WHO II, 8 WHO III) and studied with MRI including T2 TSE, FLAIR, Gradient Echo, DWI, and pre- and post-contrast T1 sequences. Lesion masks were segmented on post-contrast T1 sequences and rigidly registered to ADC maps to extract quantitative parameters from conventional DWI and intravoxel incoherent motion model assessing tumor perfusion. Two expert neuroradiologists assessed morphological features of meningiomas with semi-quantitative scores.

Results: Univariate analysis showed different distributions (p < 0.05) of quantitative diffusion parameters (Wilcoxon rank-sum test) and morphological features (Pearson's chi-square; Fisher's exact test) among meningiomas grouped in low-grade (WHO I) and higher grade forms (WHO II/III); the only exception consisted of the tumor-brain interface. A multivariate logistic regression, combining all parameters showing statistical significance in the univariate analysis, allowed discrimination between the groups of meningiomas with high sensitivity (0.968) and specificity (0.925). Heterogeneous contrast enhancement and low ADC were the best independent predictors of atypia and anaplasia.

Conclusion: Our multi-parametric MRI assessment showed high sensitivity and specificity in predicting histological grading of meningiomas. Such an assessment may be clinically useful in characterizing lesions without histological diagnosis. Key points • When surgery and biopsy are not feasible, parameters obtained from both conventional and diffusion-weighted MRI can predict atypia and anaplasia in meningiomas with high sensitivity and specificity. • Low ADC values and heterogeneous contrast enhancement are the best predictors of higher grade meningioma.
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http://dx.doi.org/10.1007/s00234-020-02476-yDOI Listing
November 2020

Organ motion quantification and margins evaluation in carbon ion therapy of abdominal lesions.

Phys Med 2020 May 30;75:33-39. Epub 2020 May 30.

Centro Nazionale di Adroterapia Oncologica, Str. Campeggi, 53, 27100 Pavia, Italy; Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, 20133 Milan, Italy.

Purpose: In image-guided particle radiotherapy of abdominal lesions, respiratory motion hinders treatment accuracy. In this study, 2D cineMRI data were used to quantify the tumor (GTV) motion and to evaluate the clinical approach based on deriving an internal target volume (ITV) from a planning 4DCT for gating treatments.

Methods: Seven patients with abdominal lesions were treated with carbon-ion therapy at the National Centre of Oncological Hadron-therapy (Italy). The MR scan was performed on the same day of the 4DCT acquisition. For four patients, an additional MR was acquired approximately after 1 week. The cineMRI combined with deformable image registration algorithm was used to quantify tumor motion. Afterwards, two ITVs were defined considering (1) all phases (ITV) and (2) only phases within the gating window (ITV), and then compared with the clinical (4DCT-derived) ITVs (ITV and ITV).

Results: Tumor residual motion estimated by cineMRI data in the two MRI sessions resulted not significantly different from 4DCT, although cineMRI accounted for cycle-to-cycle variations. The ITV normalized for the GTV median values were higher for ITV with respect to ITV, ITV and ITV. The Hausdorff distances with respect to the GTV were up to 10.55 mm, 3.13 mm, 5.56 mm and 2.51 mm, for ITV, ITV, ITV and ITV, respectively. According to both metrics, ITV and ITV were not found significantly different.

Conclusions: CineMRI acquisitions allowed to quantify organ motion without delivering additional dose to the patient and to verify treatment margins in gated carbon-ion therapy of abdominal lesions.
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http://dx.doi.org/10.1016/j.ejmp.2020.05.014DOI Listing
May 2020

A proposal of an updated classification for pelvic relapses of rectal cancer to guide surgical decision-making.

J Surg Oncol 2020 Aug 18;122(2):350-359. Epub 2020 May 18.

Colorectal Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background And Objectives: Selection of patients affected by pelvic recurrence of rectal cancer (PRRC) who are likely to achieve a R0 resection is mandatory. The aim of this study was to propose a classification for PRRC to predict both radical surgery and disease-free survival (DFS).

Methods: PRRC patients treated at the National Cancer Institute of Milan (Italy) were included in the study. PRRC were classified as S1, if located centrally (S1a-S1b) or anteriorly (S1c) within the pelvis; S2, in case of sacral involvement below (S2a) or above (S2b) the second sacral vertebra; S3, in case of lateral pelvic involvement.

