F-18 FDG PET/CT metabolic tumor volume predicts overall survival in patients with disseminated epithelial ovarian cancer.

OBJECTIVE: We evaluated the prognostic impact of quantitative assessment by maximum standardized uptake value (SUVmax), metabolic tumour volume (MTV) and tumour lesion glycolysis (TLG) on [F-18] FDG PET/CT for patients with peritoneal carcinomatosis from epithelial ovarian cancer (EOC). METHODS: Thirty-one patients with EOC underwent PET/CT for an early restaging after cytoreductive surgery, having been diagnosed with carcinomatosis (before chemotherapy). The SUVmax, MTV (cm3; 42% threshold) and TLG (g) were registered on residual peritoneal lesions. The patients were followed up 20±12months thereafter. The PET/CT results were compared to overall survival (OS). RESULTS: The Kaplan-Meier survival analysis for the SUVmax did not reveal significant differences in OS (p=0.48). The MTV survival analysis showed a significant higher OS in patients presenting with a higher tumour burden than those with less tumour burden (p=0.01; 26 vs. 14 months), whereas TLG exhibited a similar trend though not significant (p=0.06). Apart from chemo-resistance, the higher the MTV, the better will be the response to chemotherapy. CONCLUSIONS: Quantitative assessment by MTV rather than by SUVmax and TLG on PET/CT may be helpful for stratifying patients who present with peritoneal carcinomatosis from EOC, in order to implement the appropriate therapeutic regimen.

A radiotherapy technique for palliative total scalp irradiation.

A scalp irradiation technique for palliative treatment of a squamous cell carcinoma was discussed. A patient with multiple cutaneous scalp lesions resulting in bleeding and pain was treated with a 3D conformal radiotherapy technique was performed with five 6 MV electron beams without shifting the field borders during the course of the treatment, due to the finality of the treatment (palliative intent). A reduction of planning and delivery complexity has been obtained not considering the junctioning problems. Nevertheless, the 90% of gross tumor volume (GTV) was covered by the 85% of prescription dose with a significant reduction of patient's symptoms (pain and bleeding). Our patient achieved a significant pain response and resolution of bleeding with this technique. Our study revealed that the scalp irradiation by means of electron beam without considering the junction problem is easy and effective for the palliative intent in elderly patients with squamous cell carcinoma.

Clinical radiobiology of glioblastoma multiforme: estimation of tumor control probability from various radiotherapy fractionation schemes.

BACKGROUND AND PURPOSE: The aim of this study was to estimate a radiobiological set of parameters from the available clinical data on glioblastoma (GB). PATIENTS AND METHODS: A number of clinical trial outcomes from patients affected by GB and treated with surgery and adjuvant radiochemotherapy were analyzed to estimate a set of radiobiological parameters for a tumor control probability (TCP) model. The analytical/graphical method employed to fit the clinical data allowed us to estimate the intrinsic tumor radiosensitivity (α), repair capability (b), and repopulation doubling time (T d ) in a first phase, and subsequently the number of clonogens (N) and kick-off time for accelerated proliferation (T(k)). The results were used to formulate a hypothesis for a schedule expected to significantly improve local control. The 95 % confidence intervals (CI(95 %)) of all parameters are also discussed. RESULTS: The pooled analysis employed to estimate the parameters summarizes the data of 559 patients, while the studies selected to verify the results summarize data of 104 patients. The best estimates and the CI(95 %) are α = 0.12 Gy⁻¹ (0.10-0.14), b = 0.015 Gy⁻² (0.013-0.020), α/b = 8 Gy (5.0-10.8), T(d) = 15.4 days (13.2-19.5), N = 1.104(1.2.10³ - 1.105), and T(k) = 37 days (29-46). The dose required to offset the repopulation occurring after 1 day (D(prolif)) and starting after T k was estimated as 0.30 Gy/day (0.22-0.39). CONCLUSION: The analysis confirms a high value for the α/b ratio. Moreover, a high intrinsic radiosensitivity together with a long kick-off time for accelerated repopulation and moderate repopulation kinetics were found. The results indicate a substantial independence of the duration of the overall treatment and an improvement in the treatment effectiveness by increasing the total dose without increasing the dose fraction.

