Role of Chemoradiation in the Adjuvant Treatment of Radically Resected Pancreatic Cancer Patients: A Mono-Institutional Retrospective Analysis.

INTRODUCTION: Pancreatic cancer (PC) represents an unfavorable prognosis condition, even in patients with resectable disease. The aim of this series was to investigate the role of treatment intensification with adjuvant chemoradiation (CRT) in radically resected PC patients. METHODS: Data from PC patients who underwent radical surgery, adjuvant chemotherapy (CT), and CRT throughout a 20-year period were retrospectively collected. Actuarial local control (LC) and the overall survival (OS) were the primary endpoints, with disease-free survival and metastasis-free survival (MFS) representing secondary endpoints. RESULTS: The analysis included 108 PC patients treated with adjuvant CRT and CT from January 2000 to August 2019. Median age was 66 years (range: 40-83), and all patients underwent radical surgical resection with adjuvant CT (88, 81.5%) plus concomitant CRT (101, 93.5%) or radiotherapy alone (7, 6.5%). The median dose delivered to the tumor bed was 50.4 Gy (range: 45-50.6 Gy), while median dose to regional lymphatic drainage stations was 39.6 Gy (range 39.6-45 Gy). Concomitant CT was a gemcitabine-based regimen in the vast majority of patients (87, 80.6%). Median follow-up time was 21 months; the 2- and 5-year LC rates were 75.8% and 59.1%, respectively. Perineural invasion at pathological assessment was found significantly associated with LC (p = 0.028). Median OS was 40 months with 2- and 5-year OS rates of 73.9% and 41.6%, respectively. CONCLUSIONS: The outcomes of this series suggest to investigate the possible impact of adding adjuvant CRT to CT in PC patients. Timing and combination of modern CRT with new systemic therapies need to be further investigated to personalize therapy and optimize clinical advantages.

The Porto European Cancer Research Summit 2021.

Key stakeholders from the cancer research continuum met in May 2021 at the European Cancer Research Summit in Porto to discuss priorities and specific action points required for the successful implementation of the European Cancer Mission and Europe's Beating Cancer Plan (EBCP). Speakers presented a unified view about the need to establish high-quality, networked infrastructures to decrease cancer incidence, increase the cure rate, improve patient's survival and quality of life, and deal with research and care inequalities across the European Union (EU). These infrastructures, featuring Comprehensive Cancer Centres (CCCs) as key components, will integrate care, prevention and research across the entire cancer continuum to support the development of personalized/precision cancer medicine in Europe. The three pillars of the recommended European infrastructures - namely translational research, clinical/prevention trials and outcomes research - were pondered at length. Speakers addressing the future needs of translational research focused on the prospects of multiomics assisted preclinical research, progress in Molecular and Digital Pathology, immunotherapy, liquid biopsy and science data. The clinical/prevention trial session presented the requirements for next-generation, multicentric trials entailing unified strategies for patient stratification, imaging, and biospecimen acquisition and storage. The third session highlighted the need for establishing outcomes research infrastructures to cover primary prevention, early detection, clinical effectiveness of innovations, health-related quality-of-life assessment, survivorship research and health economics. An important outcome of the Summit was the presentation of the Porto Declaration, which called for a collective and committed action throughout Europe to develop the cancer research infrastructures indispensable for fostering innovation and decreasing inequalities within and between member states. Moreover, the Summit guidelines will assist decision making in the context of a unique EU-wide cancer initiative that, if expertly implemented, will decrease the cancer death toll and improve the quality of life of those confronted with cancer, and this is carried out at an affordable cost.

Management of the kidney transplant patient with Cancer: Report from a Multidisciplinary Consensus Conference.

