External validation of a composite bio-humoral index in anal cancer patients undergoing concurrent chemoradiation.

BACKGROUND AND PURPOSE: A prognostic scoring system based on laboratory inflammation parameters, [Hemo-Eosinophils-Inflammation (HEI) index], including baseline hemoglobin level, the systemic inflammatory index and eosinophil count was recently proposed in patients with squamous cell carcinoma of the anus (ASCC). HEI was shown to discriminate disease-free (DFS) and overall (OS) survival in ASCC patients treated with concurrent chemoradiation (CRT). We tested the accuracy of the model on a multicentric cohort for external validation. MATERIALS AND METHODS: Patients treated with CRT were enrolled. The Kaplan-Meier curves for DFS and OS based on HEI risk group were calculated and the log-rank test was used. Cox proportional hazards models were used to assess the prognostic factors for DFS and OS. The exponential of the regression coefficients provided an estimate of the hazard ratio (HR). For model discrimination, we determined Harrell's C-index, Gönen & Heller K Index and the explained variation on the log relative hazard scale. RESULTS: A total of 877 patients was available. Proportional hazards were adjusted for age, gender, tumor-stage, and chemotherapy. Two-year DFS was 77 %(95 %CI:72.0-82.4) and 88.3 %(95 %CI:84.8-92.0 %) in the HEI high- and low- risk groups. Two-year OS was 87.8 %(95 %CI:83.7-92.0) and 94.2 %(95 %CI:91.5-97). Multivariate Cox proportional hazards model showed a HR = 2.02(95 %CI:1.25-3.26; p = 0.004) for the HEI high-risk group with respect to OS and a HR = 1.53(95 %CI:1.04-2.24; p = 0.029) for DFS. Harrel C-indexes were 0.68 and 0.66 in the validation dataset, for OS and DFS. Gonen-Heller K indexes were 0.67 and 0.71, respectively. CONCLUSION: The HEI index proved to be a prognosticator in ASCC patients treated with CRT. Model discrimination in the external validation cohort was acceptable.

Stomach and duodenum dose-volume constraints for locally advanced pancreatic cancer patients treated in 15 fractions in combination with chemotherapy.

Purpose: To assess dosimetry predictors of gastric and duodenal toxicities for locally advanced pancreatic cancer (LAPC) patients treated with chemo-radiotherapy in 15 fractions. Methods: Data from 204 LAPC patients treated with induction+concurrent chemotherapy and radiotherapy (44.25 Gy in 15 fractions) were available. Forty-three patients received a simultaneous integrated boost of 48-58 Gy. Gastric/duodenal Common Terminology Criteria for Adverse Events v. 5 (CTCAEv5) Grade ≥2 toxicities were analyzed. Absolute/% duodenal and stomach dose-volume histograms (DVHs) of patients with/without toxicities were compared: the most predictive DVH points were identified, and their association with toxicity was tested in univariate and multivariate logistic regressions together with near-maximum dose (D0.03) and selected clinical variables. Results: Toxicity occurred in 18 patients: 3 duodenal (ulcer and duodenitis) and 10 gastric (ulcer and stomatitis); 5/18 experienced both. At univariate analysis, V44cc (duodenum: p = 0.02, OR = 1.07; stomach: p = 0.01, OR = 1.12) and D0.03 (p = 0.07, OR = 1.19; p = 0.008, OR = 1.12) were found to be the most predictive parameters. Stomach/duodenum V44Gy and stomach D0.03 were confirmed at multivariate analysis and found to be sufficiently robust at internal, bootstrap-based validation; the results regarding duodenum D0.03 were less robust. No clinical variables or %DVH was significantly associated with toxicity. The best duodenum cutoff values were V44Gy < 9.1 cc (and D0.03 < 47.6 Gy); concerning the stomach, they were V44Gy < 2 cc and D0.03 < 45 Gy. The identified predictors showed a high negative predictive value (>94%). Conclusion: In a large cohort treated with hypofractionated radiotherapy for LAPC, the risk of duodenal/gastric toxicities was associated with duodenum/stomach DVH. Constraining duodenum V44Gy < 9.1 cc, stomach V44Gy < 2 cc, and stomach D0.03 < 45 Gy should keep the toxicity rate at approximately or below 5%. The association with duodenum D0.03 was not sufficiently robust due to the limited number of events, although results suggest that a limit of 45-46 Gy should be safe.

