The use of radiation therapy for oligoprogressive/oligopersistent oncogene-driven non small cell lung cancer: State of the art.

Oncogene-driven non small cell lung cancer (NSCLC) is a distinct entity in thoracic oncology. The availability of effective target therapies, like EGFR inhibitors or ALK inhibitors, have revolutionized the prognosis of these patients. However, despite an initial response in the majority of patients, drug resistance ultimately occurs. In some cases, this resistance develops in few clonal cells (oligoprogression), so that a local ablation of these resistant deposits could allow to maintain the same systemic therapy and possibly to prolong patients' survival. For these purposes, stereotactic body radiation therapy (SBRT) is an ideal local ablative treatment, because it is effective, non invasive and with limited side effects. In this review, we aim to analyze available clinical data to verify whether SBRT can allow these patients to continue with existing target therapy longer, delay the switch to other systemic therapies and improve their outcome modifying the natural history of the disease.

The Potential Role of Intensity-modulated Proton Therapy in the Regional Nodal Irradiation of Breast Cancer: A Treatment Planning Study.

AIMS: To investigate the role of intensity-modulated proton therapy (IMPT) for regional nodal irradiation in patients with breast carcinoma in comparison with volumetric-modulated arc therapy (VMAT). MATERIALS AND METHODS: A cohort of 20 patients (10 in the breast-conserving surgery group and 10 post-mastectomy patients with tissue expander implants) was investigated. Proton plans were also computed using robust optimisation methods. Plan quality was assessed by means of dose-volume histograms and scored with conventional metrics. Estimates of the risk of secondary cancer induction (excess absolute risk, EAR) were carried out, taking into account fractionation, repopulation and repair. RESULTS: Concerning target coverage, the data proved a substantial equivalence of VMAT and IMPT: for example, coverage for the 50 Gy target, expressed in terms of V98%, was 47.8 ± 0.4, 47.6 ± 0.4, 47.3 ± 0.8, consistent with the objective of 47.5 Gy, for post-mastectomy patients for the three groups of patients. Also, the conformality of the dose distributions was similar for the two techniques, about 1.1, without statistically significant differences. Organ at risk planning aims were achieved for all structures for both techniques. The mean dose to the ipsilateral lung was 10.8 ± 1.1, 6.2 ± 0.8, 7.2 ± 1.0; for the contralateral lung was 3.2 ± 0.7, 0.3 ± 0.2, 0.4 ± 0.2; for the contralateral breast was: 3.1 ± 0.7, 0.3 ± 0.3 and 0.3 ± 0.3, whereas it was 3.9 ± 0.9, 0.4 ± 0.3 and 0.5 ± 0.5, respectively, for the heart for VMAT, IMPT and robust IMPT plans over the whole group of patients. Robust optimisation affected the near-to-maximum dose values for contralateral lung and breast, the mean dose for the heart and ipsilateral lung, with a deterioration ranging from 20 to 40% of the nominal value of IMPT plans (e.g. from 8.1 ± 6.4 to 11.4 ± 8.8 for the heart compared with 16.2 ± 5.2 for the VMAT plans). The numerical values of EAR per 10 000 patient-years were about one order of magnitude higher for VMAT than for IMPT for contralateral structures: 11.66 ± 2.01, 0.89 ± 0.80, 0.98 ± 0.77 for the contralateral breast and the three groups of plans, respectively; 14.31 ± 2.75, 1.42 ± 0.80, 1.78 ± 0.87 for the contralateral lung; and 34.86 ± 2.64, 18.85 ± 2.15, 20.98 ± 2.35 for the ipsilateral lung. CONCLUSION: IMPT with or without robust optimisation seems to be a potentially promising approach for the radiation treatment of breast cancer when nodal volumes should be irradiated. This was measured in terms of dosimetric advantage and predicted clinical benefit. In fact, the significant reduction in estimated EAR could add further clinical value to the dosimetric sparing of the organs at risk achievable with IMPT.

Evaluation of target dose inhomogeneity in breast cancer treatment due to tissue elemental differences.