Results: Of 280 reviewed PRRC patients, 152 (54.3%) were evaluated for curative surgery. The strongest predictor of R+ resection was the S3 category (OR, 6.37; P = .011). Abdominosacral resection (P = .012), anterior exenteration (P = .012) and extended rectal re-excision (P = .003) were predictive of R0 resection. S3 category was highly predictive of poor DFS (HR 2.53; P = .038). DFS was significantly improved after R0 surgery for S1 (P < .0001) and S2 (P = .015) patients but not for S3 cases (P = .525).

Conclusions: The proposed classification allows selection of subjects candidates to curative surgery, emphasizing that lateral pelvic involvement is the main predictor of R+ resection and independently affects the DFS.
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http://dx.doi.org/10.1002/jso.25938DOI Listing
August 2020

Adenoid Cystic Carcinoma of Bartholin's Gland: What Is the Best Approach?

Oncology 2020 14;98(8):513-519. Epub 2020 May 14.

National Center of Oncological Hadrontherapy (Fondazione CNAO), Pavia, Italy.

Background and summary: Among all vulvar cancers, primary adenoid cystic carcinoma (ACC) of Bartholin's gland is a very rare tumor characterized by a slow growth, a high local aggressiveness, and a remarkable recurrence rate. Due to its rarity, treatment remains a challenge for oncologists and gynecological surgeons. Key message: The present paper reports clinical, radiological, and histological features of ACC of Bartholin's gland and reviews the literature data on the treatment options with a particular focus on the potential role of particle radiation therapy.
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http://dx.doi.org/10.1159/000506485DOI Listing
August 2020

Non-Operative Management Versus Total Mesorectal Excision for Locally Advanced Rectal Cancer with Clinical Complete Response After Neoadjuvant Chemoradiotherapy: a GRADE Approach by the Rectal Cancer Guidelines Writing Group of the Italian Association of Medical Oncology (AIOM).

J Gastrointest Surg 2020 09 11;24(9):2150-2159. Epub 2020 May 11.

Sant'Andrea Hospital, La Spezia, Italy.

Background: The standard approach for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME). After nCRT 20% of patients achieve a clinical complete response (pCR) and could be treated with a non-operative management (NOM).

Methods: The panel of the Italian Association of Medical Oncology (AIOM) Guidelines on rectal cancer applied the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach addressing the following question: Should NOM vs. TME be used for patients with rectal cancer with clinical complete response after nCRT? Five outcomes were identified: disease-free survival (DFS), mortality, local recurrence, colostomy rate, and functional outcomes.

Results: Nine studies were included in the analysis. A higher risk of disease recurrence was observed in the NOM group compared to the TME group (RR = 1.69, 95% CI 1.08, 2.64) on the other hand, we observed a slightly positive but not significant effect on mortality of NOM (RR = 0.82, 95% CI 0.46, 1.45). Patients in the NOM group were more likely to experience local recurrence (RR = 5.37, 95% CI 2.56, 11.27) and patients in the TME group were more likely to have a permanent colostomy (RR = 0.15, 95% CI 0.08, 0.29). Only one study evaluated functional outcomes. The overall certainty of evidence was rated as very low.

Conclusions: NOM was found to correlate with a higher risk of local recurrence which did not translate in worse OS and a lower colostomy rate. Due to the paucity of evidences, no recommendations are possible. NOM remains an experimental treatment; thus, patients managed with NOM should be enrolled in clinical trials with a dedicated follow-up schedule.
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http://dx.doi.org/10.1007/s11605-020-04635-1DOI Listing
September 2020

Outcome and Toxicity of Carbon Ion Radiotherapy for Axial Bone and Soft Tissue Sarcomas.

Anticancer Res 2020 May;40(5):2853-2859

National Center of Oncological Hadrontherapy (Fondazione CNAO), Pavia, Italy.

Background/aim: Definitive radiotherapy for bone and soft tissues sarcomas benefits patients deemed unfit for surgery; poor outcomes have been reported with conventional photons, while interesting preliminary results have been described with particle in single-Institution experiences. The aim of the study was to retrospectively evaluate preliminary results of carbon ion radiotherapy (CIRT) in patients with axial bone and soft tissue sarcomas (BSTS) treated with curative intent at the National Center for Oncological Hadrontherapy (CNAO).

