Barbara Vischioni

Correlation between egfr expression and accelerated proliferation during radiotherapy of head and neck squamous cell carcinoma

PurposeTo investigate the correlation between the expression of Epidermal Growth Factor receptor (EGFr) and the reduction of the effective doubling time (TD) during radiotherapy treatment and also to determine the dose per fraction to be taken into account when the overall treatment time (OTT) is reduced in accelerated radiotherapy of head and neck squamous cell carcinoma (HNSCC).MethodsA survey of the published papers comparing 3-years of local regional control rate (LCR) for a total of 2162 patients treated with conventional and accelerated radiotherapy and with a pretreatment assessment of EGFr expression, was made. Different values of TD were obtained by a model incorporating the overall time corrected biologically effective dose (BED) and a 3-year clinical LCR for high and low EGFr groups of patients (HEGFr and LEGFr), respectively. By obtaining the TD from the above analysis and the sub-sites’ potential doubling time (Tpot) from flow cytometry and immunohistochemical methods, we were able to estimate the average TD for each sub-site included in the analysis. Moreover, the dose that would be required to offset the modified proliferation occurring in one day (Dprolif), was estimated.ResultsThe averages of TD were 77 (27-90)95% days in LEGFr and 8.8 (7.3-11.0)95% days in HEGFr, if an onset of accelerated proliferation TK at day 21 was assumed. The correspondent HEGFr sub-sites’ TD were 5.9 (6.6), 5.9 (6.6), 4.6 (6.1), 14.3 (12.9) days, with respect to literature immunohistochemical (flow cytometry) data of Tpot for Oral-Cavity, Oro-pharynx, Hypo-pharynx, and Larynx respectively. The Dprolif for the HEGFr groups were 0.33 (0.29), 0.33 (0.29), 0.42 (0.31), 0.14 (0.15) Gy/day if α = 0.3 Gy-1 and α/β = 10 Gy were assumed.ConclusionsA higher expression of the EGFr leads to enhanced proliferation. This study allowed to quantify the extent of the effect which EGFr expression has in terms of reduced TD and Dprolif for each head and neck sub-site.

Image Guided Hypofractionated Radiotherapy and Quality of Life for Localized Prostate Cancer: Prospective Longitudinal Study in 337 Patients

PURPOSE We prospectively analyzed quality of life in a cohort of patients with prostate cancer undergoing a course of hypofractionated image guided radiotherapy. MATERIALS AND METHODS Between August 2006 and January 2011, 337 patients with a median age of 73 years who had cT1-T2N0M0 prostate cancer were eligible for this prospective, longitudinal study of hypofractionated image guided radiotherapy (70.2 Gy/26 fractions) using 1 of 3 image guided radiotherapy modalities (transabdominal ultrasound, x-ray or cone beam computerized tomography) available in our radiation oncology department. Patients completed 4 questionnaires before treatment, and 6, 12 and 24 months later, including the International Index of Erectile Function-5, International Prostate Symptom Score, and EORTC (European Organization for Research and Treatment of Cancer) prostate cancer specific QLQ-PR25 and QLQ-C30. RESULTS Patient followup was updated to at least the last questionnaire time point. Median followup was 19 months. Significant deterioration in erectile function on the International Index of Erectile Function-5 was documented with time only in patients without androgen deprivation (p = 0.0002). No change with time was observed in urinary symptom related quality of life on the QLQ-PR25 or International Prostate Symptom Score. Slight deterioration in QLQ-PR25 bowel symptom related quality of life was observed (p = 0.02). Overall QLQ-C30 Global Health Status improved with time (p = 0.03). On univariate analysis it significantly correlated with the maximum RTOG (Radiation Therapy Oncology Group)/EORTC urinary and bowel late toxicity scores after radiotherapy. CONCLUSIONS The regimen of hypofractionated image guided radiotherapy with multiple imaging modalities adopted in our radiation oncology department for localized prostate cancer might be a successful strategy for dose escalation with a limited impact on different aspects of quality of life with time.

