Computed tomography-derived myocardial extracellular volume: an early biomarker of cardiotoxicity in esophageal cancer patients undergoing radiation therapy.

OBJECTIVES: We aimed to assess extracellular volume (ECV) through non-gated, contrast-enhanced computed tomography (CT) before and after radiation therapy (RT) in patients with esophageal cancer (EC). MATERIALS AND METHODS: EC patients who had undergone CT before and after RT were retrospectively assessed. Patients with preexisting cardiovascular disease or with heavily artifacted CT were excluded. ECV was calculated using density values for the myocardial septum and blood pool. Data were reported as mean and standard deviation or median and interquartile range according to their distribution; t test or Wilcoxon and Pearson r or Spearman ρ were subsequently used. RESULTS: Twenty-one patients with stage ≥ IB EC, aged 64 ± 18 years, were included. Mean and maximum RT doses were 21.2 Gy (16.9-24.1) and 42.5 Gy (41.8-49.2), respectively. At baseline (n = 21), hematocrit was 39% ± 4%, ECV 27.9% ± 3.5%; 35 days (30-38) after RT (n = 20), hematocrit was 36% ± 4%, lower than at baseline (p = 0.002), ECV 30.3% ± 8.3%, higher than at baseline (p = 0.081); at follow-up 420 days (244-624) after RT (n = 13), hematocrit was 36% ± 5%, lower than at baseline (p = 0.030), ECV 31.4% ± 4.5%, higher than at baseline (p = 0.011). No patients showed signs of overt cardiotoxicity. ECV early after RT was moderately positively correlated with maximum RT dose (ρ = 0.50, p = 0.036). CONCLUSIONS: In EC patients, CT-derived myocardial ECV was increased after RT and may thus appear as a potential early biomarker of cardiotoxicity.

Impact of sentinel lymph-node biopsy and FDG-PET in staging and radiation treatment of anal cancer patients.

To assess the role of sentinel lymph-node biopsy (SLNB) and FDG-PET in staging and radiation treatment (RT) of anal cancer patients. This retrospective study was performed on 80 patients (male: 32, female: 48) with a median age of 60 years (39-89 years) with anal squamous cell carcinoma who were treated from March 2008 to March 2018 at the IRCCS San Raffaele Hospital. Patients without clinical evidence of inguinal LNs metastases and/or with discordance between clinical evidence and imaging features were considered for SLNB. FDG-PET was performed in 69/80 patients. Patients with negative imaging in inguinal region and negative SLNB could avoid RT on groin to spare inguinal toxicity. CTV included GTV (primary tumour and positive LNs) and pelvic ± inguinal LNs. PTV1 and PTV2 corresponded to GTV and CTV, respectively, adding 0.5 cm. RT dose was 50.4 Gy/28 fractions to PTV2 and 64.8 Gy/36 fractions to PTV1, delivered with 3DCRT (n = 24) or IMRT (n = 56), concomitant to Mitomycin-C and 5-FU chemotherapy. FDG-PET showed inguinal uptake in 21/69 patients (30%) and was negative in 48/69 patients (70%). Lymphoscintigraphy was performed in 11/21 positive patients (4 patients SLNB confirmed inguinal metastases, 6 patients false positive and 1 patient SLN not found), and in 29/48 negative patients (5/29 showed metastases, 23/29 true negative and 1 SLN not found). Sensitivity, specificity, positive and negative predictive value of FDG-PET were 62%, 79%, 40% and 82%, respectively. Median follow-up time from diagnosis was 40.3 months (range: 4.6-136.4 months): 69 patients (86%) showed a complete response, 10 patients (13%) a partial response, 1 patient (1%) a stable disease. Patients treated on groin (n = 54) versus not treated (n = 26) showed more inguinal dermatitis (G1-G2: 50% vs. 12%; G3-G4: 17% vs. 0%, p < 0.05). For patients treated on groin, G3-G4 inguinal dermatitis, stomatitis and neutropenia were significantly reduced with IMRT against 3DCRT techniques (13% vs. 36%, p = 0.10; 3% vs. 36%, p = 0.003; 8% vs. 29%, p = 0.02, respectively). SLNB improves the FDG-PET inguinal LNs staging in guiding the decision to treat inguinal nodes. IMRT technique significantly reduced G3-G4 toxicities when patients are treated on groin.

