Older age and comorbidity in breast cancer: is RT alone the new therapeutic frontier?

AIM: To assess the impact of age, comorbidities and endocrine therapy (ET) in older breast cancer (BC) patients treated with hypofractionated radiotherapy (Hypo-RT). METHODS: From June 2009 to December 2017, we enrolled in this study 735 ER-positive BC patients (stage pT1-T2, pNx-1, M0 and age ≥ 65 years) receiving hypo-RT and followed them until September 2019. Baseline comorbidities included in the hypertension-augmented Charlson Comorbidity Index were retrospectively retrieved. Logistic regression model estimated adjusted-odds ratios (ORs) of ET prescription in relation to baseline patient and tumor characteristics. Competing risk analysis estimated 5-year cumulative incidence function (CIF) of ET discontinuation due to side effects (with BC progression or death as competing events), and its effect on locoregional recurrence (LRR) and distant metastasis (DM) (with death as competing event). RESULTS: ET has been prescribed in 89% patients. In multivariable analysis, the odds of ET prescription was significantly reduced in older patients (≥ 80 years, OR 0.08, 95% CI 0.03-0.20) and significantly increased in patients with moderate comorbidity. Patients ≥ 80 years discontinued the prescribed therapy earlier and more frequently than younger (65-69 years) patients (p = 0.060). Five-year CIF of LLR, DM and death from causes other that BC were 1.7%, 2.2% and 7.5%, respectively. Patients who discontinued ET had higher chance of LRR (p = 0.004). ET use did not impact on OS in any of the analyzed groups. CONCLUSIONS: In older patients, ET did not show a benefit in terms of overall survival. Further studies focusing on tailored treatment approaches are warranted to offer the best care in terms of adjuvant treatment to these patients.

VMAT partial-breast irradiation: acute toxicity of hypofractionated schedules of 30 Gy in five daily fractions.

PURPOSE: To report acute toxicities in breast cancer (BC) patients (pts) recruited in a prospective trial and treated with accelerated partial-breast irradiation (APBI) using Volumetric Modulated Arc Therapy (VMAT) delivered with a hypofractionated schedule. METHODS: From March 2014 to June 2019, pts with early-stage BC (Stage I), who underwent breast conservative surgery (BCS), were recruited in a prospective study started at the National Cancer Institute of Milan. Pts received APBI with a hypofractionated schedule of 30 Gy in five daily fractions. Radiotherapy treatment (RT) was delivered using VMAT. Acute toxicity was assessed according to RTOG/EORTC criteria at the end of RT. RESULTS: Between March 2014 and June 2019, 151 pts were enrolled in this study. 79 Pts had right-side and 72 had left-side breast cancer. Median age was 69 (range 43-92). All pts presented with pathological stage IA BC, molecular classification was Luminal A in 128/151 (85%) and Luminal B in 23/151 (15%) cases. Acute toxicity, assessed at the end of RT, consisted of G1 erythema in 37/151 (24. 5%) pts and skin toxicities higher than G1, did not occur. Fibrosis G1 and G2 were reported in 41/151 (27. 1%) pts and in 2/151 pts (1. 3%), respectively. Edema G1 occurred in 8/151 (5. 3%) pts and asthenia G1 occurred in 1/151 (0. 6%) pts. CONCLUSIONS: APBI with VMAT proved to be feasible and can be a valid alternative treatment option after BCS in selected early breast cancer pts according to ASTRO guidelines. A longer follow-up is needed to assess late toxicity.

Clinical application of MOSkin dosimeters to rectal wall in vivo dosimetry in gynecological HDR brachytherapy.

