Piernicola Pedicini

In Regard to Miralbell et al

To the Editor: In a recent analysis of 7 international institutional datasets, Miralbell et al (1) contributed to the wellknown debate on how low is the a/b value of prostate cancer (2-4). Based on the multiple primary datasets collected for analysis, the authors deduced the dose fractionation sensitivity of prostate cancer as a/b Z 1.4 Gy. Moreover, when the a/b ratio was allowed to vary among risk groups, the values of 0.6, 1.7, and 1.6 Gy for low-, intermediate-, and high-risk groups were obtained. However, in arriving at those results, the authors obtained extremely low values for a, and correspondingly the estimated number of prostate clonogens were inconsistent and difficult to be interpreted from the biological point of view. To investigate this aspect, we tried to use all of the Miralbell et al clinical data and results, with exception of the number of clonogens and intrinsic radiosensitivity a. Our final aim was to verify the compatibility of the results obtained by Miralbell et al about a/b, with a more realistic number of clonogenic cells. In particular, with regard to the number of clonogens, we used values as those reported by Wang et al (5) that have estimated this number for low-, intermediate-, and high-risk groups. Furthermore, to estimate the intrinsic radiosensitivitydconsidered as a free parameter in our analysisdthe following standard formula of tumor control probability (ie, biological relapse free survival [bRFS]) based on the linear quadratic model was used:

Estimation of a Self-Consistent Set of Radiobiological Parameters From Hypofractionated Versus Standard Radiation Therapy of Prostate Cancer

PURPOSE To determine a self-consistent set of radiobiological parameters in prostate cancer. METHODS AND MATERIALS A method to estimate intrinsic radiosensitivity (α), fractionation sensitivity (α/β), repopulation doubling time, number of clonogens, and kick-off time for accelerated repopulation of prostate cancer has been developed. Based on the generalized linear-quadratic model and without assuming the isoeffective hypothesis, the potential applications of the method were investigated using the clinical outcome of biochemical relapse-free survival recently reviewed in the literature. The strengths and limitations of the method, regarding the fitted parameters and 95% confidence intervals (CIs), are also discussed. RESULTS Our best estimate of α/β is 2.96 Gy (95% CI 2.41-3.53 Gy). The corresponding α value is 0.16 Gy(-1) (95% CI 0.14-0.18 Gy(-1)), which is compatible with a realistic number of clonogens: 6.5 × 10(6) (95% CI 1.5 × 10(6)-2.1 × 10(7)). The estimated cell doubling time is 5.1 days (95% CI 4.2-7.2 days), very low if compared with that reported in the literature. This corresponds to the dose required to offset the repopulation occurring in 1 day of 0.52 Gy/d (95% CI 0.32-0.68 Gy/d). However, a long kick-off time of 31 days (95% CI 22-41 days) from the start of radiation therapy was found. CONCLUSION The proposed analytic/graphic method has allowed the fitting of clinical data, providing a self-consistent set of radiobiological parameters for prostate cancer. With our analysis we confirm a low value for α/β with a correspondingly high value of intrinsic radiosensitivity, a realistic average number of clonogens, a long kick-off time for accelerated repopulation, and a surprisingly fast repopulation that suggests the involvement of subpopulations of specifically tumorigenic stem cells during continuing radiation therapy.

F-18 FDG PET/CT quantization parameters as predictors of outcome in patients with diffuse large B-cell lymphoma

We evaluated the prognostic significance of standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) obtained by F‐18 FDG PET/CT (PET/CT) in patients with diffuse large B‐cell Lymphomas (DLBCL) presenting intermediate IPI score.

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.

Parotid gland volumetric changes during intensity-modulated radiotherapy in head and neck cancer.

OBJECTIVE To evaluate volumetric changes of parotid glands (PGs) during intensity-modulated radiotherapy (IMRT) in head and neck cancer patients. METHODS During IMRT all patients underwent kilovolt cone-beam CT (CBCT) scans to verify the set-up positioning in a protocol study. On each CBCT scan, the PGs were retrospectively contoured and evaluated with a dose-volume histogram. RESULTS From February to June 2011, 10 patients were enrolled. 140 CBCT scans were registered (280 PGs): for each patient, a median of 14 CBCT scans were performed (range 14-16). At the start of radiation, the average volume for ipsilateral PGs (iPGs) was 18.77 ml (range 12.9-31.2 ml), whereas for contralateral PGs (cPGs) it was 16.63 ml (range 8.3-28.7 ml). At the last CBCT scan, the average volume loss was 43.5% and 44.0% for the iPG and cPG, respectively. When we analysed the percentage of volume loss, we observed that the volume decreased by linear regression (r(2)=0.92 for iPG; r(2)=0.91 for cPG), with an average volume loss rate of 1.5% per day for both PGs. During the third week of treatment the volume of both PGs reduced by 24-30%. CONCLUSION Our data show that, during IMRT, the shrinkage of PGs should be taken into account. A replan could be indicated in the third week of radiotherapy.

