Niccolò Giaj Levra

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 In this regard, the concept of extended-field irradiation has now been replaced by the use of detectable nodal irradiation that uses [F]fluorodeoxyglucose positron emission tomography, with results similar to those achieved with large volumes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.

Postoperative Radiotherapy for Patients With Completely Resected Pathologic N2 Non-Small- Cell Lung Cancer: A Retrospective Analysis

BACKGROUNDnAdjuvant radiotherapy in non-small-cell lung cancer (NSCLC) is still controversial. The purpose of this retrospective study was to evaluate the role of postoperative radiotherapy (PORT) in terms of local control and survival in pathologic N2 NSCLC.nnnPATIENTS AND METHODSnFrom January 2003 to December 2008, 66 patients with pathologic N2 NSCLC received PORT. Mediastinal lymph node metastases were classified into single (12 patients) or multiple (54 patients) stations. All patients received conformal radiation therapy, with a median total dose of 50.4 Gy. Target volumes included the bronchial stump, ipsilateral hilum, all pathologically involved lymph node regions, and all the lymph nodes between 2 noncontiguous pathologic nodal stations. The pattern of failure was considered as locoregional or systemic, or a combination of both. Locoregional failure was defined as in field or out of field.nnnRESULTSnMedian follow-up time was 34.9 months (range 3.5-62.8 months). Local control was 80% at 12 months, 77.2% at both 24 and 36 months, and 72.1% at 60 months. The pattern of failure was locoregional in 3 patients (1 out of field and 2 in field) and systemic in 25 patients, with 12 patients presenting both locoregional and distant disease. Overall survival at 12, 36, and 60 months was 77%, 44%, and 37%, respectively. Median survival time was 34 months. The number of pathologically involved lymph node stations was a prognostic factor for local control (P = .05), cancer-specific survival (CSS) (P = .04), and disease-free survival (DFS) (P = .04).nnnCONCLUSIONnDespite the limitations of the present study, mainly represented by its retrospective nature, our data support the role of PORT in terms of locoregional control and overall survival benefit; the number of involved mediastinal lymph nodes represents a significant prognostic factor in patients with pathologic N2 NSCLC.

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.

Whole brain radiotherapy with hippocampal avoidance and simultaneous integrated boost for brain metastases: a dosimetric volumetric-modulated arc therapy study

ObjectiveTo develop a feasible volumetric modulated arc therapy (VMAT) treatment in whole brain radiotherapy (WBRT) with a simultaneous integrated boost (SIB) and hippocampal (HP) sparing in 1–5 brain metastases (BMs).Methods and materialsTen patients with 20 BMs received a WBRT prescription of 20xa0Gy, SIB dose on BMs of 40xa0Gy/5 fractions. PTVWBRT was generated from brain minus BMs-PTVs (PTVSIB) and planning organ at risk volume to HP. All plans were evaluated in: homogeneity index (HI), target coverage (TC), maximum dose to prescription dose ratio (MDPD), prescription isodose to target volume ratio (PITV) and paddick conformity index (CI). We also evaluate D100xa0%, mean and maximum doses to HP. Planning objectives were for PTVWBRT, D2xa0%xa0=xa025xa0Gy with acceptable deviation of 26.7xa0Gy and D98xa0%xa0≥xa016.7xa0Gy; for PTVSIB D95xa0%xa0≥xa038xa0Gy; for HP, D100xa0%xa0=xa06xa0Gy with acceptable deviation of 6.7xa0Gy, Dmaxxa0=xa010.7xa0Gy with acceptable deviation of 11.3xa0Gy, a mean dose of 8xa0Gy.ResultsMean number of BMs was 2 (range 1–5). Mean values for BMs were volume of PTVSIBxa0=xa05.1xa0±xa04.9xa0cc, dose to 95xa0% of PTVSIB 39.3xa0±xa00.9xa0Gy, HI 0.083xa0±xa00.03, TC 0.96xa0±xa00.24, CI 0.78xa0±xa00.17. Mean MDPD was 1.06xa0±xa00.02 and PITV 0.96xa0±xa00.24. For WBRT, mean target volume was (13.46xa0±xa02)*102xa0cc, mean dose to 90xa0% of PTVWBRT 19.8xa0±xa00.2xa0Gy, mean HI 0.42xa0±xa00.12 and TC 0.78xa0±xa00.11. Mean and maximum HP doses were 7.7xa0±xa00.3xa0Gy and 10.5xa0±xa00.5xa0Gy. Mean dose to 100xa0% of HP volume (D100xa0%) was 6.7xa0±xa00.3xa0Gy.ConclusionsWBRT plus SIB with HP avoidance with VMAT was feasible. All dosimetric parameters were satisfied for PTVWBRT and PTVSIB.