PURPOSE: Three MOSkins dosimeters were assembled over a rectal probe and used to perform in vivo dosimetry during HDR brachytherapy treatments of vaginal cancer. The purpose of this study was to verify the applicability of the developed tool to evaluate discrepancies between planned and measured doses to the rectal wall. MATERIALS AND METHODS: MOSkin dosimeters from the Centre for Medical Radiation Physics are particularly suitable for brachytherapy procedures for their ability to be easily incorporated into treatment instrumentation. In this study, 26 treatment sessions of HDR vaginal brachytherapy were monitored using three MOSkin mounted on a rectal probe. A total of 78 measurements were collected and compared to doses determined by the treatment planning system. RESULTS: Mean dose discrepancy was determined as 2.2±6.9%, with 44.6% of the measurements within ±5%, 89.2% within ±10% and 10.8% higher than ±10%. When dose discrepancies were grouped according to the time elapsed between imaging and treatment (i.e., group 1: ≤90min; group 2: >90min), mean discrepancies resulted in 4.7±3.6% and 7.1±5.0% for groups 1 and 2, respectively. Furthermore, the position of the dosimeter on the rectal catheter was found to affect uncertainty, where highest uncertainties were observed for the dosimeter furthest inside the rectum. CONCLUSIONS: This study has verified MOSkin applicability to in-patient dose monitoring in gynecological brachytherapy procedures, demonstrating the dosimetric rectal probe setup as an accurate and convenient IVD instrument for rectal wall dose verification. Furthermore, the study demonstrates that the delivered dose discrepancy may be affected by the duration of treatment planning.

Factors influencing acute and late toxicity in the era of adjuvant hypofractionated breast radiotherapy.

PURPOSE: To evaluate toxicity in breast cancer patients treated with anthracycline and taxane based chemotherapy and whole breast hypofractionated radiotherapy, and to identify the risk factors for toxicity. METHODS AND MATERIALS: 537 early breast cancer patients receiving hypofractionated radiotherapy after conservative surgery were enrolled from April 2009 to December 2014, in an Italian cancer institute. The dose was 42.4 Gy in 16 daily fractions, 2.65 Gy per fraction. The boost to the tumor bed was administered only in grade III breast cancer patients and in patients with close or positive margins. Acute and late toxicity were prospectively assessed during and after radiotherapy according to RTOG scale. The impact of patients clinical characteristics, performed treatments and dose inhomogeneities on the occurrence of an higher level of acute skin toxicity and late fibrosis has been evaluated by univariate and multivariate analysis. RESULTS: The mean age was 74 (range 46-91 yrs). 27% of patients received boost. 22% of cases (n = 119) received also chemotherapy. The median follow-up was 32 months. G1 and G2/G3 acute skin toxicity were 61.3% and 20.5% and G1 and G2/G3 late fibrosis 12.6% and 4.3% respectively. Chemotherapy (p = 0.04), diabetes (p = 0.04) and boost administration (p < 0.01) were found to be statistically significant on the occurrence of late fibrosis, but a multivariate analysis did not show any factors connected. The boost administration (p < 0.01), the breast volume (p = 0.05), dose inhomogeneities (p < 0.01) and boost volume (p = 0.04) were found to be statistically significant as concerns the occurrence of acute skin reaction at the univariate analysis, but only the boost administration (p = 0.02), at multivariate analysis. CONCLUSIONS: The results of our study, according to the large randomized trials, confirmed that hypofractionated whole breast irradiation is safe, and only the boost administration seems to be an important predictor for toxicity. Chemotherapy does not impact on acute and late skin toxicity.

Measurements of gamma dose and thermal neutron fluence in phantoms exposed to a BNCT epithermal beam with TLD-700.

Gamma dose and thermal neutron fluence in a phantom exposed to an epithermal neutron beam for boron neutron capture therapy (BNCT) can be measured by means of a single thermoluminescence dosemeter (TLD-700). The method exploits the shape of the glow curve (GC) and requires the gamma-calibration GC (to obtain gamma dose) and the thermal-neutron-calibration GC (to obtain neutron fluence). The method is applicable for BNCT dosimetry in case of epithermal neutron beams from a reactor because, in most irradiation configurations, thermal neutrons give a not negligible contribution to the TLD-700 GC. The thermal neutron calibration is not simple, because of the impossibility of having thermal neutron fields without gamma contamination, but a calibration method is here proposed, strictly bound to the method itself of dose separation.

Online in vivo dosimetry in high dose rate prostate brchytherapy with MOSkin detectors: in phantom feasibility study.