Predicting pathological response after radio-chemotherapy for rectal cancer: Impact of late oxaliplatin administration.

BACKGROUND AND PURPOSE: A previously introduced index based on early tumor (GTV) regression (ERITCP) during neo-adjuvant radio-chemotherapy of rectal cancer was used to investigate the impact of changes of oxaliplatin (OXA) delivery on the prediction of pathological complete response (pCR) and residual vital cell (RVC) fraction. MATERIALS AND METHODS: Ninety-five patients were treated following an adaptive protocol (41.4 Gy/18fr; 2.3 Gy/fr) delivering a simultaneous integrated boost to the residual GTV in the last 6 fractions (3 Gy/fr). OXA was delivered on days -14, 0 (start of RT) and +14. Based on the oncologist's preference, the last OXA cycle was not administered for 36 patients. MRIs taken at planning and at mid-RT were used to calculate ERITCP, before the timing of the third OXA cycle. The impact of OXA cycles and the discriminative power of ERITCP in predicting the pathological response (pCR, RVC >10%) were quantified. Multivariate logistic regression was performed to assess predictive models. RESULTS: Two patients with complete clinical remission refused surgery (cCR_ww). Complete post-surgical data of 54/59 and 35/36 patients were available for the two groups (3 vs 2 OXA cycles). pCR/pCR + cCR_ww/RVC >10% rates were 31.5/33.9/27.8% and 14.3/14.3/54.3% respectively (p = 0.01-0.07). ERITCP showed high negative predictive value (85-91%) for all end-points. The logistic predictive model for pCR included ERITCP (OR: 0.93) and OXA cycles (OR: 3.5), with AUC = 0.78. Internal validation through bootstrap confirmed the robustness of the results. CONCLUSIONS: Late omission of OXA dramatically reduced the pathological response. OXA delivery after the assessment of ERITCP significantly influenced the relationship between ERITCP and pCR.

Early variation of 18-fluorine-labelled fluorodeoxyglucose PET-derived parameters after chemoradiotherapy as predictors of survival in locally advanced pancreatic carcinoma patients.

OBJECTIVE: To investigate if early variation of PET-derived parameters after concomitant chemoradiotherapy (CRT) predicts overall survival (OS), local relapse free survival (LRFS), distant relapse free survival (DRFS) and progression free survival (PFS) in locally advanced pancreatic cancer (LAPC) patients. METHODS: Fifty-two LAPC patients (median age: 61 years; range: 35-85) with available FDG PET/CT before and after RT (2-6 months, median: 2) were enrolled from May 2005 to June 2015. The predictive value of the percentage variation of mean/maximum standard uptake value (ΔSUVmean/max), metabolic tumour volume (ΔMTV) and total lesion glycolysis (ΔTLG), estimated considering different uptake thresholds (40-50-60%), was investigated between pre- and post-RT PET. The percentage difference between gastrointestinal cancer-associated antigen (ΔGICA) levels measured at the time of PET was also considered. Log-rank test and Cox regression analysis were performed to assess the prognostic value of considered PET-derived parameters on survival outcomes. RESULTS: The median follow-up was 13 months (range: 4-130). At univariate analysis, ΔTLG50 showed borderline significance in predicting OS (P = 0.05) and was the most significant parameter correlated to LRFS and PFS (P = 0.001). Median LRFS was 4 and 33 months if ΔTLG50 was below or above 35% respectively (P = 0.0003); similarly, median PFS was 3 vs 6 months (P = 0.0009). No significant correlation was found between PET-derived parameters and DRFS, while the ΔGICA was the only borderline significant prognostic value for this endpoint (P = 0.05). CONCLUSION: PET-derived parameters predict survival in LAPC patients; in particular, ΔTLG50 is the strongest predictor. The combination of these biochemical and imaging biomarkers is promising in identifying patients at higher risk of earlier relapse.