Patients And Methods: From January 2013 to September 2018, 54 patients with axial BSTS were treated with CIRT at CNAO. Their median age was 50 years (range=19-79 years), males/females=1.4:1. Tumor site was the pelvis in 50% of cases (n=27), thoracic region in 24% (n=13), cervical spine in 15% (n=8) and lumbar in 11% (n=6). A total of 76% (n=41) of patients had primary disease, while 24% (n=13) had recurrent disease. Before CIRT, surgery was performed in 47% of cases, including positive margins (R1) in 8 patients, and macroscopic residual disease (R2) in 17. Histological subtypes were mainly represented by chondrosarcomas in 39% (n=21) of patients and osteosarcomas in 24% (n=13). Pre-treatment chemotherapy was administered in 40% of cases (n=22); no patient received previous radiotherapy. All treatments were performed with active scanning CIRT for a median total dose of 73.6 Gy (range=70.4-76.8 Gy), in 16 fractions (4 fractions per week).

Results: Median follow-up was 24 months (range=4-61 months). Four patients were lost to follow-up. Acute toxicities were mild, no >G2 event was reported and no treatment interruption was required. For late toxicity, only G3 neuropathy was detected in 4% of cases (n=2). With a median time to local progression of 13 months (3-35), 15 local failures were observed, resulting in 2- and 3-year local control rates of 67.4% for both. Distant progression occurred in 12 patients, with 1-year progression-free survival (PFS) rate of 97.5%; 2- and 3-year rates were 92.2%. Fifteen patients died resulting in 1- 2- and 3-years overall survival (OS) rates of 87.1%, 75.4% and 64%, respectively. At log-rank test, gross total volume (GTV) >1,000 ml was found to be predictive of local failure (p=0.04), pre-treatment chemotherapy was found to be significantly related to PFS and OS (p=0.02 and p=0.016); also, recurrent disease and distant progression were significantly related to OS (p=0.019 and p=0.0013). Cox proportional-hazards model confirmed that GTV >1,000 ml was related to worse local control (p=0.0010).

Conclusion: CIRT for axial BSTS resulted in mild toxicity, showing promising results in terms of clinical outcomes. A longer follow-up is warranted.
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http://dx.doi.org/10.21873/anticanres.14260DOI Listing
May 2020

Re-irradiation With Carbon Ion Radiotherapy for Pelvic Rectal Cancer Recurrences in Patients Previously Irradiated to the Pelvis.

In Vivo 2020 May-Jun;34(3):1547-1553

National Center of Oncological Hadrontherapy (Fondazione CNAO), Pavia, Italy.

Background/aim: Re-irradiation of locally recurrent rectal cancer poses challenges due to the proximity of critical organs, such as the bowel. This study aimed at evaluating the safety and efficacy of re-irradiation with Carbon Ion Radiotherapy (CIRT) in rectal cancer patients with local recurrence.

Patients And Methods: Between 2014 and 2018, 14 patients were treated at the National Center of Oncological Hadrontherapy (CNAO Foundation) with CIRT for locally recurrent rectal cancer.

Results: All patients concluded the treatment. No G≥3 acute/late reaction nor pelvic infections were observed. The 1-year and 2-year local control rates were, 78% and 52%, respectively, and relapse occurred close to the bowel in 6 patients. The 1-year and 2-year overall survival rates were 100% and 76.2% each; while the 1-year and 2-year metastasis free survival rates were 64.3% and 43%.

Conclusion: CIRT as re-irradiation for locally recurrent rectal cancer emerges as a safe and valid treatment with an acceptable rate of morbidity of surrounding healthy tissue.
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http://dx.doi.org/10.21873/invivo.11944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279804PMC
February 2021

4D strategies for lung tumors treated with hypofractionated scanning proton beam therapy: Dosimetric impact and robustness to interplay effects.

Radiother Oncol 2020 May 26;146:213-220. Epub 2020 Mar 26.

CNAO, National Center for Oncological Hadrontherapy, Pavia, Italy.

Purpose: To investigate the impact of four-dimensional robust optimization (4DRO) on dose delivered to lung cancer patients in pencil beam scanning proton therapy.