Radiotherapy with Intensity-Modulated (IMRT) Techniques in the Treatment of Anal Carcinoma (RAINSTORM): A Multicenter Study on Behalf of AIRO (Italian Association of Radiotherapy and Clinical Oncology) Gastrointestinal Study Group.

A multi-institutional retrospective study was conducted to evaluate the pattern of care and clinical outcomes of anal cancer patients treated with intensity-modulated radiotherapy (IMRT) techniques. In a cohort of 987 patients, the clinical complete response (CR) rate (beyond 6 months) was 90.6%. The 3-year local control (LC) rate was 85.8% (95% CI: 84.4-87.2), and the 3-year colostomy-free survival (CFS) rate was 77.9% (95% CI: 76.1-79.8). Three-year progression-free survival (PFS) and overall survival (OS) rates were 80.2% and 88.1% (95% CI: 78.8-89.4) (95% CI: 78.5-81.9), respectively. Histological grade 3 and nodal involvement were associated with lower CR (p = 0.030 and p = 0.004, respectively). A statistically significant association was found between advanced stage and nodal involvement, and LC, CFS, PFS, OS and event-free survival (EFS). Overall treatment time (OTT) ≥45 days showed a trend for a lower PFS (p = 0.050) and was significantly associated with lower EFS (p = 0.030) and histological grade 3 with a lower LC (p = 0.025). No statistically significant association was found between total dose, dose/fraction and/or boost modality and clinical outcomes. This analysis reports excellent clinical results and a mild toxicity profile, confirming IMRT techniques as standard of care for the curative treatment of anal cancer patients. Lymph node involvement and histological grade have been confirmed as the most important negative prognostic factors.

Tailoring the radiotherapy approach in patients with anal squamous cell carcinoma based on inguinal sentinel lymph node biopsy.

BACKGROUND AND OBJECTIVES: The aim of our study was to analyze the results of selective inguinal node irradiation in patients with anal cancer, based on the biopsy of the inguinal sentinel lymph node (SLN), in terms of local control and prognosis. METHODS: Records of patients with anal squamous cell carcinoma from January 2001 to December 2016 were retrospectively reviewed. Tc99 lymphoscintigraphy was performed in all the clinically inguinal negative patients, followed by radio-guided surgical removal of the inguinal SLN. All patients were treated with combined radiochemotherapy. In patients with negative sentinel nodes, the inguinal area was excluded in the radiotherapy field. RESULTS: A total of 123 patients, 76 females (61.8%), mean age 60.1 ± 12.19 years old, underwent intraoperative lymph node retrieval. The histological analysis showed metastasis in the SLN in 28 patients (22.8%). The mean follow-up was 43.44 ± 31.86 months. No inguinal recurrence was observed in patients with negative inguinal sentinel node(s). A statistically significant difference was observed for overall and disease-free survivals in a patient with positive and negative inguinal sentinel nodes. CONCLUSIONS: In patients with anal canal cancer, the exclusion of the inguinal regions from the radiotherapy field, in patients with negative SLN, does not compromise locoregional control nor prognosis.

Impact of molecular subtype on 1325 early-stage breast cancer patients homogeneously treated with hypofractionated radiotherapy without boost: Should the indications for radiotherapy be more personalized?