MOSkin detectors were studied to perform real-time in vivo dose measurements in high dose rate prostate brachytherapy. Measurements were performed inside an urethral catheter in a gel phantom simulating a real prostate implant. Measured and expected doses were compared and the discrepancy was found to be within 8.9% and 3.8% for single MOSkin and dual-MOSkin configurations, respectively. Results show that dual-MOSkin detectors can be profitably adopted in prostate brachytherapy treatments to perform real-time in vivo dosimetry inside the urethra.

Dosimetric verification of a commercial 3D treatment planning system for conformal radiotherapy with a dynamic multileaf collimator.

The dosimetric accuracy of a 3D treatment planning system (TPS) for conformal radiotherapy with a computer-assisted dynamic multileaf collimator (DMLC) was evaluated. The DMLC and the TPS have been developed for clinical applications where dynamic fields not greater than 10 x 10 cm2 and multiple non-coplanar arcs are required. Dosimetric verifications were performed by simulating conformal treatments of irregularly shaped targets using several arcs of irradiation with 6 MV x-rays and a spherical-shaped, tissue-simulating phantom. The accuracy of the delivered dose at the isocentre was verified using an ionization chamber placed in the centre of the phantom. Isodose distributions in the axial and sagittal planes passing through the centre of the phantom were measured using double-layer radiochromic films. Measured dose at the isocentre as well as isodose distributions were compared to those calculated by the TPS. The maximum percentage difference between measured and prescribed dose was less than 2.5% for all the simulated treatment plans. The mean (+/-SD) displacement between measured and calculated isodoses was, in the axial planes, 1.0 +/- 0.6 mm, 1.2 +/- 0.7 mm and 1.5 +/- 1.1 mm for 80%, 50% and 20% isodose curves, respectively, whereas in the sagittal planes it was 2.0 +/- 1.2 mm and 2.2 +/- 2 mm for 80% and 50% isodose curves, respectively. The results indicate that the accuracy of the 3D treatment planning system used with the DMLC is reasonably acceptable in clinical applications which require treatments with several non-coplanar arcs and small dynamic fields.

Dosimetry of Gamma Knife and linac-based radiosurgery using radiochromic and diode detectors.

In stereotactic radiosurgery the choice of appropriate detectors, whether for absolute or relative dosimetry, is very important due to the steep dose gradient and the incomplete lateral electronic equilibrium. For both linac-based and Leksell Gamma Knife radiosurgery units, we tested the use of calibrated radiochromic film to measure absolute doses and relative dose distributions. In addition a small diode was used to estimate the relative output factors. The data obtained using radiochromic and diode detectors were compared with measurements performed with other conventional methods of dosimetry, with calculated values by treatment planning systems and with data prestored in the treatment planning system supplied by the Leksell Gamma Knife (LGK) vendor. Two stereotactic radiosurgery techniques were considered: Leksell Gamma Knife (using gamma-rays from 60Co) and linac-based radiosurgery (LR) (6 MV x-rays). Different detectors were used for both relative and absolute dosimetry: relative output factors (OFs) were estimated by using radiochromic and radiographic films and a small diode; relative dose distributions in the axial and coronal planes of a spherical polystyrene phantom were measured using radiochromic film and calculated by two different treatment planning systems (TPSs). The absolute dose at the sphere centre was measured by radiochromic film and a small ionization chamber. An accurate selection of radiochromic film was made: samples of unexposed film showing a percentage standard deviation of less than 3% were used for relative dose profiles, and for absolute dose and OF evaluations this value was reduced to 1.5%. Moreover a proper calibration curve was made for each set of measurements. With regard to absolute doses, the results obtained with the ionization chamber are in good correlation with radiochromic film-generated data, for both LGK and LR, showing a dose difference of less than 1%. The output factor evaluations, performed using different methods, are in good agreement with a maximum difference of 1.5% for all field sizes considered (LGK and LR) except the 4 mm helmet used in the LGK unit. In this case, differences exist between diode and radiochromic film measurements and both detectors show data values larger than the prestored OF value of 0.80. Dose profiles measured by radiochromic film and calculated are in excellent agreement for both LGK and LR with a maximum deviation of less than 1.0 mm, when full widths of the dose profiles at 20%, 50%, 80% levels are considered. When external photon beams are used in stereotactic radiosurgery, the 'well selected' radiochromic films are very accurate detectors both for relative and absolute dosimetry. The experimental results, obtained using both radiochromic and diode detectors, show that the 4 mm helmet relative output factor could be underestimated.