Methods And Materials: 2 strategies were compared for 20 lung cancer patients, using a different number of breathing phases of the reconstructed 4D computed tomography (CT) included in the plan optimization problem. In the restricted approach combined with gating, only 3 phases close to reference end-exhale were considered instead of the whole breathing cycle. The prescribed dose was 60 Gy(RBE) in 10 fractions. Target coverage (D98%) and dose to healthy tissues were evaluated using Wilcoxon signed-rank test. To assess the robustness against interfractional anatomical and respiratory variations, the optimized plans were recalculated on re-evaluation 4DCTs. To compare the sensitivity of both strategies to interplay effects, we implemented an end-to-end test with a home-made heterogeneous moving phantom and ionization chambers measurements. Robustly optimized plans with prescription doses of 6 Gy(RBE) were delivered in different dynamic conditions.

Results: Both 4D robustly optimized plans reached the same target coverage (p = 0.56), while a statistically significant decrease of the homolateral lung dose was observed using the restricted approach (p < 0.0001). Plan recalculations within 15 days from the treatment simulation showed the same robustness of target D98% against interfractional variations (p = 0.48), with an average decrease of approximately 3 Gy(RBE). Phantom measurements confirmed the delivery accuracy of the restricted approach (mean dose deviations <5%). Higher deviations were found for ungated full 4DRO and larger motion amplitude.

Conclusion: The restricted approach combined with gating improved normal tissue sparing and was shown to be more robust to single fraction deliveries and large motion amplitude.
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http://dx.doi.org/10.1016/j.radonc.2020.02.025DOI Listing
May 2020

Proton and carbon ion radiotherapy in skull base chordomas: a prospective study based on a dual particle and a patient-customized treatment strategy.

Neuro Oncol 2020 09;22(9):1348-1358

Scientific Directorate, European Institute of Oncology, IRCCS, Milan, Italy.

Background: The aim of this study is to evaluate results in terms of local control (LC), overall survival (OS), and toxicity profile and to better identify factors influencing clinical outcome of skull base chordoma treated with proton therapy (PT) and carbon ion radiotherapy (CIRT).

Methods: We prospectively collected and analyzed data of 135 patients treated between November 2011 and December 2018. Total prescription dose in the PT group (70 patients) and CIRT group (65 patients) was 74 Gy relative biological effectiveness (RBE) delivered in 37 fractions and 70.4 Gy(RBE) delivered in 16 fractions, respectively (CIRT in unfavorable patients). LC and OS were evaluated using the Kaplan-Meier method. Univariate and multivariate analyses were performed, to identify prognostic factors on clinical outcomes.

Results: After a median follow-up of 44 (range, 6-87) months, 14 (21%) and 8 (11%) local failures were observed in CIRT and PT group, respectively. Five-year LC rate was 71% in CIRT cohort and 84% in PT cohort. The estimated 5-year OS rate in the CIRT and PT group was 82% and 83%, respectively. On multivariate analysis, gross tumor volume (GTV), optic pathways, and/or brainstem compression and dose coverage are independent prognostic factors of local failure risk. High rate toxicity grade ≥3 was reported in 11% of patients.

Conclusions: Particle radiotherapy is an effective treatment for skull base chordoma with acceptable late toxicity. GTV, optic pathways, and/or brainstem compression and target coverage were independent prognostic factors for LC.

Key Points: • Proton and carbon ion therapy are effective and safe in skull base chordoma.• Prognostic factors are GTV, organs at risk compression, and dose coverage.• Dual particle therapy and customized strategy was adopted.
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http://dx.doi.org/10.1093/neuonc/noaa067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523440PMC
September 2020

Predictive role of Apparent Diffusion Coefficient (ADC) from Diffusion Weighted MRI in patients with sacral chordoma treated with carbon ion radiotherapy (CIRT) alone.

Eur J Radiol 2020 May 3;126:108933. Epub 2020 Mar 3.

Radiotherapy Unit, National Center of Oncology Hadrontherapy (CNAO), Pavia, Italy.

Purpose: To evaluate if baseline ADC from DWI sequences could predict response to treatment in patients with sacral chordoma not suitable for surgery treated with carbon ion radiotherapy (CIRT) alone compared with volume changes.

Methods: Fifty-nine patients with sacral chordoma not suitable for surgery underwent one cycle of CIRT alone and a minimum of 12-months follow-up. All patients underwent MRI before treatment (baseline), every three months in the first two years after treatment, and every six months afterwards. For each MRI, lesion volume was obtained and median, kurtosis, and skewness ADC were analyzed within the whole lesion volume. Volume changes between baseline and the last available follow-up were used to divide patients with partial response, progression of disease and stable disease (PR, PD, and SD).