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

AIM: 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. MATERIAL AND METHODS: Fifty-two patients (61 ± 13 yr) underwent PET/CT before the first-line chemotherapy. The mean SUVmax value, the summed MTV (cm(3) ; 42% threshold), and the cumulative TLG (g) were registered. The patients were followed up 18 months thereafter (range 3-41 months). The PET/CT results were compared to the event-free survival (EFS). RESULTS: At univariate analysis, SUVmax and lactate dehydrogenase (LDH) levels were predictive, but discordantly. The Kaplan-Meier survival analysis for SUVmax showed a significant better EFS in patients presenting higher values as compared to those having lesser (P = 0.0002, HR 0.13). Summed MTV and cumulative TLG were not suitable for predicting EFS. CONCLUSION: Despite the availability of new tools for the quantitative assessment of disease activity on PET/CT, the SUVmax rather than MTV and TLG remains the only predictor for EFS in DLBCL patients. The magnitude of glycolytic activity rather than the amount of metabolically active burden holds a predominant value for determining the response to chemotherapy in DLBCL.

Head and neck intensity modulated radiotherapy parotid glands: time of re-planning.

PURPOSE: To investigate the correct time point for re-planning by evaluating dosimetric changes in the parotid glands (PGs) during intensity-modulated radiotherapy (IMRT) in head and neck cancer patients. MATERIALS AND METHODS: Patients with head and neck cancer treated with IMRT were enrolled. During treatment all patients underwent cone-beam computed tomography (CBCT) scans to verify the set-up. CBCT scans at treatment days 10, 15, 20 and 25 were used to transfer the original plan (CBCTplan I, II, III, IV, respectively) using rigid registration between the two. The PGs were retrospectively contoured and evaluated with the dose-volume histogram. The mean dose, the dose to 50 % of volume, and the percentage of volume receiving 30 and 50 Gy were evaluated for each PG. The Wilcoxon sign ranked test was used to evaluate the effects of dosimetric variations and values <0.05 were taken to be significant. RESULTS: From February to June 2011, ten patients were enrolled and five IMRT plans were evaluated for each patient. All the dosimetric parameters increased throughout the treatment course. However, this increase was statistically significant at treatment days 10 and 15 (CBCTplan I, II; p = 0.02, p = 0.03, respectively). CONCLUSION: CBCT is a feasible method to assess the dosimetric changes in the PGs. Our data showed that checking the PG volume and dose could be indicated during the third week of treatment.

Critical dose and toxicity index of organs at risk in radiotherapy: analyzing the calculated effects of modified dose fractionation in non-small cell lung cancer.

To increase the efficacy of radiotherapy for non-small cell lung cancer (NSCLC), many schemes of dose fractionation were assessed by a new "toxicity index" (I), which allows one to choose the fractionation schedules that produce less toxic treatments. Thirty-two patients affected by non resectable NSCLC were treated by standard 3-dimensional conformal radiotherapy (3DCRT) with a strategy of limited treated volume. Computed tomography datasets were employed to re plan by simultaneous integrated boost intensity-modulated radiotherapy (IMRT). The dose distributions from plans were used to test various schemes of dose fractionation, in 3DCRT as well as in IMRT, by transforming the dose-volume histogram (DVH) into a biological equivalent DVH (BDVH) and by varying the overall treatment time. The BDVHs were obtained through the toxicity index, which was defined for each of the organs at risk (OAR) by a linear quadratic model keeping an equivalent radiobiological effect on the target volume. The less toxic fractionation consisted in a severe/moderate hyper fractionation for the volume including the primary tumor and lymph nodes, followed by a hypofractionation for the reduced volume of the primary tumor. The 3DCRT and IMRT resulted, respectively, in 4.7% and 4.3% of dose sparing for the spinal cord, without significant changes for the combined-lungs toxicity (p < 0.001). Schedules with reduced overall treatment time (accelerated fractionations) led to a 12.5% dose sparing for the spinal cord (7.5% in IMRT), 8.3% dose sparing for V20 in the combined lungs (5.5% in IMRT), and also significant dose sparing for all the other OARs (p < 0.001). The toxicity index allows to choose fractionation schedules with reduced toxicity for all the OARs and equivalent radiobiological effect for the tumor in 3DCRT, as well as in IMRT, treatments of NSCLC.

Twenty years of radiobiology in clinical practice: the Italian contribution.