Monte Carlo simulation of light fluence in tissue in a cylindrical diffusing fibre geometry.

The propagation of light emitted by a linear light diffuser in a cylindrical hollow organ was investigated by means of the Monte Carlo (MC) method. The height and radius of the cavity, scattering (mu(s)) (or reduced scattering, mu'(s)) and absorption (mu(a)) coefficients, anisotropy (g), and refractive indices of the media involved (n1, n2) are required as input data by the MC code, as are characteristics of the light diffuser (length, delivered power and emission profile). Results of our MC model were tested by measuring the light fluence rate in a tissue-simulating phantom (mu(a) = 0.5 cm(-1), mu(s) = 23 cm(-1) and g = 0.75) irradiated at 633 nm with a cylindrical diffuser. Since geometric and optical parameters determine the behaviour of light propagation in tissue, MC simulations with different sets of input parameters were carried out to provide qualitative as well as quantitative data useful in planning photodynamic therapy. Data are reported on light penetration and fluence rate build-up at mu(a) and mu'(s) values ranging between 0.1 and 5 cm(-1) and 2.5 and 50 cm(-1), respectively. Furthermore, results suggest that a shift and spread could occur in the isofluence curves along the symmetry axis, which depend on the diameter of the treated lumen as well as on the emission profile of the light diffuser. Using our data it is possible to estimate how inaccuracy in knowledge of the optical coefficients can affect (i.e. usually by increasing) the light dose scheduled at a certain depth into tissue.

Accuracy evaluation of fusion of CT, MR, and spect images using commercially available software packages (SRS PLATO and IFS).

PURPOSE: A problem for clinicians is to mentally integrate information from multiple diagnostic sources, such as computed tomography (CT), magnetic resonance (MR), and single photon emission computed tomography (SPECT), whose images give anatomic and metabolic information. METHODS AND MATERIALS: To combine this different imaging procedure information, and to overlay correspondent slices, we used commercially available software packages (SRS PLATO and IFS). The algorithms utilize a fiducial-based coordinate system (or frame) with 3 N-shaped markers, which allows coordinate transformation of a clinical examination data set (9 spots for each transaxial section) to a stereotactic coordinate system. The N-shaped markers were filled with fluids visible in each modality (gadolinium for MR, calcium chloride for CT, and 99mTc for SPECT). The frame is relocatable, in the different acquisition modalities, by means of a head holder to which a face mask is fixed so as to immobilize the patient. Position errors due to the algorithms were obtained by evaluating the stereotactic coordinates of five sources detectable in each modality. RESULTS: SPECT and MR position errors due to the algorithms were evaluated with respect to CT: deltax was < or = 0.9 mm for MR and < or = 1.4 mm for SPECT, deltay was < or = 1 mm and < or = 3 mm for MR and SPECT, respectively. Maximal differences in distance between estimated and actual fiducial centers (geometric mismatch) were in the order of the pixel size (0.8 mm for CT, 1.4 mm for MR, and 1.8 mm for SPECT). In an attempt to distinguish necrosis from residual disease, the image fusion protocol was studied in 35 primary or metastatic brain tumor patients. CONCLUSIONS: The image fusion technique has a good degree of accuracy as well as the potential to improve the specificity of tissue identification and the precision of the subsequent treatment planning.

Design and characterization of a dynamic multileaf collimator.