Radiation therapy for retroperitoneal sarcoma

PurposeRetroperitoneal sarcomas (RPS) are rare tumours with an annual reported incidence of 2.7 per million persons. In spite of improvements in both diagnostic imaging and therapeutic strategies, patients afflicted by RPS still have poor prognoses. There are currently many different therapeutic strategies for these rare tumours and combining several different multi-modality strategies have not proved to have superior long-term clinical results. This review analyses the available published data and discusses multi-modality management of this rare entity. In particular, the role of radiation therapy, treatment-related side effects and the use of modern radiation treatment techniques will be discussed.Materials and methodsA comprehensive literature search was conducted using PubMed in January 2011. Relevant international articles published from January 1980 to January 2011 were assessed. The keywords for search purposes were: retroperitoneum, sarcoma, radiotherapy, and radiation therapy. The search was limited to articles published in English. All articles were read in full by the authors and selected for inclusion based on relevance to this article.ConclusionsThe addition of radiation therapy (RT) to wide surgical excision for RPS has improved local control rates when compared with surgery alone. Preoperative RT is preferred over postoperative RT. New types and delivery techniques in radiation therapy could further improve patient outcomes. Emerging therapies that employ charged particles (such as protons and carbon ions) are expected to be superior in sparing of normal tissues and efficacy over conventional photon therapy radiation, due to their physical and radiobiological properties.

Modelling the correlation between EGFr expression and tumour cell radiosensitivity, and combined treatments of radiation and monoclonal antibody EGFr inhibitors

PurposeTo estimate the effects of heterogeneity on tumour cell sensitivity to radiotherapy combined with radiosensitizing agents attributable to differences in expression levels of Epidermal Growth Factor Receptor (EGFr).Materials and methodsDifferences in radiosensitivity are not limited to cells of different cancer histotypes but also occur within the same cancer, or appear during radiotherapy if radiosensitizing drugs are combined with ionizing radiation. A modified biologically effective dose (MBED), has been introduced to account for changes in radiosensitivity parameters (α and α/β) rather than changes in dose/fraction or total dose as normally done with standard biologically effective dose (BED). The MBED approach was applied to cases of EGFr over-expression and cases where EGFr inhibitors were combined with radiation. Representative examples in clinical practice were considered.ResultsAssuming membrane EGFr over-expression corresponds to reduced radiosensitivity (αH = 0.15 Gy-1 and αH/βH = 7.5 Gy) relative to normal radiosensitivity (α = 0.2 Gy-1 and α/β = 10 Gy), an increased dose per fraction of 2.42 Gy was obtained through the application of MBED, which is equivalent to the effect of a reference schedule with 30 fractions of 2 Gy. An equivalent hypo-fractionated regime with a dose per fraction of 2.80 Gy is obtained if 25 fractions are set. Dose fractionations modulated according to drug pharmacokinetics are estimated for combined treatments with biological drugs. Soft and strong modulated equivalent hypo-fractionations result from subtraction of 5 or 10 fractions, respectively.ConclusionsDuring this computational study, a new radiobiological tool has been introduced. The MBED allows the required dose per fraction to be estimated when tumour radiosensitivity is reduced because EGFr is over-expressed. If radiotherapy treatment is combined with EGFr inhibitors, MBED suggests new treatment strategies, with schedules modulated according to drug pharmacokinetics.

Dose prescription in carbon ion radiotherapy: How to compare two different RBE-weighted dose calculation systems.

BACKGROUND AND PURPOSE In carbon ion radiotherapy (CIRT), the use of different relative biological effectiveness (RBE) models in the RBE-weighted dose (DRBE) calculation can lead to deviations in the physical dose (Dphy) delivered to the patient. Our aim is to reduce target Dphy deviations by converting prescription dose values. MATERIAL AND METHODS Planning data of patients treated at the National Institute of Radiological Sciences (NIRS) were collected, with prescribed doses per fraction ranging from 3.6Gy (RBE) to 4.6Gy (RBE), according to the Japanese semi-empirical model. The Dphy was Monte Carlo (MC) re-calculated simulating the NIRS beamline. The local effect model (LEM)_I was then applied to estimate DRBE. Target median DRBE ratios between MC+LEM_I and NIRS plans determined correction factors for the conversion of prescription doses. Plans were re-optimized in a LEM_I-based commercial system, prescribing the NIRS uncorrected and corrected DRBE. RESULTS The MC+LEM_I target median DRBE was respectively 15% and 5% higher than the NIRS reference, for the lowest and highest dose levels. Uncorrected DRBE prescription resulted in significantly lower target Dphy in re-optimized plans, with respect to NIRS plans. CONCLUSIONS Prescription dose conversion factors could minimize target physical dose variations due to the use of different radiobiological models in the calculation of CIRT RBE-weighted dose.