AIM: We report molecular subtype impact on 1325 early breast cancer (BCa) patients treated with whole breast hypofractionated (WBH) adjuvant forward-planned intensity modulated radiotherapy (F-IMRT) without boost. METHODS AND MATERIALS: From 02/2009-05/2017 1325 patients with pTis-pT3, pNx-N1aM0 BCa who underwent breast conservation surgery were treated with WBHF-IMRT in our institute, to a total dose of 40 Gy/15 fractions, without boost. Median age: 62 (interquartile range-IQR-:51.14-70.53) years. HISTOLOGY: 8% in situ carcinoma (ISC), 92% invasive tumors. Molecular subtypes (invasive tumors): 49.9% Luminal A, 33.1% Luminal B Her2 negative (-), 6.2% Luminal B Her2 positive (+), 3.6% Hormone Receptor (HR)- Her2+, 7.1% Triple negative (TNBC), and 0.2% HR+. Chemotherapy (CT) was prescribed in 28% of patients, hormonal therapy in 80.3%, monoclonal antibodies (MAb) in 86.8% of Luminal B Her2+ and 97.7% of HR- Her2+ patients. RESULTS: Median follow up was 72.43 (IQR: 44.63-104.13) months. The 5-year Kaplan-Meier estimates of local relapse-free survival (LRFS) was 97.8%, regional-(RRFS) 98.6%, loco-regional- (LRRFS) 96.9%, distant- (DRFS) 96.6%, disease-free survival (DFS) 94.8% and overall survival (OS) 95.5%. Considering molecular subtypes, 5-year LRFS was: 99.8% for Luminal A, 96.7% for Luminal B Her2-, 94.1% for Luminal B Her2+, 87.9% for HR- Her2+, 95.1% for TNBC and 99.1% for in situ carcinoma. CONCLUSION: While the overall estimated probability of LR within 5 years after WBHF-IMRT without boost is good (2.2%), molecular subtypes have a strong impact, despite MAb therapy in Her2+ patients, and CT for TNBC patients, and could be used as a parameter in deciding the boost prescription.

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.

Patterns of radiotherapy practice for pancreatic cancer: Results of the Gastrointestinal Radiation Oncology Study Group multi-institutional survey.

No information is currently available regarding pancreatic cancer (PC) pattern of care in Italy. In the present study, a nationwide survey using a questionnaire was performed to enquire the local standards for PC diagnosis and radiotherapy treatment. Fifty-seven percent of 140 Italian centres completed questionnaire. The main causes of no radiotherapy indication were poor general condition (45%) and lack of guidelines (25%). Physicians (38%) employed neoadjuvant therapy in locally advanced PC patients, while in other centres (62%) adjuvant chemoradiation was administered. Adjuvant gemcitabine-based chemotherapy was selected as the treatment of choice by 59% of centres. Patients were treated mostly with doses of 50-54.9 Gy on the tumour (or bed) plus lymph nodes. A 3D-CRT technique was used in 81.2% of centres, while IMRT and IGRT were available in 61.2 and 48.7% of cases, respectively. Extensive variation exists with regard to patterns of care for PC in Italy. Nevertheless, cooperative studies emerging from this survey appeared beneficial.

Assessment and clinical validation of margins for adaptive simultaneous integrated boost in neo-adjuvant radiochemotherapy for rectal cancer.

PURPOSE: An adaptive concomitant boost (ACB) for the neo-adjuvant treatment of rectal cancer was clinically implemented. In this study population margins M(90,90) considering rectal deformation were derived for 10 consecutive patients treated at 18 × 2.3Gy with Helical Tomotherapy (HT) and prospectively validated on 20 additional patients treated with HT, delivering ACB in the last 6 fractions. METHODS: Sectorial margins M(90,90) of the whole and second treatment parts were assessed for 90% population through a method combining the 90% coverage probability maps of rectal positions (CPC90%) with 3D local distance measurements between the CPC90% and a reference rectal contour. M(90,90) were compared with the margins M(90,90)(95%/99%), ensuring CPC90% coverage with 95%/99% confidence level. M(90,90) of the treatment second part were chosen as ACB margins which were clinically validated for each patient by means of %volume missing of CPC5/6 excluded by the ACB margins. RESULTS: The whole treatment M(90,90) ranged between 1.9 mm and 9 mm in the lower-posterior and upper-anterior sectors, respectively. Regarding ACB, M(90,90) were 7 mm in the anterior direction and <5 mm elsewhere. M(90,90)(95%/99%) did not significantly differ from M(90,90). The %volume excluded by the ACB margin was<2% for all male and <5% for 9/10 female patients. The dosimetry impact on R_adapt for the patients with the largest residual error was negligible. CONCLUSIONS: Local deformation measurements confirm an anisotropic motion of rectum once set-up error is rigidly corrected. Margins of 7 mm anterior and 5 mm elsewhere are adequate for ACB. Female patients show a slightly larger residual error.

Hypofractionated image-guided IMRT in advanced pancreatic cancer with simultaneous integrated boost to infiltrated vessels concomitant with capecitabine: a phase I study.