The characteristics of a prototype computer-assisted dynamic multileaf collimator (DMLC), specifically designed for small-field conformal radiotherapy, were evaluated at the Istituto Nazionale Tumori of Milan. The collimating device consists of two opposing banks of 16 pairs of 8 cm thick, 3.6 mm wide tungsten leaves and allows shaping of a radiation field up to a size of 10 x 10 cm2 at the isocentre. The screening thickness of each leaf is 6.25 mm at the accelerator gantry isocentre. The leaves have a trapezoidal cross section and move along an arched path, thus providing a 'double focused' collimation system. The DMLC was installed on the head of a Varian Clinac 2100C linear accelerator. Mechanical and dosimetric evaluations were performed to test the stability of the mechanical isocentre and to determine leaf leakage, penumbra width, accuracy of leaf positions and uniformity of leaf speed. Displacement of the mechanical isocentre was less than 1 mm at all gantry angles. Standard radiographic films exposed to 6 MV x-ray radiation were used for dosimetric evaluations. Leakage between leaves was less than 2.5%, and leakage through abutted leaves was less than 5.5%. The penumbra width between 20% and 80% isodose at different positions of leaf banks was 2.7 mm in the direction of the leaf motion and 3.1 mm along the side of the leaf with a standard deviation of 0.2 mm in both directions. Accuracy in the positioning of the leaf was 0.3 mm, whereas the maximum repositioning error was less than 0.2 mm. Finally, during movement of the leaves at the maximum speed of 0.5 mm s(-1), the standard deviation of the leaf positioning error was 0.2 mm, proving an accurate uniformity of leaf speed.

Potential and limitations of magnetic resonance imaging for real-time monitoring of interstitial laser phototherapy.

RATIONALE AND OBJECTIVES: Magnetic resonance (MR) imaging has been suggested as a method to monitor interstitial laser phototherapy (ILP) in deep tissues. Unfortunately, a reliable relation between temperature and MR parameters has not yet been demonstrated. In this study, we examined whether such a relation exists and whether MR imaging can measure absolute temperature or temperature changes. METHODS: We evaluated, in the range of 21 degrees C to 80 degrees C, the temperature dependence of the MR imaging signal and T1 in samples of liver, water, CuSO4, and oil. Spin-echo and fast low-angle shot (FLASH) sequences were used. RESULTS: The MR imaging signal of liver, CuSO4, and water continuously decreased when the temperature was increased from 21 degrees C to 80 degrees C. By contrast, the MR imaging signal of the oil increased with increasing temperature up to 40-50 degrees C and then decreased at higher temperatures. We observed a reliable linear relation only between T1 and temperature in a range' of 30-60 degrees C for oil and CuSO4. CONCLUSION: MR imaging has the potential to measure thermal variations with an uncertainty of approximately +/- 10 degrees C. However, the use of MR imaging to monitor the real-time thermal effect induced in biologic tissues during laser irradiation requires further investigation before it can be applied clinically.

In vivo spectrophotometric evaluation of neoplastic and non-neoplastic skin pigmented lesions. III. CCD camera-based reflectance imaging.

Reflectance spectroscopy, which allows an objective evaluation of the color of surfaces, has recently been proposed as a useful tool to discriminate cutaneous melanoma from other pigmented cutaneous lesions. A novel spectrophotometric system based on the use of a charge coupled device camera provided with a set of interference filters has been developed to acquire images of cutaneous pigmented lesions at selected wavelengths ranging from 420 to 1040 nm. For each filter, an image was captured, digitized by a frame grabber and stored in a personal computer to perform off-line data handling. Reflectance images were acquired of 22 cutaneous pigmented lesions including melanoma and dysplastic, compound and junctional nevus. From each spectral image, three parameters, i.e. mean reflectance, variegation index and lesion area; were derived at the corresponding wavelength. The wavelength dependence of the three parameters was significantly different when melanoma was compared to the other investigated lesions. Although preliminary, our results suggest that telespectrophotometry gives useful information and could be utilized as an aid in the clinical diagnosis of cutaneous pigmented lesions.

Natural fluorescence of normal and neoplastic human colon: a comprehensive "ex vivo" study.