[11C]Choline PET/CT Impacts Treatment Decision Making in Patients With Prostate Cancer Referred for Radiotherapy

BACKGROUND The purpose of our study was to analyze the role of [(11)C]choline-positron emission tomography/computed tomography (cho-PET/CT) in the management of patients with prostate cancer referred for radiotherapy. PATIENTS AND METHODS Inclusion criteria for this retrospective study were (1) presence of prostate cancer, (2) referral for first radiotherapy course (for primary or recurrent tumor) between February 2007 and July 2010, and (3) performance of cho-PET/CT. All cho-PET/CT scans were classified according to whether they were positive in the prostate/prostate bed (T), pelvic lymph nodes (N), and distant metastases (M) or negative. Therapeutic strategy based on the cho-PET/CT evaluation was compared with the strategy that would have been proposed had cho-PET/CT imaging not been available, following international and national prostate cancer guidelines. RESULTS Eighty-two cho-PET/CT scans performed in 74 patients were analyzed. Cho-PET/CT was positive in 49 studies (60%): T only in 22 (45% of all positive studies); N only in 4 (8%); T in combination with N in 3 (6%); and M in combination with T or N, or both, in 16 (33%). Treatment after positive cho-PET/CT examination included radiotherapy ± androgen deprivation (29 patients), surgery ± radiotherapy (6 patients), androgen deprivation only (8 patients), and other treatment (6 patients). In 22 cases, cho-PET/CT (27%) altered the treatment approach compared with the treatment that would have been adopted in the absence of cho-PET/CT analysis. CONCLUSION Cho-PET/CT is valuable in defining the extent of disease and supporting therapeutic decisions in the management of prostate cancer. The therapeutic strategy turned out to be influenced by cho-PET/CT imaging in about one third of the patients included in this study.

Rationale and protocol of AIRC IG-13218, short-term radiotherapy for early prostate cancer with concomitant boost to the dominant lesion.

Introduction Of the different treatments for early prostate cancer, hypofractionated external-beam radiotherapy is one of the most interesting and studied options. Methods The main objective of this phase II clinical study is to evaluate the feasibility, in terms of the incidence of acute side effects, of a new ultra-hypofractionated scheme for low- or intermediate-risk prostate cancer patients treated with the latest imaging and radiotherapy technology, allowing dose escalation to the dominant intraprostatic lesion identified by multiparametric magnetic resonance imaging. Secondary endpoints of the study are the evaluation of the long-term tolerability of the treatment in terms of late side effects, quality of life, and efficacy (oncological outcome). Results The study is ongoing, and we expect to complete recruitment by the end of 2016. Conclusions Like in previous studies, we expect ultra-hypofractionated radiation treatment for prostate cancer to be well tolerated and effective. Trial registration ClinicalTrials.gov identifier: NCT01913717.

Impact of medical discipline and observer gender on cosmetic outcome evaluation in breast reconstruction using transverse rectus abdominis myocutaneous (TRAM) flap and radiotherapy