Integration between in vivo dosimetry and image guided radiotherapy for lung tumors

The article reports a feasibility study about the potentiality of an in vivo dosimetry method for the adaptive radiotherapy of the lung tumors treated by 3D conformal radiotherapy techniques (3D CRTs). At the moment image guided radiotherapy (IGRT) has been used for this aim, but it requires taking many periodic radiological images during the treatment that increase workload and patient dose. In vivo dosimetry reported here can reduce the above efforts, alerting the medical staff for the commissioning of new radiological images for an eventual adaptive plan. The in vivo dosimetry method applied on 20 patients makes use of the transit signal St on the beam central axis measured by a small ion chamber positioned on an electronic portal imaging device (EPID) or by the EPID itself. The reconstructed in vivo dosimetry at the isocenter point Diso requires a convolution between the transit signal St and a dose reconstruction factor C that essentially depends on (i) tissue inhomogeneities along the beam central axis and (ii) the in-patient isocenter depth. The C factors, one for every gantry angle, are obtained by processing the patients computed tomography scan. The method has been recently applied in some Italian centers to check the radiotherapy of pelvis, breast, head, and thorax treatments. In this work the dose reconstruction was carried out in five centers to check the Diso in the lung tumor during the 3D CRT, and the results have been used to detect the interfraction tumor anatomy variations that can require new CT imaging and an adaptive plan. In particular, in three centers a small ion chamber was positioned below the patient and used for the St measurement. In two centers, the St signal was obtained directly by 25 central pixels of an a-Si EPID, equipped with commercial software that enabled its use as a stable detector. A tolerance action level of +/- 6% for every checked beam was assumed. This means that when a difference greater than 6% between the predicted dose by the treatment planning system, Diso,TPS, and the Diso was observed, the clinical action started to detect possible errors. 60% of the patients examined presented morphological changes during the treatment that were checked by the in vivo dosimetry and successively confirmed by the new CT scans. In this work, a patient that showed for all beams Diso values outside the tolerance level, new CT scans were commissioned for an adaptive plan. The lung dose volume histograms (DVHs) for a Diso,TPs=2 Gy for fraction suggested the adaptive plan to reduce the dose in lung tissue. The results of this research show that the dose guided radiotherapy (DGRT) by the Diso reconstruction was feasible for daily or periodic investigation on morphological lung tumor changes. In other words, since during 3D CRT treatments the anatomical lung tumor changes occur frequently, the DGRT can be well integrated with the IGRT.

A new model for predicting acute mucosal toxicity in head-and-neck cancer patients undergoing radiotherapy with altered schedules.

PURPOSE One of the worst radiation-induced acute effects in treating head-and-neck (HN) cancer is grade 3 or higher acute (oral and pharyngeal) mucosal toxicity (AMT), caused by the killing/depletion of mucosa cells. Here we aim to testing a predictive model of the AMT in HN cancer patients receiving different radiotherapy schedules. METHODS AND MATERIALS Various radiotherapeutic schedules have been reviewed and classified as tolerable or intolerable based on AMT severity. A modified normal tissue complication probability (NTCP) model has been investigated to describe AMT data in radiotherapy regimens, both conventional and altered in dose and overall treatment time (OTT). We tested the hypothesis that such a model could also be applied to identify intolerable treatment and to predict AMT. This AMT NTCP model has been compared with other published predictive models to identify schedules that are either tolerable or intolerable. The area under the curve (AUC) was calculated for all models, assuming treatment tolerance as the gold standard. The correlation between AMT and the predicted toxicity rate was assessed by a Pearson correlation test. RESULTS The AMT NTCP model was able to distinguish between acceptable and intolerable schedules among the data available for the study (AUC = 0.84, 95% confidence interval = 0.75-0.92). In the equivalent dose at 2 Gy/fraction (EQD2) vs OTT space, the proposed model shows a trend similar to that of models proposed by other authors, but was superior in detecting some intolerable schedules. Moreover, it was able to predict the incidence of ≥G3 AMT. CONCLUSION The proposed model is able to predict ≥G3 AMT after HN cancer radiotherapy, and could be useful for designing altered/hypofractionated schedules to reduce the incidence of AMT.