BACKGROUND AND OBJECTIVE: A microspectrofluorometric analysis on "ex vivo" samples from normal tissue and adenocarcinoma of the human colon has been performed to characterize the histological, biochemical, and biophysical bases of the autofluorescence. STUDY DESIGN/MATERIALS AND METHODS: Differences between normal and tumor tissues are found that concern both the intensity distribution and spectral shape of the autofluorescence emission. The different pattern of the fluorescence intensity can be related to the histological organization of the tissue, and involves mainly the arrangement of the submucosa, the most fluorescent layer. RESULTS: The most evident differences in the spectral shape found in the 480-580 nm range involve the stromal compartment, seem to be due to the presence of different fluorochromes, and are possibly related to the host response to the tumor. CONCLUSION: The nature and the extent of the autofluorescence modification between normal and tumor tissue in sections explain at least partly the evidence of the "in vivo" analysis and highlight the importance of excitation for full exploitation of the potentials of autofluorescence in diagnosis.

Ex vivo optical properties of human colon tissue.

Using a spectrophotometer equipped with an internal integrating sphere, the absorption (mu a) and the reduced scattering (microseconds') coefficients of ex vivo human colon tissues were evaluated from reflectance and transmittance measurements. Mu a and microseconds' varied from 47.7 to 1.0 cm-1 and from 14.2 to 6.2 cm-1, respectively, on passing from 300 nm to 800 nm. These results can be used to estimate the optical penetration depths when photodynamic therapy or light-induced fluorescence procedures are used.

Optical properties of in vitro epidermis and their possible relationship with optical properties of in vivo skin.

Using a spectrophotometer with an internal integrating sphere, the absorption (mu a) and reduced scattering (mu s') coefficients of in vitro epidermis were evaluated from reflectance and transmittance measurements. mu a and mu s' varied from 24 to 0.2 cm-1, and from 32 to 21 cm-1 respectively, on passing from 400 to 800 nm. Moreover, using an external integrating sphere, the reflectance spectrum of in vivo skin was compared with the reflectance spectrum calculated with a Monte Carlo model, in which the mean values of mu a and mu s' and different anisotropy parameters were used as input data. In vivo results show that the principle of similarity is entirely valid for wavelengths greater than 600 nm and may be considered a good approximation in the 400-600 nm band, and suggest that optical characteristics of in vivo skin may be inferred from reflectance measurements.

Light-induced fluorescence spectroscopy of adenomas, adenocarcinomas and non-neoplastic mucosa in human colon. I. In vitro measurements.

In an attempt to evaluate whether induced fluorescence could be exploited to discriminate neoplastic from non-neoplastic tissue, fluorescence spectroscopy was performed at 450-800 nm on 83 biopsy specimens of colonic mucosa. Measurements showed that fluorescence spectra of adenoma, adenocarcinoma and non-neoplastic mucosa manifest dissimilar patterns. Nine variables, whose photophysical and/or biological bases need further investigation, were derived from the spectra. Discriminant functions between the groups of lesions were determined by using a stepwise discriminant analysis. The diagnostic test had a sensitivity of 80.6% and 88.2%, and a specificity of 90.5% and 95.2% in discriminating neoplastic from non-neoplastic mucosa and adenoma from non-neoplastic mucosa respectively. These results suggest that fluorescence spectroscopy has the potential to improve endoscopic diagnosis of premalignant and malignant lesions of colonic mucosa.

In vivo spectrophotometric evaluation of neoplastic and non-neoplastic skin pigmented lesions. II: Discriminant analysis between nevus and melanoma.

Reflectance spectrophotometry from 420 to 780 nm on 31 primary melanoma and 31 benign nevi has been performed by using an external integrating sphere coupled to a spectrophotometer. Measurements show that reflectance spectra of melanoma and nevi manifest dissimilar patterns. From these spectra four variables, whose physical and/or physiological meanings remain to be investigated, have been derived. All of them are significantly different when compared between melanoma and nevi. A discriminant function between the two groups of lesions has been determined by using a stepwise discriminant analysis, resulting in a test with a sensitivity of 90.3% and a specificity of 77.4%. This method of discrimination between melanoma and nevi seems to have a discriminating power almost equal to that of a clinical judgement from a specialized medical doctor, thus suggesting a new method for screening skin pigmented lesions.