AIMS AND BACKGROUND: To present the Italian state-of-the-art contribution to radiobiology of external beam radiotherapy, brachytherapy, and radionuclide radiotherapy. METHODS AND STUDY DESIGN: A survey of the literature was carried out, using PubMed, by some independent researchers of the Italian group of radiobiology. Each paper was reviewed by researchers of centers not comprising its authors. The survey was limited to papers in English published over the last 20 years, written by Italian investigators or in Italian institutions, excluding review articles. RESULTS: A total of 135 papers have been published in journals with an impact factor, with an increase in the number of published papers over time, for external beam radiotherapy rather than radionuclide radiotherapy. The quantity and quality of the papers researched constitutes a proof of the enduring interest in clinical radiobiology among Italian investigators. CONCLUSIONS: The survey could be useful to individuate expert partners for an Italian network on clinical radiobiology, addressing future collaborative investigations.

Impact of comorbidity in elderly prostate cancer patients treated with brachytherapy.

OBJECTIVE: To analyze the correlations among comorbidity and overall survival (OS), biochemical progression-free survival (b-PFS) and toxicity in elderly patients with localized prostate cancer treated with (125)I brachytherapy. METHODS: Elderly men, aged ≥65 years, with low-intermediate risk prostate cancer, were treated with permanent (125)I brachytherapy as monotherapy. Comorbidity data were obtained from medical reports using age-adjusted Charlson comorbidity index (a-CCI). The patients were categorized into two age groups (<75 and ≥75 years old), and two comorbidity score groups (a-CCI ≤3 and >3). Toxicity was scored with Radiation Therapy Oncology Group (RTOG) scale. RESULTS: From June 2003 to October 2009, a total of 92 elderly patients underwent prostate brachytherapy, including 57 men (62%) with low-risk prostate cancer, and 35 men (38%) with intermediate-risk prostate cancer. The median age of patients was 75 years (range, 65-87 years). Forty-seven patients (51%) had a-CCI ≤3 and 45 patients (49%) a-CCI >3. With a median follow-up period of 56 months (range, 24-103 months), the 5-year actuarial OS and b-PFS were 91.3% and 92.4% respectively, without statistical significance between two Charlson score groups. Toxicity was mild. None of the patients experienced gastrointestinal (GI) toxicity, and only 4 patiens (4%) experienced late genitourinary (GU) grade-3 (G3) toxicity. No correlation between acute GU and GI toxicity and comorbidity was showed (P=0.50 and P=0.70, respectively). CONCLUSIONS: Our data suggest that elderly men with low-intermediate risk prostate cancer and comorbidity can be considered for a radical treatment as (125)I low-dose rate brachytherapy.

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.

Local tumor control probability to evaluate an applicator-guided volumetric-modulated arc therapy solution as alternative of 3D brachytherapy for the treatment of the vaginal vault in patients affected by gynecological cancer.

The purpose of this study was to evaluate the applicator-guided volumetric-modulated arc therapy (AGVMAT) solution as an alternative to high-dose-rate brachytherapy (HDR-BRT) treatment of the vaginal vault in patients with gynecological cancer (GC). AGVMAT plans for 51 women were developed. The volumetric scans used for plans were obtained with an implanted CT-compatible vaginal cylinder which provides spatial registration and immobilization of the gynecologic organs. Dosimetric and radiobiological comparisons for planning target volume (PTV) and organs at risk (OARs) were performed by means of a dose-volume histogram (DVH), equivalent uniform dose (EUD), and local tumor control probability (LTCP). In addition, the integral dose and the overall delivery time, were evaluated. The HDR-BRT averages of EUD and minimum LTCP were significantly higher than those of AGVMAT. Doses for the OARs were comparable for the bladder and sigmoid, while, although HDR-BRT was able to better spare the bowel, AGVMAT provided a significant reduction of d2cc, d1cc, and dmax (p < 0.01) for the rectum. AGVMAT integral doses were higher than HDR-BRT with low values in both cases. Delivery times were about two or three times higher for HDR-BRT with respect to the single arc technique (AGVMAT1) and dual arc technique (AGVMAT2), respectively. The applicator-guided volumetric-modulated arc therapy seems to have the potential of improving rectum avoidance. However, brachytherapy improves performance in terms of PTV coverage, as demonstrated by a greater EUD and better LTCP curves.

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/ß), 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/ß 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/ß 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.