BACKGROUND Despite the complication rate, the majority of studies report a satisfactory cosmetic outcome in patients undergoing transverse rectus abdominis myocutaneous (TRAM) flap breast reconstruction both before and after radiotherapy (RT). The lack of a universal agreement on the use of a validated scale for cosmetic assessment in clinical practise leads to subjective criteria of evaluation and causes a great deal of interobserver variability. This study investigates whether there is any difference in the evaluation of cosmesis according to gender and specialisation of the observer. METHODS Fifty-two photographs of the patients who had undergone TRAM reconstruction for breast cancer, divided into three groups according to the treatment (TRAM only, TRAM→RT, RT→TRAM), were evaluated by 21 specialists, 10 male and 11 female from radiotherapy, breast surgery and plastic reconstructive surgery. Cosmetic outcome was classified using the four-category Harvard scale: a score of excellent/good was considered acceptable. RESULTS The overall rate of good/excellent ratings was 66.6%, which was lower than the score reported in the literature. A significantly worse score was registered in the TRAM→RT group compared with the other groups. The probability for male physicians to award a positive judgement is 24% higher than that of female ones. In general, there is a decent agreement among the judgement raters. CONCLUSIONS No statistically significant difference in cosmetic evaluation was noted overall between male physicians and female ones. However, within each specialisation, the difference between the two genders was great. Breast surgeons gave the worst opinion, and among them female surgeons judged most severely, whereas plastic surgeons gave the best opinion, and among them females provided the highest favourable judgement.

Surgical spacer placement prior carbon ion radiotherapy (CIRT): an effective feasible strategy to improve the treatment for sacral chordoma

BackgroundSacral chordoma (SC) is a neoplasm arising from residual notochordal cells degeneration. SC is difficult to manage mainly because of anatomic location and tendency to extensive spread. Carbon ion radiotherapy (CIRT) is highly precise to selectively deliver high biological effective dose to the tumor target sparing the anatomical structure on its path even if when SC is contiguous to the intestine, and a surgical spacer might be an advantageous tool to create a distance around the target volume allowing radical curative dose delivery with a safe dose gradient to the surrounding organs. This paper describes a double approach—open and hand-assisted laparoscopic—for a silicon spacer placement in patients affected by sacral chordoma undergoing carbon ion radiotherapy.MethodsSix consecutive patients have been enrolled for surgical spacer placement—open (three) or hand-assisted (three)—prior carbon ion radiotherapy treatment in order to increase efficacy of carbon ion radiotherapy minimizing its side effects.ResultsResults showed that silicon spacer placement for SC treatment is feasible both via laparoscopic and laparotomic approach.ConclusionsIts use might improve CIRT safety and thus efficacy for SC treatment.

Phase II multi-institutional clinical trial on a new mixed beam RT scheme of IMRT on pelvis combined with a carbon ion boost for high-risk prostate cancer patients

Purpose Definition of the optimal treatment schedule for high-risk prostate cancer is under debate. A combination of photon intensity modulated radiotherapy (IMRT) on pelvis with a carbon ion boost might be the optimal treatment scheme to escalate the dose on prostate and deliver curative dose with respect to normal tissue and quality of dose distributions. In fact, carbon ion beams offer the advantage to deliver hypofractionated radiotherapy (RT) using a significantly smaller number of fractions compared to conventional RT without increasing risks of late effects. Methods This study is a prospective phase II clinical trial exploring safety and feasibility of a mixed beam scheme of carbon ion prostate boost followed by photon IMRT on pelvis. The study is designed to enroll 65 patients with localized high-risk prostate cancer at 3 different oncologic hospitals: Istituto Europeo di Oncologia, Fondazione IRCCS Istituto Nazionale dei Tumori, and Centro Nazionale di Adroterapia Oncologica. The primary endpoint is the evaluation of safety and feasibility with acute toxicity scored up to 1 month after the end of RT. Secondary endpoints are treatment early (3 months after the end of RT) and long-term tolerability, quality of life, and efficacy. Results The study is not yet recruiting; in silico studies are ongoing and we expect to start recruitment by 2017. Conclusions The present clinical trial aims at improving the current treatment for high-risk prostate cancer, evaluating safety and feasibility of a new RT mixed-beam scheme including photons and carbon ions. Encouraging results are coming from carbon ion facilities worldwide on the treatment of different tumors including prostate cancers. Carbon ions combine physical properties allowing for high dose conformity and advantageous radiobiological characteristics. The proposed mixed beam treatment has the advantage to combine a photon high conformity standard of care IMRT phase with a hypofractionated carbon ion RT boost delivered in a short overall treatment time.