Rosario Mazzola

Radiation Dose-Response Relationship for Risk of Coronary Heart Disease in Survivors of Hodgkin Lymphoma

TO THE EDITOR: In their recent article in Journal of Clinical Oncology, van Nimwegen et al described a case-control study in a cohort of Hodgkin lymphoma (HL) survivors treated between 1965 and 1995 who had an increased risk of coronary heart disease (CHD) that was linearly related to mean heart radiation dose. The authors noted that “the linear radiation dose-response relationship identified can be used to predict CHD risk for future HL patients and survivors.” These findings are relevant in the management of long-termHL survivors, but in themodern era of combinedmodality treatment of HL, the role of radiation therapy (RT) has been significantly modified, leading to personalized RT in terms of clinical and technical aspects. In several settings, RT in combination with systemic therapies influences the natural history and management of malignancies, irrespective of adverse effects. A consequence of this therapeutic process is that prolongation of the survival of these patients inevitably exposes them to a greater risk of chronic diseases over the years. The issue of late cardiac toxicity is not new in the setting of irradiation for thoracic malignancies such as breast cancer. This aspect remains well recognized in the modern RT era, although there is a warning derived from retrospective evaluations in the era of old RT. The combination of RT and chemotherapy is considered the standard approach in HL. The use of limited radiation field (involved-field and involved-site RT) allows control of known tumor sites, whereas the use of limited cycles of chemotherapy can eradicate HL cells outside the radiation field. This approach, when compared with chemotherapy alone, has an advantage in diseasefree survival. The impact of reduced volumes and doses has been addressed, especially with the integration of modern imaging and advanced techniques for delivery of treatment. In this regard, the concept of extended-field irradiation has now been replaced by the use of detectable nodal irradiation that uses [F]fluorodeoxyglucose positron emission tomography, with results similar to those achieved with large volumes but fewer adverse events. The rationale for this therapeutic change is that recurrences in patients treated for HL occur in sites of previous involvement. Conversely, technological advances in RT, such as image-guided RT by means of on-board imaging, allow clinicians to improve the accuracy of delivery and thus minimize irradiation of healthy tissues. Apart from the adoption of intensitymodulated RT techniques (eg, volumetric-modulated arc therapy) that are potentially able to better reduce high doses tothe heart, other approaches could minimize heart radiation exposure in these patients. For example, in other thoracic diseases, breathing-adapted RT delivery could reduce the dose to the heart and left coronary artery. Using these techniques could improve the toxicity profile of RT in the near future. In regard to this scenario of new RT techniques and technologies, the study by van Nimwegen et al deserves critical evaluation. Most of patients analyzed in the study were treated with two-dimensional RT from 1965, which had a large impact on cardiac outcomes. Moreover, radiation charts and simulation radiographs were used to estimate in-field heart volume and mean heart dose without considering patient anatomy. In our opinion, the method seems rather crude. In the modern era of RT, it would be unthinkable to avoid accurate dosimetry using modern algorithms that adjust for tissue inhomogeneities. Thus, although RT allows radiation oncologists to improve the safety profile in their patients, the role of systemic therapy in treating cardiovascular damage is crucial. Anthracycline-based chemotherapy, a mainstay in HL as well as in other neoplastic diseases, has had a significant impact on cardiovascular morbidity. In conclusion, the issue of RT-induced cardiac risk needs to be revisited, especially considering the data emerging from the use of new RT techniques and reduced treatment volumes and doses. In the absence of these data, it seems that we are watching a black and white silent movie in the digital movie era.