3D dosimetry in patients with early breast cancer undergoing Intraoperative Avidination for Radionuclide Therapy (IART) combined with external beam radiation therapy.

PURPOSE: Intraoperative Avidination for Radionuclide Therapy (IART) is a novel targeted radionuclide therapy recently used in patients with early breast cancer. It is a radionuclide approach with (90)Y-biotin combined with external beam radiotherapy (EBRT) to release a boost of radiation in the tumour bed. Two previous clinical trials using dosimetry based on the calculation of mean absorbed dose values with the hypothesis of uniform activity distribution (MIRD 16 method) assessed the feasibility and safety of IART. In the present retrospective study, a voxel dosimetry analysis was performed to investigate heterogeneity in distribution of the absorbed dose. The aim of this work was to compare dosimetric and radiobiological evaluations derived from average absorbed dose vs. voxel absorbed dose approaches. METHODS: We evaluated 14 patients who were injected with avidin into the tumour bed after conservative surgery and 1 day later received an intravenous injection of 3.7 GBq of (90)Y-biotin (together with 185 MBq (111)In-biotin for imaging). Sequential images were used to estimate the absorbed dose in the target region according to the standard dosimetry method (SDM) and the voxel dosimetry method (VDM). The biologically effective dose (BED) distribution was also evaluated. Dose/volume and BED volume histograms were generated to derive equivalent uniform BED (EUBED) and equivalent uniform dose (EUD) values. RESULTS: No "cold spots" were highlighted by voxel dosimetry. The median absorbed-dose in the target region was 20 Gy (range 15-27 Gy) by SDM, and the median EUD was 20.4 Gy (range 16.5-29.4 Gy) by the VDM; SDM and VDM estimates differed by about 6 %. The EUD/mean voxel absorbed dose ratio was >0.9 in all patients, indicative of acceptable uniformity in the target. The median BED and EUBED values were 21.8 Gy (range 15.9-29.3 Gy) and 22.8 Gy (range 17.3-31.8 Gy), respectively. CONCLUSION: VDM highlighted the absence of significant heterogeneity in absorbed dose in the target. The EUD/mean absorbed dose ratio indicated a biological efficacy comparable to that of uniform distribution of absorbed dose. The VDM is recommended for improving accuracy, taking into account actual activity distribution in the target region. The radiobiological model applied allowed us to compare the effects of IART® with those of EBRT and to match the two irradiation modalities.

Correlation between EGFr expression and accelerated proliferation during radiotherapy of head and neck squamous cell carcinoma.

PURPOSE: To 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). METHODS: A 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. RESULTS: The 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/ß = 10 Gy were assumed. CONCLUSIONS: A 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.

Modelling the correlation between EGFr expression and tumour cell radiosensitivity, and combined treatments of radiation and monoclonal antibody EGFr inhibitors.

PURPOSE: To 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 METHODS: Differences 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/ß) 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. RESULTS: Assuming membrane EGFr over-expression corresponds to reduced radiosensitivity (α(H) = 0.15 Gy(-1) and α(H)/ß(H) = 7.5 Gy) relative to normal radiosensitivity (α = 0.2 Gy(-1) and α/ß = 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. CONCLUSIONS: During 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.

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.

Comorbidity assessment and adjuvant radiochemotherapy in elderly affected by glioblastoma.

To assess the role of comorbidity on outcome in elderly patients with glioblastoma treated with radiotherapy plus concomitant and adjuvant Temozolomide, patients over 65 years with glioblastoma, who underwent surgical resection or biopsy and radiochemotherapy, were evaluated. The Adjusted-Age Charlson Comorbidity Index and the Adult Comorbidity Evaluation-27 were used to assess comorbidity. From April 2005 to January 2011, 35 patients (median age 72 years) were treated in our Institution. Thirteen patients had a Charlson score more than 3, while, according to the Adult Comorbidity Evaluation-27, 21 patients had mild or severe comorbid conditions. Patients with low Charlson comorbidity score experienced a longer survival time than those with higher score (22 vs. 10 months, respectively). The Adjusted-Age Charlson Comorbidity Index influenced survival at univariate and multivariate analysis (p = 0.004, p = 0.001, respectively). No comorbidity index was a predictor for progression-free survival. Our data suggested that the association of radiotherapy with TMZ was safe and effective. Perhaps, the comorbidity assessment could be an appropriate tool in the treatment decision for elderly patients with glioblastoma.