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.

Adjuvant radiochemotherapy in the elderly affected by glioblastoma: single-institution experience and literature review

PurposeRadiochemotherapy (RCT) is the standard adjuvant treatment for patients affected by glioblastoma (GBM). As there is no evidence in elderly patients with GBM, combined, single modality or best supportive care is used. The aim of this retrospective study was to evaluate acute toxicity and outcome of elderly patients with GBM treated with RCT with temozolomide (TMZ).Materials and methodsPatients >65 years with newly diagnosed GBM who underwent surgery or biopsy and RCT were evaluated. Recursive Partitioning Analysis (RPA) class and National Cancer Institute — Common Toxicity Criteria (NCI-CTC) version 3 were used to classify patients and evaluate acute toxicity, respectively.ResultsFrom April 2005 to January 2011, 35 patients (18 women and 17 men) with GBM were treated at our institution. Only 31.43% of cases underwent complete resection. Median progression-free survival (PFS) was 8 months and median overall survival (OS) 13 months. At univariate and multivariate analysis, only RPA class correlated with OS (p=0.01, p=0.03, respectively). During RCT, toxicity was mild (thrombocytopaenia G3–4, 11.43%; neurological toxicity, G3–4, 8.57%).ConclusionsOur data suggest that RCT with TMZ seems to produce a better outcome with a mild toxicity profile in elderly patients affected by GBM.RiassuntoObiettivoLa radiochemioterapia (RTCHT) è il trattamento standard nei pazienti affetti da glioblastoma (GBM), ma a causa della mancanza di evidenze nei pazienti anziani, la radioterapia e la chemioterapia possono essere utilizzate singolarmente o integrate. Il nostro studio retrospettivo valuta la tossicità acuta e l’outcome della RTCHT con temozolomide (TMZ) nei pazienti anziani affetti da GBM.Materiali e metodiSono stati valutati pazienti con età superiore a 65anni affetti da GBM sottoposti a chirurgia o biopsia e RTCHT. I pazienti sono stati suddivisi secondo le classi prognostiche del radiation Therapy Oncology Group (RTOG)- recursive partitioning analysis (RPA). La tossicità acuta durante RTCHT è stata valutata secondo la scala National Cancer Institute-Common Toxicity Criteria (NCICTC) vers.3.RisultatiDa aprile 2005 a gennaio 2011, 35 pazienti (18 donne e 17 uomini) sono stati trattati presso la nostra divisione. Solo 11 pazienti (31,43%) sono stati sottoposti a resezione completa. La sopravvivenza libera da progressione e la sopravvivenza mediane sono state di 8 e 13 mesi, rispettivamente. All’analisi univariata e multivariata solo la classe RPA ha mostrato influenzare la sopravvivenza (p=0,01; p=0,03). La tossicità acuta, durante RTCHT, è stata accettabile (11,43% di trombocitopenia G3–4; 8,57% di tossicità neurologica G3–4).ConclusioniI nostri dati suggeriscono che nei pazienti anziani l’associazione di radioterapia e temozolomide sembra essere efficace e sicura.

Coexistence of two different mutations in codon 12 of the Kras gene in colorectal cancer: Report of a case supporting the concept of tumoral heterogeneity

Evaluation of the mutational status of KRAS is a crucial step for the correct therapeutic approach in treating advanced colorectal cancer as the identification of wild-type KRAS tumors leads to more specific and less toxic treatments for patients. Although several studies have highlighted the differences between primary and metastatic tumors, the possibility of two or more mutations in the same codon has seldom been reported. The present study reports an additional case of an advanced adenocarcinoma of the colon showing two somatic mutations (p.G12D and p.G12V) in the same codon (codon 12) of exon 2 of the KRAS gene, thus supporting the possibility of two differing clonal origins of the tumor. Although the clinical significance of multiple mutations remains unknown at present, based on the limited data available in the literature, this rare event appears to be associated with a more aggressive disease, as in the present case. This case report demonstrates the existence of intratumoral heterogeneity and the coexistence of distinct clones within a tumor that may have profound clinical implications for disease progression and therapeutic responses.