Results: Ten patients were excluded since DWI sequences from baseline MRI were not available. ADC maps obtained from baseline DWI examinations of 50 lesions in the remaining 49 patients were considered. Seven lesions were categorized as PD, 30 PR, and 13 SD. PD showed significantly higher median ADC values at baseline (p = 0.003) compared with both PR and SD (1665vs1253vs1263 *10 mm²/s), and more negative skewness values (-0.26vs0.26vs0.08), although not significantly different (p = 0.16).

Conclusions: Preliminary results suggest that baseline ADC could predict response to treatment with CIRT, particularly to detect potential non-responder patients.
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http://dx.doi.org/10.1016/j.ejrad.2020.108933DOI Listing
May 2020

Is Proton Beam Radiotherapy Worthwhile in the Management of Angiosarcoma of the Scalp?

Anticancer Res 2020 Mar;40(3):1645-1649

National Center of Oncological Hadrontherapy (Fondazione CNAO), Pavia, Italy.

In inoperable patients, the management of angiosarcoma of the scalp is challenging. Due to intrinsic, dosimetric and radiobiological properties, proton beam radiotherapy may be an effective and safe option to offer to these difficult-to-cure patients. Here, we report a case of angiosarcoma of the scalp treated successfully with proton beam radiotherapy. Angiosarcoma is a rare malignancy concerning around 2% of soft-tissue sarcomas and 5% of cutaneous soft-tissue sarcomas. Cutaneous angiosarcomas can occur in any part of the body, but the head and neck region is a common primary site and the scalp is a frequent site in elderly patients.
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http://dx.doi.org/10.21873/anticanres.14114DOI Listing
March 2020

Mixed-beam approach in locally advanced nasopharyngeal carcinoma: IMRT followed by proton therapy boost versus IMRT-only. Evaluation of toxicity and efficacy.

Acta Oncol 2020 May 23;59(5):541-548. Epub 2020 Feb 23.

Scientific Direction, European Institute of Oncology IRCCS, Milan, Italy.

To compare radiation-induced toxicity and dosimetry parameters in patients with locally advanced nasopharyngeal cancer (LANPC) treated with a mixed-beam (MB) approach (IMRT followed by proton therapy boost) with an historic cohort of patients treated with a full course of IMRT-only. Twenty-seven patients with LANPC treated with the MB approach were compared to a similar cohort of 17 patients treated with IMRT-only. The MB approach consisted in a first phase of IMRT up to 54-60 Gy followed by a second phase delivered with a proton therapy boost up to 70-74 Gy (RBE). The total dose for patients treated with IMRT-only was 69.96 Gy. Induction chemotherapy was administrated to 59 and 88% and concurrent chemoradiotherapy to 88 and 100% of the MB and IMRT-only patients, respectively. The worst toxicity occurring during the entire course of treatment (acute toxicity) and early-late toxicity were registered according to the Common Terminology Criteria Adverse Events V4.03. The two cohorts were comparable. Patients treated with MB received a significantly higher median total dose to target volumes ( = .02). Acute grade 3 mucositis was found in 11 and 76% ( = .0002) of patients treated with MB and IMRT-only approach, respectively, while grade 2 xerostomia was found in 7 and 35% ( = .02) of patients treated with MB and IMRT-only, respectively. There was no statistical difference in late toxicity. Local progression-free survival (PFS) and progression-free survival curves were similar between the two cohorts of patients ( = .17 and  = .40, respectively). Local control rate was 96% and 81% for patients treated with MB approach and IMRT-only, respectively. Sequential MB approach for LANPC patients provides a significantly lower acute toxicity profile compared to full course of IMRT. There were no differences in early-late morbidities and disease-related outcomes (censored at two-years) but a longer follow-up is required to achieve conclusive results.
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http://dx.doi.org/10.1080/0284186X.2020.1730001DOI Listing
May 2020

Hypofractionation in prostate cancer radiotherapy: a step forward towards clinical routine.

Transl Androl Urol 2019 Dec;8(Suppl 5):S528-S532

Radiation Oncology Department, CNAO National Center for Oncological Hadrontherapy, Pavia, Italy.