Dose–volume-related dysphagia after constrictor muscles definition in head and neck cancer intensity-modulated radiation treatment

OBJECTIVE Dysphagia remains a side effect influencing the quality of life of patients with head and neck cancer (HNC) after radiotherapy. We evaluated the relationship between planned dose involvement and acute and late dysphagia in patients with HNC treated with intensity-modulated radiation therapy (IMRT), after a recontouring of constrictor muscles (PCs) and the cricopharyngeal muscle (CM). METHODS Between December 2011 and December 2013, 56 patients with histologically proven HNC were treated with IMRT or volumetric-modulated arc therapy. The PCs and CM were recontoured. Correlations between acute and late toxicity and dosimetric parameters were evaluated. End points were analysed using univariate logistic regression. RESULTS An increasing risk to develop acute dysphagia was observed when constraints to the middle PCs were not respected [mean dose (Dmean) ≥50 Gy, maximum dose (Dmax) >60 Gy, V50 >70% with a p = 0.05]. The superior PC was not correlated with acute toxicity but only with late dysphagia. The inferior PC was not correlated with dysphagia; for the CM only, Dmax >60 Gy was correlated with acute dysphagia ≥ grade 2. CONCLUSION According to our analysis, the superior PC has a major role, being correlated with dysphagia at 3 and 6 months after treatments; the middle PC maintains this correlation only at 3 months from the beginning of radiotherapy, but it does not have influence on late dysphagia. The inferior PC and CM have a minimum impact on swallowing symptoms. ADVANCES IN KNOWLEDGE We used recent guidelines to define dose constraints of the PCs and CM. Two results emerge in the present analysis: the superior PC influences late dysphagia, while the middle PC influences acute dysphagia.

Spinal metastases: Is stereotactic body radiation therapy supported by evidences?

Stereotactic body radiotherapy (SBRT) is becoming widely adopted in the treatment of primary and secondary tumors. Spinal bone metastases are frequently discovered in cancer patients, and in the past have been usually treated with a palliative goal. Nevertheless, in some particular clinical settings, such as oligometastatic patients and/or those with a long life expectancy, spinal SBRT could be considered a valid therapeutic option to obtain long-lasting palliation and, when possible, with a curative goal. This review aims to summarize available clinical and dosimetric data of published studies about spinal SBRT.

Intensity modulated radiation therapy with simultaneous integrated boost in early breast cancer irradiation. Report of feasibility and preliminary toxicity.

PURPOSE To investigate the feasibility and tolerance in the use of adjuvant intensity modulated radiation therapy (IMRT) and simultaneous integrated boost in patients with a diagnosis of breast cancer after breast-conserving surgery. PATIENTS AND METHODS Between September 2011 to February 2013, 112 women with a diagnosis of early breast cancer (T1-2, N0-1, M0) were treated with IMRT and simultaneous integrated boost after breast-conserving surgery in our institution. A dose of 50Gy in 25 fractions was prescribed to the whole breast and an additional dose of radiation was prescribed on the tumour bed. A dose prescription of 60Gy in 25 fractions to the tumour bed was used in patients with negative margins after surgery, whereas if the margins were close (<1mm) or positive (without a new surgical resection) a dose of 64Gy was prescribed. All patients were followed with periodic clinical evaluation. Acute and late toxicity were scored using the EORTC/RTOG radiation morbidity score system. Both patient and physician recorded cosmetic outcome evaluation with a subjective judgment scale at the time of scheduled follow-up. RESULTS The median follow-up was 28 months (range 24-40 months). The acute skin grade toxicity during the treatment was grade 0 in 8 patients (7%), grade 1 in 80 (72%), grade 2 in 24 cases (21%). No grade 3 or higher acute skin toxicity was observed. At 12 months, skin toxicity was grade 0 in 78 patients (70%), grade 1 in 34 patients (30%). No toxicity grade 2 or higher was registered. At 24 months, skin toxicity was grade 0 in 79 patients (71%), grade 1 in 33 patients (29%). No case of grade 2 toxicity or higher was registered. The pretreatment variables correlated with skin grade 2 acute toxicity were adjuvant chemotherapy (P=0.01) and breast volume ≥700cm(3) (P=0.001). Patients with an acute skin toxicity grade 2 had a higher probability to develop late skin toxicity (P<0.0001). In the 98% of cases, patients were judged to have a good or excellent cosmetic outcome. The 2-year-overall survival and 2-year-local control were 100%. CONCLUSION These data support the feasibility and safety of IMRT with simultaneous integrated boost in patients with a diagnosis of early breast cancer following breast-conserving surgery with acceptable acute and late treatment-related toxicity. A longer follow-up is needed to define the efficacy on outcomes.