Stereotactic radiosurgery for intracranial metastases: linac-based and gamma-dedicated unit approach

ABSTRACT Introduction: For intracranial metastases, the role of stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy is well recognized. Areas covered: Historically, the first technology, for stereotactic device able to irradiate a brain tumor volume, was Gamma Knife® (GK). Due to the technological advancement of linear accelerator (Linac), there was a continuous increasing interest in SRS Linac-based applications. In those decades, it was assumed a superiority of GK compared to SRS Linac-based for brain tumor in terms of dose conformity and rapid fall-off dose close to the target. Expert commentary: Recently, due to the Linac technologic advancement, the choice of SRS GK-based is not necessarily so exclusive. The current review discussed in details the technical and clinical aspects comparing the two approaches for brain metastases.

Cone-beam computed tomography in lung stereotactic ablative radiation therapy: predictive parameters of early response.

OBJECTIVE:nTo analyze lung lesion volume variations by contouring on cone-beam CT (CBCT) images to evaluate the early predictive parameters of stereotactic ablative radiation therapy (SABR) treatment response.nnnMETHODS:nThe prescribed dose of SABR was varied according to the tumour site (central or peripheral) and maximum diameter of the lesions by using a strategy of risk-adapted dose prescription with a dose range between 48 and 70u2009Gy in 3-10 consecutive fractions. For the purpose of the analysis, the gross tumour volume (GTV) was recontoured for each patient at first and last CBCT using two lung levels/windows: (a) -600/1000u2009HU and (b) -1000/250u2009HU. Univariate analysis was performed to evaluate a correlation between lung lesion variations on CBCT using the two levels/windows and treatment response 6 months after SABR. Independent variables were the number of fractions, time between initial and final fraction, biologically effective dose and pre-SABR GTV. Cut points of lesion volume reduction were evaluated to determine the correlation with complete response 6 months after SABR.nnnRESULTS:n41 lung lesions were evaluated. 82 lung lesions were recontoured for each CBCT level/window. A lung lesion shrinkage of at least 20% was revealed to be statistically related to complete response 6 months after SABR for both the CBCT levels/windows used. The probability of complete response ranged between six and eight times higher in respect to CBCT levels/windows -600/1000u2009HU and -1000/250u2009HU, respectively, compared with patients without a lesion shrinkage of 20% at the last session of SABR.nnnCONCLUSION:nAccording to current findings, a lung lesion shrinkage of at least 20% at the last session of SABR could be predictable of complete response 6 months thereafter. Further investigations about this topic are needed.nnnADVANCES IN KNOWLEDGE:nPrediction of the early tumour response could be useful to personalize imaging restaging after the completion of SABR or to incorporate additional therapies in case of poor responders to improve clinical outcomes.

Regarding Ening et al. Charlson comorbidity index: an additional prognostic parameter for preoperative glioblastoma patient stratification

For GBM patients, the CCI was evaluated only in 3 studies (Ening et al. 2015; Balducci et al. 2012; Fiorentino et al. 2012). In the study of Balducci et al., CCI was evaluated in 146 patients with GBM, showing that CCI < 2 did not correlated with survival. Only 10 patients had a CCI score 3, while 136 patients a score ≤2 (Balducci et al. 2012). In another published study, only the GBM elderly population (more than 65 years old) was evaluated using the adjusted-age CCI (ACCI). It can be used in association with age; thus, the scoring receives the addiction of the specific weighting of age. From the age of 50, one point was assigned for each 10-year period: 50–59 years, 1 point; 60–69 years, 2 points; 70–79 years, 3 points; 80–89 years, 4 points. In this analysis, 35 patients were analysed and ACCI correlated with survival in univariate and multivariate analysis (p = 0.004, p = 0.001) (Fiorentino et al. 2012). In the Eninig et al. study, the CCI was analysed for 233 GBM patients with a median age of 62 (15–84) who underwent surgery with or without adjuvant treatments (standard radiochemotherapy in 68 % of cases, no therapies in 10 %). In this retrospective analysis with a non-homogeneous population (patients under 18 years, different treatments approach, etc.), CCI more than 3 statistically influenced survival (p < 0.0001) and progression-free survival (p < 0.002). Despite the limits of the study, the authors excluded that the worst prognosis of GBM patients with a higher presurgery CCI was influenced by a higher surgery morbidity (considering the low surgical morbidity rate, 7 %) (Ening et al. 2015). These findings were obtained for the entire population of the study (233 patients), but it could be very interesting to analyse the impact of CCI also for the patients who receive the standard adjuvant treatments (68 %) to evaluate Dear Editor,

May non-metastatic clinically localized castration-resistant prostate cancer after primary androgen ablation benefit from salvage prostate radiotherapy?