BACKGROUND: Monte Carlo simulations were run to estimate the dose variations generated by thedifference arising from the chemical composition of the tissues. METHODS: CT datasets of five breast cancer patients were selected. Mammary gland was delineated as clinical target volume CTV, as well as CTV_lob and CTV_fat, being the lobular and fat fractions of the entire mammary gland. Patients were planned for volumetric modulated arc therapy technique, optimized in the Varian Eclipse treatment planning system. CT, structures and plans were imported in PRIMO, based on Monte Carlo code Penelope, to run three simulations: AdiMus, where the adipose and muscle tissues were automatically assigned to fat and lobular fractions of the breast; Adi and Mus, where adipose and muscle, respectively were assigned to the whole mammary gland. The specific tissue density was kept identical from the CT dataset. Differences in mean doses in the CTV_lob and CTV_fat structures were evaluated for the different tissue assignments. Differences generated by the tissue composition and estimated by Acuros dose calculations in Eclipse were also analysed. RESULTS: From Monte Carlo simulations, the dose in the lobular fraction of the breast, when adipose tissue is assigned in place of muscle, is overestimated by 1.25 ± 0.45%; the dose in the fat fraction of the breast with muscle tissue assignment is underestimated by 1.14 ± 0.51%. Acuros showed an overestimation of 0.98 ± 0.06% and an underestimation of 0.21 ± 0.14% in the lobular and fat portions, respectively. Reason of this dissimilarity resides in the fact that the two calculations, Monte Carlo and Acuros, differently manage the range of CT numbers and the material assignments, having Acuros an overlapping range, where two tissues are both present in defined proportions. CONCLUSION: Although not clinically significant, the dose deposition difference in the lobular and connective fat fraction of the breast tissue lead to an improved knowledge of the possible dose distribution and homogeneity in the breast radiation treatment.

Organs at risk in lung SBRT.

Lung stereotactic body radiotherapy (SBRT) is an accurate and precise technique to treat lung tumors with high 'ablative' doses. Given the encouraging data in terms of local control and toxicity profile, SBRT has currently become a treatment option for both early stage lung cancer and lung oligometastatic disease in patients who are medically inoperable or refuse surgical resection. Dose-adapted fractionation schedules and ongoing prospective trials should provide further evidence of SBRT safety trying to reduce toxicities and complications. In this heterogeneous scenario, a non-systematic review of dose constraints for lung SBRT was performed, including the main organs at risk in the thorax.

Radical hypo-fractionated radiotherapy with volumetric modulated arc therapy in lung cancer : A retrospective study of elderly patients with stage III disease.

BACKGROUND: This study aimed to analyse the feasibility and acute toxicity of radical hypo-fractionated radiotherapy (RT) for elderly patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We conducted a retrospective evaluation of treatment with volumetric modulated arc therapy (VMAT) of elderly patients affected by stage III inoperable NSCLC. The dose prescription was 56 Gy in 20 fractions, 55 Gy in 22 fractions, or 50 Gy in 20 fractions. Target volume included only the primary lesion and the infiltrated lymph nodes. The primary end point was acute and late toxicity, while secondary end points were progression-free survival (PFS), and overall survival (OS). RESULTS: In all, 41 patients were included in this analysis. The mean age of the patients was 78.6 years, and 22 patients had staged IIIA while 19 patients had stage IIIB disease. All but one patient had pathological nodal involvement; 15 patients received chemotherapy before RT. Acute grade 1-2 toxicity was recorded in 25 (61%) patients. Late toxicity was recorded in 13 (32%) patients. No cases of G3 or G4 toxicity were recorded. Complete response was obtained in two (5%) patients, 26 (63%) showed a partial response, and two (5%) experience disease progression. At a mean follow-up of 9.9 months (range, 1.1-25.4), 17 patients had died from disease progression, one died from other causes, and 23 were alive. Median OS was 13.7 ± 1.5 months (95% CI: 10.7-16.7), OS at 12 and 18 months was 51.3 ± 9.5% and 35.1 ± 10.1%, respectively. Median PFS was 13.7 ± 2.3 months (95% CI: 9.1-18.2), and PFS at 12 and 18 months was 50.1 ± 9.9% and 38.9 ± 10.4%, respectively. CONCLUSION: Radical hypo-fractionated VMAT is a promising treatment for locally advanced NSCLC in the elderly. The use of hypo-fractionated radiotherapy for lung cancer in older patients can be considered a valuable approach, particularly for patients with poor performance status or refusing other treatment approaches.

Can Stereotactic Body Radiation Therapy Be a Viable and Efficient Therapeutic Option for Unresectable Locally Advanced Pancreatic Adenocarcinoma? Results of a Phase 2 Study.