Accurate outcome prediction after neo-adjuvant radio-chemotherapy for rectal cancer based on a TCP-based early regression index.

BACKGROUND AND PURPOSE: An early tumor regression index (ERITCP) was previously introduced and found to predict pathological response after neo-adjuvant radio-chemotherapy of rectal cancer. ERITCP was tested as a potential biomarker in predicting long-term disease-free survival. MATERIALS AND METHODS: Data of 65 patients treated with an early regression-guided adaptive boosting technique (ART) were available. Overall, loco-regional relapse-free and distant metastasis-free survival (OS, LRFS, DMFS) were considered. Patients received 41.4 Gy in 18 fractions (2.3 Gy/fr), including ART concomitant boost on the residual GTV during the last 6 fractions (3 Gy/fr, Dmean: 45.6 Gy). Chemotherapy included oxaliplatin and 5-fluorouracil (5-FU). T2-weighted MRI taken before (MRIpre) and at half therapy (MRIhalf) were available and GTVs were contoured (Vpre, Vhalf). The parameter ERITCP = -ln[(1 - (Vhalf/Vpre))Vpre] was calculated for all patients. Cox regression models were assessed considering several clinical and histological variables. Cox models not including/including ERITCP (CONV_model and REGR_model respectively) were assessed and their discriminative power compared. RESULTS: At a median follow-up of 47 months, OS, LRFS and DMFS were 94%, 95% and 78%. Due to too few events, multivariable analyses focused on DMFS: the resulting CONV_model included pathological complete remission or clinical complete remission followed by surgery refusal (HR: 0.15, p = 0.07) and 5-FU dose >90% (HR: 0.29, p = 0.03) as best predictors, with AUC = 0.75. REGR_model included ERITCP (HR: 1.019, p < 0.0001) and 5-FU dose >90% (HR: 0.18, p = 0.005); AUC was 0.86, significantly higher than CONV_model (p = 0.05). Stratifying patients according to the best cut-off value for ERITCP and to 5-FU dose (> vs <90%) resulted in 47-month DMFS equal to 100%/69%/0% for patients with two/one/zero positive factors respectively (p = 0.0002). ERITCP was also the only variable significantly associated to OS (p = 0.01) and LRFS (p = 0.03). CONCLUSION: ERITCP predicts long-term DMFS after radio-chemotherapy for rectal cancer: an independent impact of the 5-FU dose was also found. This result represents a first step toward application of ERITCP in treatment personalization: additional confirmation on independent cohorts is warranted.

A TCP-based early regression index predicts the pathological response in neo-adjuvant radio-chemotherapy of rectal cancer.

PURPOSE: Introducing a radiobiological index based on early tumor regression during neo-adjuvant radio-chemotherapy (RCT, including oxaliplatin) of rectal adenocarcinoma and testing its discriminative power in predicting the tumor response. METHODS: Seventy-four patients were treated with Helical Tomotherapy following an adaptive (ART) protocol (41.4 Gy/18 fr, 2.3 Gy/fr) delivering a simultaneous integrated boost on the residual tumor in the last 6 fractions up to 45.6 Gy. T2-weighted MRI were taken before (MRIpre) and at mid (MRImid) therapy and the corresponding tumor volumes were considered (Vpre,Vmid). The "Early Regression Index" [Formula: see text] was introduced and its discriminative power was assessed in terms of AUC, sensitivity/specificity, positive/negative predictive value (PPV/NPV). Two end-points were considered: (a) pathological complete response (pCR) or clinical complete response followed by watch-and-wait, (cCR); (b) limited response (residual vital cells (RVC) in the surgical specimen >10%). RESULTS: Complete data were available for 65 patients: pCR, cCR and RVC >10% were 20, 2 and 19 respectively. The discriminative power of ERITCP was moderately high (AUC = 0.81/0.75 for /pCRorcCR/RVC >10% respectively, p < 0.0005). ERITCP was highly sensitive (86-89%) with very high NPV (90-94%). The discriminative power of ERITCP was confirmed on a subgroup of 44/65 patients when considering tumor volumes delineated by a skilled radiologist. CONCLUSION: A radiobiologically consistent index based on early regression showed high performances in predicting the pathological response after neo-adjuvant RCT for rectal cancer with relevant potentialities for ART/treatment customization.