ABSTRACTPurposenA proportion of patients with localized prostate cancer is still treated with primary androgen deprivation therapy (PADT) alone. Some of these patients may develop a PSA rising despite castration. The purpose of this study was to retrospectively evaluate the potential benefit of external beam radiotherapy (EBRT) in this cohort.MethodsForty-two patients presenting a non-metastatic castration-resistant prostate cancer after PADT were referred to our institution and underwent RT between June 2003 and July 2011. Biochemical failure (BF) after EBRT was defined according to Phoenix criteria (nadirxa0+xa02xa0ng/mL “at call”). Median RT dose was 78xa0Gy.ResultsMedian duration of PADT was 54xa0months (range 10.2–181xa0months). Median follow-up after EBRT was 53xa0months. Twenty-one patients had BF after EBRT (median time 27.4xa0months): 13 presented with loco-regional and/or distant metastases, while in 8 patients, a PSA rise only was observed. Ten patients died of prostate cancer (and no patient died of causes other than prostate cancer). Five-year biochemical disease-free survival (bDFS), distant metastases-free survival (DMFS) and cancer-specific survival (CSS) were, respectively, 39.4, 60 and 65xa0%. On multivariate analysis, GS, nadir PSA (nPSA) and a pre-EBRT PSA ≤5xa0ng/mL significantly affected bDFS, while Gleason score (GS) and T stage significantly affected distant metastases onset. No factors affected CSS at multivariate analysis.ConclusionsEBRT may be a suitable therapeutic option, able to provide an excellent loco-regional control and to obtain a systemic disease control in up to 60xa0% of patients at 5xa0years, especially in patients presenting with lower Gleason score and T stage at diagnosis and lower pre-RT PSA and nPSA post-RT.n

Stereotactic Ablative Radiation Therapy for Lung Oligometastases: Predictive Parameters of Early Response by (18)FDG-PET/CT

Objectives: The objective of this study was to investigate fludeoxyglucose F 18 positron emission tomography/computed tomography (18FDG‐PET/CT) parameters as predictive of response after stereotactic ablative radiotherapy (SABR) for lung oligometastases. Methods: The inclusion criteria of the current retrospective study were as follows: (1) lung oligometastases treated by SABR, (2) presence of 18FDG‐PET/CT before and after SABR for at least two subsequent evaluations, (3) Karnofsky performance status higher than 80, and (4) life expectancy longer than 6 months. All patients were treated with a biologically equivalent dose of at least 100 Gy with an alpha/beta ratio of 10. The following metabolic parameters were semiquantitatively defined: maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume, and total lesion glycolysis. Results: A total of 50 patients met the inclusion criteria, for a total of 70 lung metastases. The pre‐SABR median SUVmax was 6.5 (range 4–17), the median SUVmean was 3.7 (range 2.5–6.5), and the median metabolic tumor volume was 2.3 cm3 (0.2–31 cm3). The following metabolic parameters were significantly related to complete response at 6 months: SUVmax less than 5 (p < 0.001) and SUVmean less than 3.5 (p = 0.03). &Dgr;SUVmax at 3 to 6 months was +126% for lesions with in‐field progression versus –26% for the remaining lesions (p = 0.002). &Dgr;SUVmean at 3 to 6 months was +15% for lesions with in‐field progression versus –26% for the remaining metastases (p = 0.008). Conclusions: In the current analysis, complete response from lung metastasis at 6 months after stereotactic body radiation therapy was significantly associated with both the maximum and mean values of pre‐SABR 18FDG‐PET/CT SUV. Longer‐term trials are strongly advocated to improve the personalization of the monitoring of tumor response in patients with lung oligometastases and, consequently, monitoring of the cost‐effectiveness of the health care.

Efficacy and safety of stereotactic ablative radiotherapy in patients with previous pneumonectomy.

Background Thoracic surgery for a newly diagnosed primary lung tumor following a previous pneumonectomy is rarely indicated. Stereotactic ablative radiotherapy (SABR) might represent a curative option. This report focuses on outcomes, toxicity and quality of life (QoL) after SABR. Methods Nine patients were treated with SABR between 2004 and 2011; median time since surgery was 8.4 years. In 4 cases, a histological confirmation was possible with bronchoscopy. In 5 cases, the clinical proof of malignancy was based on radiological criteria. Forced expiratory volume in 1 second (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO) were tested in all patients. A SABR biologically equivalent dose of >100 Gy was prescribed in all cases. QoL questionnaire forms were administered before SABR and during follow-up. Results Median follow-up was 41.8 months. We did not observe grade >3 acute toxicity, and concerning late toxicity, we registered 2 cases. QoL was decreased during the first 12 months of follow-up, followed by a progressive improvement after this time. One patient had a local relapse at 7.4 years; 1 developed a new nodule at 5.5 years, associated with metastases; and 1 developed a new nodule without any systemic disease at 3 years. There were 2 cancer-related deaths (18.2%) at 3 and 12 months after progression. Conclusions Data support efficacy and safety of SABR in patients with a new primary lung cancer following previous pneumonectomy, with acceptable acute, late toxicity profile and without significant impairment of QoL. Our results were comparable to those in the literature.