PURPOSE: To assess the efficacy of stereotactic body radiotherapy in patients with unresectable locally advanced pancreatic cancer. MATERIALS AND METHODS: All patients received a prescription dose of 45 Gy in 6 fractions. Primary end point was freedom from local progression. Secondary end points were overall survival, progression-free survival, and toxicity. Actuarial survival analysis and univariate or multivariate analysis were investigated. RESULTS: Forty-five patients were enrolled in a phase 2 trial. Median follow-up was 13.5 months. Freedom from local progression was 90% at 2 years. On univariate ( P < .03) and multivariate analyses ( P < .001), lesion size was statistically significant for freedom from local progression. Median progression-free survival and overall survival were 8 and 13 months, respectively. On multivariate analysis, tumor size ( P < .001) and freedom from local progression ( P < .002) were significantly correlated with overall survival. Thirty-two (71%) patients with locally advanced pancreatic cancer received chemotherapy before stereotactic body radiotherapy. Median overall survival from diagnosis was 19 months. Multivariate analysis showed that freedom from local progression ( P < .035), tumor diameter ( P < .002), and computed tomography before stereotactic body radiotherapy ( P < .001) were significantly correlated with overall survival from diagnosis. CONCLUSION: Stereotactic body radiotherapy is a safe and effective treatment for patients with locally advanced pancreatic cancer with no G3 toxicity or greater and could be a promising therapeutic option in multimodality treatment regimen.

Radiotherapy and immunotherapy: Can this combination change the prognosis of patients with melanoma brain metastases?

Brain metastases are a common occurrence in patients with melanoma. Prognosis is poor. Radiotherapy is the main local treatment for brain metastases. Recently, immunotherapy (i.e. immune checkpoints inhibitors) showed a significant impact on the prognosis of patients with metastatic melanoma, also in the setting of patients with brain metastases. Despite various possible treatments, survival of patients with melanoma brain metastases is still unsatisfactory; new treatment modalities or combination of therapies need to be explored. Being immunotherapy and radiotherapy alone both efficient in the treatment of melanoma brain metastases, the combination of these two therapies seems logical. Moreover radiotherapy can improve the efficacy of immunotherapy and the immune system plays a relevant role in the action of radiotherapy. Preclinical data support this combination. Clinical data are more contradictory. In this review, we will discuss available therapies for melanoma brain metastases, focusing on the preclinical and clinical available data supporting the possible synergism between radiotherapy and immunotherapy.

High-quality Linac-based Stereotactic Body Radiation Therapy with Flattening Filter Free Beams and Volumetric Modulated Arc Therapy for Low-Intermediate Risk Prostate Cancer. A Mono-institutional Experience with 90 Patients.

AIMS: The aim of this phase II study was to evaluate the efficacy and toxicity of stereotactic body radiotherapy in patients with low or intermediate risk prostate cancer. MATERIALS AND METHODS: Biopsy-confirmed prostate cancer patients were enrolled, provided that they had the following characteristics: initial prostate-specific antigen (PSA) ≤ 20 ng/ml, Gleason Score < 7, International Prostate Symptom Score < 7. The treatment schedule was 35 Gy in five fractions, delivered with volumetric modulated arcs with flattening filter free beams. Toxicity was recorded according to CTCAE criteria v4.0. Biochemical failure was calculated according to the Phoenix definition. The Expanded Prostate Cancer Index Composite questionnaire was used to record health-related quality of life. RESULTS: Between December 2011 and March 2015, 90 patients were enrolled (53 low risk, 37 intermediate risk). The median age was 71 years (range 48-82). In total, 58 (64.5%) of the patients had Gleason Score=6, the remaining had Gleason Score=7.The median initial PSA was 6.9 ng/ml (range 2.7-17.0). Acute toxicity was mild, with 32.2 patients presenting grade 1 urinary toxicity and 32.2% of patients presenting grade 2 urinary toxicity, mainly represented by urgency, dysuria and stranguria. Rectal grade 1 toxicity was found in 15.5% of patients, whereas grade 2 toxicity was recorded in 6.6% of patients. Regarding late toxicity, grade 1 proctitis was recorded in 11.1% of patients and grade 1 urinary in 38.8%; only two events of grade 2 urinary toxicity were observed (transient urethral stenosis, resolved by a 24 h catheterisation). At a median follow-up of 27 months (6-62 months) only two intermediate risk patients experienced a biochemical failure. Health-related quality of life revealed a slight worsening in all the domains during treatment, with a return to baseline 3 months after treatment. CONCLUSIONS: Stereotactic body radiotherapy delivered using linac-based flattening filter free volumetric modulated arc radiotherapy in low and intermediate risk prostate cancer patients is associated with mild toxicity profiles and good patient-reported quality of life.