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http://dx.doi.org/10.21037/tau.2019.11.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989845PMC
December 2019

Peri-operative prognostic factors for primary skull base chordomas: results from a single-center cohort.

Acta Neurochir (Wien) 2021 03 16;163(3):689-697. Epub 2020 Jan 16.

Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy.

Background: Skull base chordomas (SBC) are rare malignant tumors and few factors have been found to be reliable markers for clinical decision making and survival prognostication. The aim of the present work was to identify specific prognostic factors potentially useful for the management of SBC patients.

Methods: A retrospective review of all the patients diagnosed and treated for SBC at the Fondazione IRCCS Istituto Neurologico "Carlo Besta" between January 1992 and December 2017 has been performed. Survival analysis was performed and a logistic regression model was used. Statistically significant predictors were rated based on their log odds in order to preliminarily build a personalized grading scale-the Peri-Operative Chordoma Scale (POCS).

Results: Fifty-nine primary chordoma patients were included. The average follow-up from the first treatment was 82.6 months (95% CI, 65.5-99.7). POCS was built over PFS and MR contrast enhancement (intense vs mild/no, value 4), preoperative motor deficit (yes vs no, value 3), and the development of any postoperative complications (yes vs no, value 2). POCS ranges between 0 and 9, with higher scores being associated with reduced likelihood of survival and progression-free state.

Conclusions: Our results show that preoperative clinical symptoms (motor deficits), surgical features (extent of tumor resection and surgeon's experience), development of postoperative complications, and KPS decline represent significant prognostic factors. The degree of MR contrast enhancement significantly correlated to both OS and PFS. We also preliminarily developed the POCS as a prognostic grading scale which may help neurosurgeons in the personalized management of patients undergoing potential adjuvant therapies.
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http://dx.doi.org/10.1007/s00701-020-04219-7DOI Listing
March 2021

Perfusion and diffusion in meningioma tumors: a preliminary multiparametric analysis with Dynamic Susceptibility Contrast and IntraVoxel Incoherent Motion MRI.

Magn Reson Imaging 2020 04 28;67:69-78. Epub 2019 Dec 28.

Politecnico di Milano, CartCasLab, Department of Electronics Information and Bioengineering, Piazza Leonardo Da Vinci 42, Milan, Italy; Centro Nazionale di Adroterapia Oncologica, Strada Campeggi 53, Pavia, Italy.

Multiparametric MRI is a remarkable imaging method for the assessment of patho-physiological processes. In particular, brain tumor characterization has taken advantage of the development of advanced techniques such as Diffusion- (DWI) and Perfusion- (PWI) Weighted Imaging, but a thorough analysis of meningiomas is still lacking despite the variety of computational methods proposed. We compute perfusion and diffusion parametric maps relying on a well-defined methodological workflow, investigating possible correlations between pure and diffusion-based perfusion parameters in a cohort of 26 patients before proton therapy. A preliminary investigation of meningioma staging biomarkers based on IntraVoxel Incoherent Motion and Dynamic Susceptibility Contrast is also reported. We observed significant differences between the gross target volume and the normal appearing white matter for every investigated parameter, confirming the higher vascularization of the neoplastic tissue. DWI and PWI parameters appeared to be weakly correlated and we found that diffusion parameters - the perfusion fraction in particular - could be promising biomarkers for tumor staging.
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http://dx.doi.org/10.1016/j.mri.2019.12.003DOI Listing
April 2020

Virtual 4DCT from 4DMRI for the management of respiratory motion in carbon ion therapy of abdominal tumors.

Med Phys 2020 Mar 20;47(3):909-916. Epub 2020 Jan 20.

Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milano, 20133, Italy.

Purpose: To evaluate a method for generating virtual four-dimensional computed tomography (4DCT) from four-dimensional magnetic resonance imaging (4DMRI) data in carbon ion radiotherapy with pencil beam scanning for abdominal tumors.

Methods: Deformable image registration is used to: (a) register each respiratory phase of the 4DMRI to the end-exhale MRI; (b) register the reference end-exhale CT to the end-exhale MRI volume; (c) generate the virtual 4DCT by warping the registered CT according to the obtained deformation fields. A respiratory-gated carbon ion treatment plan is optimized on the planning 4DCT and the corresponding dose distribution is recalculated on the virtual 4DCT. The method was validated on a digital anthropomorphic phantom and tested on eight patients (18 acquisitions). For the phantom, a ground truth dataset was available to assess the method performances from the geometrical and dosimetric standpoints. For the patients, the virtual 4DCT was compared with the planning 4DCT.