Predictors of mucositis in oropharyngeal and oral cavity cancer in patients treated with volumetric modulated radiation treatment: A dose–volume analysis

The purpose of this study was to assess predictors of mucositis in oropharyngeal and oral cavity cancer after definitive or adjuvant volumetric modulated arc radiotherapy (VMAT) +/− chemotherapy.

Efficacy of stereotactic body radiotherapy in oligorecurrent and in oligoprogressive prostate cancer: new evidence from a multicentric study

Background:The aim of the present study is to evaluate the impact of metastases-directed stereotactic body radiotherapy in two groups of oligometastatic prostate cancer (PC) patients: oligorecurrent PC and oligoprogressive castration-resistant PC (oligo-CRPC).Methods:Inclusion criteria of the present multicentre retrospective analysis were: (1) oligorecurrent PC, defined as the presence of 1–3 lesions (bone or nodes) detected with choline positron emission tomography or CT plus bone scan following biochemical recurrence; (2) oligo-CRPC, defined as metastases (bone or nodes) detected after a prostatic-specific antigen rise during androgen deprivation therapy (ADT). Primary end points were: distant progression-free survival (DPFS) and ADT-free survival in oligorecurrent PC patients; DPFS and second-line systemic treatment-free survival in oligo-CRPC patients.Results:About 100 patients with oligorecurrent PC (139 lesions) and 41 with oligo-CRPC (70 lesions), treated between March 2010 and April 2016, were analysed. After a median follow-up of 20.4 months, in the oligorecurrent group 1- and 2-year DPFS were 64.4 and 43%. The rate of LC was 92.8% at 2 years. At a median follow-up of 23.4 months, in the oligo-CRPC group 1- and 2-year DPFS were 43.2 and 21.6%. Limitations include the retrospective design.Conclusions:Stereotactic body radiotherapy seems to be a useful treatment both for oligorecurrent and oligo-CRPC.

Impact of 18F-Choline PET/CT in the Decision-Making Strategy of Treatment Volumes in Definitive Prostate Cancer Volumetric Modulated Radiation Therapy.

Introduction Aim of the study is to evaluate the impact of Cho-PET/CT in decision-making strategy of patients with localized prostate cancer (PC) eligible to definitive radiotherapy (RT). Materials and Methods Sixty patients Cho-PET/CT before RT were prospectively enrolled. All patients were treated with volumetric modulated arc therapy with simultaneous integrated boost in 28 fractions. Androgen deprivation therapy was prescribed according to National Comprehensive Cancer Network (NCCN) risk classification. Therapeutic strategy based on the Cho-PET/CT evaluation was compared with the strategy that would have been proposed in case of PET not available and/or not strictly indicated, according to international and national PC guidelines. Results Cho-PET/CT was positive in 57 cases (95%): T in 45 (79%); T in combination with N in 8 (14%); and M (bone) in combination with T or N, or both, in 4 (7%). After Cho-PET/CT, patients were stratified as follows: 26 (43%) low risk, 10 (16%) intermediate risk, and 24 (41%) high risk. Cho-PET/CT shifted treatment indication in 13 cases (21%). The changes regarding radiation treatment volumes were as follows: 6 intermediate risk (10%) shifted to high risk and consequently were irradiated on prostate, seminal vesicles, and pelvic nodes PTVs; in 7 high risk (11%), the Cho-PET/CT showed bone and/or N uptake, and consequently, a simultaneous integrated boost on PET positive sites was prescribed. Conclusions Cho-PET/CT seems to be a promising diagnostic tool in patients who are candidates for radical RT and supporting the decision making in treatment planning, in particular in intermediate-high risk.