PURPOSE: To determine the maximum tolerated radiation dose (MTD) of an integrated boost to the tumor subvolume infiltrating vessels, delivered simultaneously with radical dose to the whole tumor and concomitant capecitabine in patients with pretreated advanced pancreatic adenocarcinoma. METHODS AND MATERIALS: Patients with stage III or IV pancreatic adenocarcinoma without progressive disease after induction chemotherapy were eligible. Patients underwent simulated contrast-enhanced four-dimensional computed tomography and fluorodeoxyglucose-labeled positron emission tomography. Gross tumor volume 1 (GTV1), the tumor, and GTV2, the tumor subvolume 1 cm around the infiltrated vessels, were contoured. GTVs were fused to generate Internal Target Volume (ITV)1 and ITV2. Biological tumor volume (BTV) was fused with ITV1 to create the BTV+Internal Target Volume (ITV) 1. A margin of 5/5/7 mm (7 mm in cranium-caudal) was added to BTV+ITV1 and to ITV2 to create Planning Target Volume (PTV) 1 and PTV2, respectively. Radiation therapy was delivered with tomotherapy. PTV1 received a fixed dose of 44.25 Gy in 15 fractions, and PTV2 received a dose escalation from 48 to 58 Gy as simultaneous integrated boost (SIB) in consecutive groups of at least 3 patients. Concomitant chemotherapy was capecitabine, 1250 mg/m(2) daily. Dose-limiting toxicity (DLT) was defined as any treatment-related G3 nonhematological or G4 hematological toxicity occurring during the treatment or within 90 days from its completion. RESULTS: From June 2005 to February 2010, 25 patients were enrolled. The dose escalation on the SIB was stopped at 58 Gy without reaching the MTD. One patient in the 2(nd) dose level (50 Gy) had a DLT: G3 acute gastric ulcer. Three patients had G3 late adverse effects associated with gastric and/or duodenal mucosal damage. All patients received the planned dose of radiation. CONCLUSIONS: A dose of 44.25 Gy in 15 fractions to the whole tumor with an SIB of 58 Gy to small tumor subvolumes concomitant with capecitabine is feasible in chemotherapy-pretreated patients with advanced pancreatic cancer.

Dosimetric and clinical predictors of toxicity following combined chemotherapy and moderately hypofractionated rotational radiotherapy of locally advanced pancreatic adenocarcinoma.

BACKGROUND AND PURPOSE: Hypofractionated radiotherapy (RT) of pancreatic adenocarcinoma is limited by the tolerance of adjacent normal tissues. A better understanding of the influence of dosimetric variables on the rate of toxicity after RT must be considered an important goal. METHODS AND MATERIALS: Sixty-one patients with histologically proven locally advanced disease (LAPD) were analyzed. The therapeutic strategy consisted of induction chemotherapy (ChT) followed by concurrent chemoradiotherapy (CRT). In 39 out of 61 patients the target volume was based on a four-dimensional CT (4D-CT) procedure. Delivered dose was 44.25Gy in 15 fractions to PTV2, which consisted of pancreatic tumor and regional lymph nodes considered radiologically involved; 23 out of 61 patients received a simultaneous integrated boost (SIB) to a tumor sub-volume infiltrating the great abdominal vessels (PTV1) with dose in the range of 48-58Gy. RT was delivered with Helical Tomotherapy. Dose-volume histograms (DVHs) of target volumes and organs at risk (OARs) were collected for analysis. The predictive value of clinical/dosimetric parameters was tested by univariate/multivariate analyses. RESULTS: The crude incidence of acute gastrointestinal (GI) grade 2 toxicity was 33%. The 12-month actuarial rate of "anatomical" (gastro-duodenal mucosa damage) toxicity was 13% (95% CI: 4-22%). On univariate analysis, several stomach and duodenum DVH endpoints are predictive of toxicity after moderately hypofractionated radiotherapy. Multivariate analysis confirmed that baseline performance status and the stomach V20[%] were strong independent predictors of acute GI grade ⩾2 toxicity. The high-dose region of duodenum DVH (V45[%]; V40[%]) was strongly correlated with grade ⩾2 "anatomical" toxicity; the best V40[%] and V45[%] cut-off values were 16% and 2.6% respectively. CONCLUSION: Regarding dosimetric indices, stomach V20[%] correlates with a higher rate of acute toxicity; more severe acute and late anatomical toxicities are related to the high dose region of duodenum DVH.