Results: In the phantom, the method exhibits a geometrical accuracy within the voxel size and Dose Volume Histograms deviations up to 3.3% for target V (mean dose difference ≤ 0.2% of the prescription dose, gamma pass rate > 98%). For patients, the virtual and the planning 4DCTs show good agreement at end-exhale (3% median D difference), whereas other respiratory phases exhibit moderate motion variability with consequent dose discrepancies, confirming the need for motion mitigation strategies during treatment.

Conclusions: The virtual 4DCT approach is feasible to evaluate treatment plan robustness against intra- and interfraction motion in carbon ion therapy delivered at the abdominal site.
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http://dx.doi.org/10.1002/mp.13992DOI Listing
March 2020

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

Cancers (Basel) 2019 Dec 21;12(1). Epub 2019 Dec 21.

Clinical Department, Centro Nazionale di Adroterapia Oncologica, 27100, Pavia, Italy.

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 ( = 22) and sacral chordoma ( = 41), were recalculated with the mMKM using an in-house developed tool. The relation between rectum dose-volume points in the two RBE systems (D and D) 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: DVHs lay largely below original constraints; the translated D values were 4.5%, 8.3%, 18.5%, and 35.4% higher than the nominal D 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 D ≤ 61 Gy(RBE) and D ≤ 66 Gy(RBE).
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http://dx.doi.org/10.3390/cancers12010046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016830PMC
December 2019

Evaluation of the early endocrinological sequelae after hadron therapy on anterior skull base lesions in the adult population.

Minerva Endocrinol 2020 06 13;45(2):162-164. Epub 2019 Nov 13.

Neurosurgery Unit, Ospedale Fatebenefratelli e Oftalmico, ASST Fatebenefratelli Sacco, Milan, Italy.

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http://dx.doi.org/10.23736/S0391-1977.19.03071-2DOI Listing
June 2020

Long-time clinical experience in patient setup for several particle therapy clinical indications: management of patient positioning and evaluation of setup reproducibility and stability.

Br J Radiol 2020 Mar 14;93(1107):20190595. Epub 2019 Nov 14.

Bioengineering Unit, Clinical Department, CNAO National Center for Oncological Hadrontherapy, Pavia, Italy.

Objective: Accurate patient positioning is crucial in particle therapy due to the geometrical selectivity of particles. We report and discuss the National Center for Oncological Hadrontherapy (CNAO) experience in positioning accuracy and stability achieved with solid thermoplastic masks fixed on index base plates and assessed by daily orthogonal X-ray imaging.

Methods: Positioning data were retrospectively collected (between 2012 and 2018) and grouped according to the treated anatomical site. 19696 fractions of 1325 patients were evaluated.The study was designed to assess:(i) the number of fractions in which a single correction vector was applied(SCV);(ii) the number of fractions in which further setup verification was performed (SV);(iii) the number of fractions in which SV lead to an additional correction within (MCV<5min) or after (MCV>5min) 5 minutes from the first setup correction;(iv) the systematic (Σ) and random (σ) error components of the correction vectors applied.

Results: A SCV was applied in 71.5% of fractions, otherwise SV was required. In 30.6% of fractions with SV, patient position was not further revised. In the remaining fractions, MCV<5min and MCV>5min were applied mainly in extracranial and cranial sites respectively.Interfraction Σ was ≤ 1.7 mm/0.7° and σ was ≤ 1.2 mm/0.6° in cranial sites while in extracranial sites Σ was ≤ 5.5 mm/0.9° and σ was ≤4.4 mm/0.9°. Setup residuals were submillimetric in all sites. In cranial patients, maximum intrafractional Σ was 0.8 mm/0.4°.

Conclusion: This report extensively quantifies inter- and intrafraction setup accuracy on an institutional basis and confirms the need of image guidance to fully benefit from the geometrical selectivity of particles.

Advances In Knowledge: The reported analysis provides a board institutional data set on the evaluation of patient immobilization and bony anatomy alignment for several particle therapy clinical indications.
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http://dx.doi.org/10.1259/bjr.20190595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066939PMC
March 2020
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