Volumetric-modulated arc stereotactic body radiotherapy for prostate cancer: dosimetric impact of an increased near-maximum target dose and of a rectal spacer

OBJECTIVE In volumetric-modulated arc therapy (VMAT) prostate stereotactic body radiotherapy (SBRT), dose coverage of the planning target volume (PTV) becomes challenging when the sparing of rectum, bladder and urethra is strictly pursued. Our current 35-Gy-in-five-fraction plans only assure 33.2 Gy to ≥95% PTV ([Formula: see text] ≥ 95%). Looking for an improved [Formula: see text], increased near-maximum target dose (D2%) and prostate-rectum spacer insertion were tested. METHODS For 11 patients, two VMAT plans, with D2% ≤ 37.5 Gy (Hom) or D2% ≤ 40.2 Gy (Het), on each of two CT studies, before or after spacer insertion, were computed. All plans assured [Formula: see text] ≥95%, and <1 cm(3) of rectum, bladder and urethra receiving ≥35 Gy. By hypothesis testing, several dose-volume metrics for target coverage and rectal sparing were compared across the four groups of plans. The impact of spacer insertion on the fractions of rectum receiving more than 18, 28 and 32 Gy ([Formula: see text]) was further tested by linear correlation analysis. RESULTS By hypothesis testing, the increased D2% was associated with improvements in target coverage, whereas spacer insertion was associated with improvements in both target coverage and rectal [Formula: see text]. By linear correlation analysis, spacer insertion was related to the reductions in rectal [Formula: see text] for X ≥ 28 Gy. CONCLUSION A slightly increased D2% or the use of spacer insertion was each able to improve [Formula: see text]. Their combined use assured [Formula: see text] ≥ 98% to all our patients. Spacer insertion was further causative for improvements in rectal sparing. ADVANCES IN KNOWLEDGE For VMAT plans in prostate SBRT, the distinct dosimetric usefulness of increased D2% and of the use of spacer insertion were validated in terms of target coverage and rectal sparing.

Radiotherapy in patients with connective tissue diseases

The decision to offer radiotherapy in patients with connective tissue diseases continues to be challenging. Radiotherapy might trigger the onset of connective tissue diseases by increasing the expression of self-antigens, diminishing regulatory T-cell activity, and activating effectors of innate immunity (dendritic cells) through Toll-like receptor-dependent mechanisms, all of which could potentially lead to breaks of immune tolerance. This potential risk has raised some debate among radiation oncologists about whether patients with connective tissue diseases can tolerate radiation as well as people without connective tissue diseases. Because the number of patients with cancer and connective tissue diseases needing radiotherapy will probably increase due to improvements in medical treatment and longer life expectancy, the issue of interactions between radiotherapy and connective tissue diseases needs to be clearer. In this Review, we discuss available data and evidence for patients with connective tissue diseases treated with radiotherapy.

Extreme hypofractionation for early prostate cancer: Biology meets technology

The aim of this review is to present the available radiobiological, technical and clinical data about extreme hypofractionation in primary prostate cancer radiotherapy. The interest in this technique is based on the favourable radiobiological characteristics of prostate cancer and supported by advantageous logistic aspects deriving from short overall treatment time. The clinical validity of short-term treatment schedule is proven by a body of non-randomised studies, using both isocentric (LINAC-based) or non-isocentric (CyberKnife®-based) stereotactic body irradiation techniques. Twenty clinical studies, each enrolling more than 40 patients for a total of 1874 treated patients, were revised in terms of technological setting, toxicity, outcome and quality of life assessment. The implemented strategies for the tracking of the prostate and the sparing of the rectal wall have been investigated with particular attention. The urinary toxicity after prostate stereotactic body irradiation seems slightly more pronounced as compared to rectal adverse events, and this is more evident for late occurring events, but no worse as respect to conventional fractionation schemes. As far as the rate of severe acute toxicity is concerned, in all the available studies the treatment was globally well tolerated. While awaiting long-term data on efficacy and toxicity, the analysed studies suggest that the outcome profile of this approach, alongside the patient convenience and reduced costs, is promising. Forty-eight ongoing clinical trials are also presented as a preview of the expectation from the near future.