Magnetic Resonance, Vendor-independent, Intensity Histogram Analysis Predicting Pathologic Complete Response After Radiochemotherapy of Rectal Cancer.

PURPOSE: The objective of this study is finding an intensity based histogram (IBH) signature to predict pathologic complete response (pCR) probability using only pre-treatment magnetic resonance (MR) and validate it externally in order to create a workflow for the external validation of an MR IBH signature and to apply the model out of the environment where it has been tuned. The impact of pCR and the final predictors on the survival outcome were also evaluated. METHODS AND MATERIALS: Three centers using different MR scanners were involved in this retrospective study. The first center recruited 162 patients for model training, and the second and third centers provided 34 plus 25 patients for external validation. Patients provided written consent. Accrual period was from May 2008 to December 2014. After surgery pathologic response was defined. T2-weighted MR scans acquired before chemoradiation therapy (CRT) were used for analysis addressed on primary lesions. Images were pre-processed using Laplacian of Gaussian (LoG) filter with multiple σ, and first order intensity histogram-based features (kurtosis, skewness, and entropy) were extracted. Features selection was performed using Mann-Whitney test. Tumor staging (cT, cN) was added to build a logistic regression model and predict pCR. Model performance was evaluated with internal and external validation using area under the curve (AUC) of the receiver operator characteristic (ROC) and calibration with Hosmer-Lemeshow test. The linear cross-correlation matrix (Pearson's coefficient) and the variance inflation factor (VIF) were used to check the correlation and the co-linearity among the final predictors. The amount of the information added through the radiomics features was estimated by using the DeLong's test, and the impact of pCR and the final predictors on survival outcomes were evaluated through the Kaplan-Meier curves by using the log-rank test and the multivariate Cox model. RESULTS: Candidate-to-analysis features were skewness (σ = 0.485, P value = .01) and entropy (σ = 0.344, P value < .05). Logistic regression analysis showed as significant covariates cT (P value < .01), skewness-σ = 0.485 (P value = .01), and entropy-σ = 0.344 (P value < .05). Model AUCs were 0.73 (internal) and 0.75 (external). CONCLUSIONS: This MR-based, vendor-independent model can be helpful for predicting pCR probability in locally advanced rectal cancer (LARC) patients only using pre-treatment imaging.

Sites of recurrent disease and prognostic factors in SCLC patients treated with radiochemotherapy.

OBJECTIVES: Concurrent radiochemotherapy (RCHT) is standard treatment in locally advanced small cell lung cancer (SCLC) patients. Due to conflicting results on elective nodal irradiation (ENI) or selective node irradiation (SNI) there is no clear evidence on optimal target volumes. Therefore, the purposes of this study were to assess the sites of recurrent disease in SCLC and to evaluate the feasibility of SNI versus ENI. METHODS: A retrospective single-institution study of 43 consecutive patients treated with RCHT was performed. After state-of-the-art staging including FDG-PET/CT, all patients underwent three-dimensional conformal radiotherapy to a total dose of 45 Gy in twice-daily fractions of 1.5 Gy starting concurrently with the first or second chemotherapy cycle. All sites of loco-regional recurrences were correlated to the initial tumor and dose delivered. The impact of potential prognostic variables on outcome was evaluated using the Cox-regression model. RESULTS: 13 patients (30%) relapsed locally or regionally: six within the initial primary tumor volume, five within the initially affected lymph nodes, one metachronously within primary tumor and initially affected lymph nodes, and one both inside and outside of the initial nodal disease. All sites of loco-regional recurrence had received 92-106% of the prescribed dose. CONCLUSION: In our study most recurrences occurred within the primary tumor or initially affected lymph nodes, or distantly. We did not register any case of isolated nodal failure, supporting the use of selective nodal irradiation, possibly with the addition of supraclavicular irradiation in patients with nodal disease in the upper mediastinum.