Feasibility of an adaptive strategy in preoperative radiochemotherapy for rectal cancer with image-guided tomotherapy: boosting the dose to the shrinking tumor.

PURPOSE: To investigate the feasibility of preoperative adaptive radiochemotherapy by delivering a concomitant boost to the residual tumor during the last 6 fractions of treatment. METHODS AND MATERIALS: Twenty-five patients with T3/T4N0 or N+ rectal cancer were enrolled. Concomitant chemotherapy consisted of oxaliplatin 100 mg/m(2) on days -14, 0, and +14, and 5-fluorouracil 200 mg/m(2)/d from day -14 to the end of radiation therapy (day 0 is the start of radiation therapy). Radiation therapy consisted of 41.4 Gy in 18 fractions (2.3 Gy per fraction) with Tomotherapy to the tumor and regional lymph nodes (planning target volume, PTV) defined on simulation CT and MRI. After 9 fractions simulation CT and MRI were repeated for the planning of the adaptive phase: PTVadapt was generated by adding a 5-mm margin to the residual tumor. In the last 6 fractions a boost of 3.0 Gy per fraction (in total 45.6 Gy in 18 fractions) was delivered to PTVadapt while concomitantly delivering 2.3 Gy per fraction to PTV outside PTVadapt. RESULTS: Three patients experienced grade 3 gastrointestinal toxicity; 2 of 3 showed toxicity before the adaptive phase. Full dose of radiation therapy, oxaliplatin, and 5-fluorouracil was delivered in 96%, 96%, and 88% of patients, respectively. Two patients with clinical complete response (cCR) refused surgery and were still cCR at 17 and 29 months. For the remaining 23 resected patients, 15 of 23 (65%) showed tumor regression grade 3 response, and 7 of 23 (30%) had pathologic complete response; 8 (35%) and 12 (52%) tumor regression grade 3 patients had ≤5% and 10% residual viable cells, respectively. CONCLUSIONS: An adaptive boost strategy is feasible, with an acceptable grade 3 gastrointestinal toxicity rate and a very encouraging tumor response rate. The results suggest that there should still be room for further dose escalation of the residual tumor with the aim of increasing pathologic complete response and/or cCR rates.

Characterisation of rectal motion during neo-adjuvant radiochemotherapy for rectal cancer with image-guided tomotherapy: implications for adaptive dose escalation strategies.

BACKGROUND: Interest in boosting the dose to the tumour during neo-adjuvant radiochemotherapy for rectal cancer is ever increasing, especially within the frame of adaptive radiotherapy. Rectal motion remains a potentially important obstacle to the full exploitation of this approach and needs to be carefully investigated. MATERIAL AND METHODS: The main purposes of this work were to: a) quantify rectal motion on all fractions of a treatment course; and b) assess margins for adaptive boosting in the second part of the treatment in order to benefit of tumour reduction during treatment. Ten consecutive patients treated with image-guided tomotherapy (41.4 Gy, 18 fractions) were selected. The cranial half of the rectum (subject to motion) was contoured by a single observer on daily MVCTs. The variations of rectal volume and of the envelope of rectum positions were investigated (169 MVCTs). The impact of applying different margins to the rectum in including all its possible positions was also investigated when considering the planning kVCT, the first fraction MVCT, the half-treatment MVCT or the median rectal contours of the whole or second half of treatment as reference volumes. RESULTS: Rectal volume reduced during treatment in all patients, with a significant time-trend in 6/10 patients. The median values of the envelope volumes were 129 cm(3) and 87 cm(3) in the first and second half of the treatment, respectively. On average, 95% of the rectal envelope was included by an isotropic expansion of 12 mm and 5 mm of the median contours when considering the whole or the second half of the treatment, respectively. CONCLUSION: A significant reduction of rectal volume was found in the second part of the treatment where rectal mobility was limited. As a consequence, relatively small margins may be used around the residual tumour volume when adaptive boost is delivered in the second half of the treatment.

A randomized phase II trial of two different 4-drug combinations in advanced pancreatic adenocarcinoma: cisplatin, capecitabine, gemcitabine plus either epirubicin or docetaxel (PEXG or PDXG regimen).