Clinical Outcome of Stereotactic Ablative Body Radiotherapy for Lung Metastatic Lesions in Non-small Cell Lung Cancer Oligometastatic Patients.

AIMS: The aim of this observational study was the evaluation of toxicity, local control and overall survival in non-small cell lung cancer (NSCLC) oligometastatic patients who had undergone stereotactic ablative body radiotherapy (SABR) for lung metastatic lesions. MATERIALS AND METHODS: SABR was carried out in oligometastatic patients with controlled primary tumour (adequate pulmonary function). We adopted the following dose prescriptions according to the site and the maximum diameter of the lung lesions: 60 Gy in three fractions for peripheral lesions with diameter ≤ 2 cm, 48 Gy in four fractions for peripheral lesions between 2 and 5 cm and 60 Gy in eight fractions for central lesions. A radiological response was defined according to RECIST criteria. Toxicity was recorded according to the Common Toxicity Criteria version 4.0. RESULTS: Between October 2010 and December 2014, 60 NSCLC patients with 90 lung lesions in total were treated at our institution. A radiological response was obtained in most patients. No pulmonary toxicity grade 4, chest pain or rib fracture occurred. The median follow-up from diagnosis was 28 months (range 5.4-104.5 months). The local control at 2 years was 88.9%. Overall survival at 1 and 2 years was 94.5 and 74.6%, respectively. CONCLUSION: SABR is well tolerated with a good radiological response and toxicity profile. Discussion within a multidisciplinary team is crucial to identify the oligometastatic patients who would probably benefit from ablative local therapy.

[Learning curve for lumbar disc surgery]. / Courbe d'apprentissage pour la chirurgie de la hernie discale lombaire.

BACKGROUND AND PURPOSE: Various techniques are available for lumbar disc surgery. But failure and severe adverse events still occur during such procedures. Recent work concluded that the use of microscope was not mandatory for such procedures. METHODS: The first 70 spinal procedures for lower limb radicular syndrome by a surgeon at the beginning of this activity where studied. Particular interest was paid on adverse events, especially complications and failures. RESULT: Average duration of surgery (50min) and rate of reoperation (six reoperations needed out of 65 patients, five of them by the same surgeon) where, as expected, a bit higher than published in experienced hands. But no battered-root syndrome, injury to neighboring structures or other severe complication was observed. Noteworthy is that no patient was neurologically worsened by surgery. CONCLUSIONS: If the use of microscope may not be needed for lumbar disc open surgery in experienced hands, we strongly advice surgeons at the beginning of their practice to use it. At least, to avoid unforgiving mistakes such as picking out the root instead of the herniation.

[Pheochromocytoma. A case report]. / Feocromocitoma. Presentazione di un caso.

The pheochromocytoma is a catecholamine-secreting tumor, localized in the adrenal gland in 90% of the cases and in extra-adrenal site in the remaining 10%. It can be single or associated with other endocrine neoplasms. On the basis of the case presented, the several clinical manifestations, the treatment of the disease and especially the recent development in imaging as MIBG, TAC, RNM are discussed.

Telangiectatic osteosarcoma of the skull. A post-Paget case.

We report a case of post-Paget telangiectatic osteosarcoma of the skull in a 75-year-old woman. Such a neoplasia is a rare variant of osteosarcoma, a tumor rare in the cranic bones. The patient was submitted for a careful analysis by the following procedures: technetium scintigram, X-rays, CT scan, and MRI. After the surgical procedure, pathological examination confirmed the diagnosis. Both radiological and pathological pattern of this tumor are discussed in relation to the differential diagnosis. Our report shows that benign lesions may represent a possible cause of diagnostic errors. They must be excluded by histological analysis.

Detection and partial characterization of circulating immune complexes in hydatid disease.

Thirty sera from eight patients with disseminated or localized hydatid disease have been examined for the presence of circulating immune complexes (CICs) by the conglutinin-binding assay and for immunoglobulin levels. The highest levels of CICs were of the immunoglobulin A (IgA) class, with lower values of IgG-CIC and IgM-CIC; these results did not correlate, except for IgG, with the free immunoglobulin levels. Efforts to identify parasitic antigen(s) involved in the CIC formation with different methods have been unsuccessful. In the follow-up of each patient, CIC appeared to be better correlated to clinical conditions than to hemagglutination titers. We have concluded that the presence of CIC in hydatid disease is probably an expression of B-cell polyclonal activation and that these complexes are valuable in the clinical monitoring of the disease.