PURPOSE: PEFG regimen (P:cisplatin, E:epirubicin, F:5-fluorouracil, G:gemcitabine) significantly prolonged progression-free (PFS) and overall survival (OS) of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine. The current trial was aimed at assessing whether the replacement of E with docetaxel (D) may improve 6 months PFS (PFS6). METHODS: Chemo-naive patients with stage III or metastatic PA received P (30 mg/m(2) day 1 and 15), G (800 mg/m(2) day 1 and 15), and capecitabine (1,250 mg/m(2)/day days 1-28, without a break) and were randomized to receive either D at 25-30 mg/m(2) day 1 and 15 (arm A: PDXG regimen) or E at 30 mg/m(2) day 1 and 15 (arm B: PEXG regimen). Cycles were repeated every 28 days for a maximum of 6 months. The Fleming design was used to calculate the sample size on the probability of being PFS6. Assuming P0 = 40% and P1 = 60%, α = 0.05 and ß = 0.10; the study was to enroll 52 patients per arm. RESULTS: Between July 2005 and September 2008, 105 patients were enrolled, stratified by stage and randomized. Patients' characteristics were (A/B) the following: median age 61/59, PS >70 92/88%, metastatic disease 66/65%. PFS6 was 58%, and median OS was 11 months in both arms. A partial response was observed in 60/37% of patients. Main per cycle G3-4 toxicity was the following: neutropenia 4/13%, thrombocytopenia 2/4%, anemia 4/4%, and fatigue 6/3%. CONCLUSIONS: The inclusion of D instead of E yielded more objective response and less G3-4 neutropenia but did not improve PFS and OS. The present trial confirms the relevant impact on outcome of advanced PA of 4-drug regimens.

Planning design of locally advanced pancreatic carcinoma using 4DCT and IMRT/IGRT technologies.

BACKGROUND AND PURPOSE: to study the impact of the 4DCT imaging technique on radiotherapy planning for pancreatic carcinoma. To evaluate the possibility of IMRT/IGRT to increase the dose to PTV subvolume. MATERIAL AND METHODS: contrast-enhanced 4DCT scans of 15 patients (PTs) with unresectable pancreatic cancer were acquired. A 4DCT based PTV (4D-PTV) was created by the convolution of contours and then expanded for geometric uncertainties; a standard PTV (STD-PTV) was derived from a single CTV plus conventional margins. Two 3D conformal treatment (3DCRT) plans and one Helical Tomotherapy (HT) plan were generated with a prescription of 60 Gy. Regarding the 3DCRT plans, the 4D-PTV was considered as the target volume for one, and the STD-PTV for the other; the HT plans were performed only for 4D-PTV. Twelve of 15 PTs were admitted to a Phase I hypofractionated study (15 fractions). The prescribed dose was 44.25 Gy to the 4D-PTV and the PTV subvolume around vascular involvement was boosted from 50 to 55 Gy; before treatment, daily patient position was corrected using MVCT. RESULTS: 4D-PTVs were smaller than STD-PTVs with a volume reduction equal to 37%. 3DCRT plans on 4D-PTV showed a significant sparing of most OARs, the use of IMRT allowed a further significant dose reduction. In the Phase I study the PTV subvolume received up to 55 Gy with modest increase in dose to OARs. CONCLUSIONS: the 4DCT procedure decreases the overlap between PTV and OARs. HT technique, compared with 3DCRT, allows efficient dose sparing in particular for the duodenum. The IMRT/IGRT approach allows a safe dose escalation to PTV subvolume.

Internal target volume defined by contrast-enhanced 4D-CT scan in unresectable pancreatic tumour: evaluation and reproducibility.

We compared customized ITVs obtained with CE-4D-CT imaging (ITV(4D)) with a population-based (ITV(PBC)) in 29 patients (PTs) and evaluated the intra-observer ITV delineation reproducibility in 5 PTs with unresectable pancreatic ductal adenocarcinoma (PDA). The ITV(PBC) was quite different from the ITV(4D), with under/over estimation of volume. Intra-observer volume delineation variability on CE-4D-CT and on a single-phase CE-CT were similar (27.6% vs 24.9%).