INTRODUCTION: Cancer is the second most common cause of mortality and morbidity in Kidney Transplant Recipients (KTRs). Immunosuppression can influence the efficacy of cancer treatment and modification of the immunosuppressive regimen may restore anti-neoplastic immune responses improving oncologic prognosis. However, patients and transplant physicians are usually reluctant to modify immunosuppression, fearing rejection and potential graft loss. Due to the lack of extensive and recognised data supporting how to manage the immunosuppressive therapy in KTRs, in the context of immunotherapy, chemotherapy, radiotherapy and loco-regional treatments, a Consensus Conference was organised under the auspices of the European Society of Organ Transplantation and the Italian Society of Organ Transplantation. The conference involved a multidisciplinary group of transplant experts in the field across Europe. METHODS: The overall process included a) the formulation of 12 specific questions based on the PICO methodology, b) systematic literature review and summary for experts for each question, c) a two-day conference celebration and the collection of experts' agreements. The conference was articulated in three sessions: "Immunosuppressive therapy and immunotherapy", "Systemic therapy", "Integrated Therapy", while the final experts' agreement was collected with a televoting procedure and defined according to the majority criterion. RESULTS: Twenty-six European experts attended the conference and expressed their vote. A total of 14 statements were finally elaborated and voted. Strong agreement was found for ten statements, moderate agreement for two, moderate disagreement for one and uncertainty for the last one. CONCLUSIONS: The consensus statements provide guidance to transplant physicians caring for kidney transplant recipients with cancer and indicate key aspects that need to be addressed by future clinical research.

Radiotherapy of Prostate Carcinoma: A Comparison of the Predictive Role of EAU Versus NCCN Risk Stratification Systems.

BACKGROUND/AIM: To compare the predictive efficacy of National Comprehensive Cancer Network (NCCN) and European Association of Urology (EAU) risk stratification systems in radiotherapy of prostate cancer. PATIENTS AND METHODS: One-thousand-nine-hundred-nine patients treated with definitive (1,074), adjuvant (381), and salvage radiotherapy (454) were analysed. RESULTS: Both systems significantly predicted biochemical-relapse-free-survival, metastasis-free-survival, and disease-free-survival, while only the NCCN system correlated with local-control in the definitive radiotherapy group. In the adjuvant setting, both systems failed to predict all outcomes. In the salvage setting, only the NCCN system significantly predicted biochemical-relapse-free-survival, metastasis-free-survival and disease-free-survival. CONCLUSION: This analysis confirms the efficacy of both systems in definitive radiotherapy and suggests the utility of the NCCN also in salvage radiotherapy.

Optimized stereotactic volumetric modulated arc therapy as an alternative to brachytherapy for vaginal cuff boost. A dosimetric study.

We evaluate the role of stereotactic body radiotherapy using volumetric modulated arc therapy (VMAT) technique as an alternative to high-dose rate brachytherapy (HDR-BT) in the treatment of vaginal cuff in postoperative endometrial cancer. CT scans of 8 patients were used in this study. The clinical target volume (CTV) was defined as the 0.5 cm tissue around the applicator (then subtracting the applicator). Total dose was 30Gy delivered in 5 fractions. In HDR-BT, dose was prescribed at a distance of 0.5 cm from the surface applicator. For VMAT irradiation, a planning target volume (PTV) was obtained from CTV by an expansion of 3 mm. Two VMAT plans were generated using a full arc rotation. The first plan was optimized with an anatomy-based optimization module (PO-VMAT) using a 1mm multileaf collimator beam margin to enhance dose heterogeneity and dose fallout outside the target. The second plan was generated with a full-inverse planning module (FI-VMAT). Conformity (CI100, CI50, CI25), gradient (GI) indexes, and integral doses were calculated. To account for various dose heterogeneity distributions we calculated the equivalent uniform dose (EUD) using the Niemerko model. A Kruskal-Wallis analysis of variance followed by Dunn's-type multiple comparisons was performed. Dose distributions were more heterogeneous with HDR-BT: Dmean was 144.2% of prescription dose for CTV in HDR-BT and 118.5 and 108.6% for PTV in PO-VMAT and FI-VMAT, respectively. The mean values of EUD for CTV were 136.9%, 130.0 %, and 111.0% of prescription dose in HDR-BT, PO-VMAT, and FI-VMAT plans, respectively. GI indexes were 2.81, 3.41, and 4.14 for HDR-BT, PO-VMAT, and FI-VMAT, respectively. Near-maximal doses (D0.1cc) for rectum and bladder were significantly higher in HDR-BT plans compared to PO-VMAT and FI-VMAT plans (rectum: 131.2% vs112.8% vs 112.0%, respectively; bladder: 129.2% vs 108.7%, and 109.8%, respectively). PO-VMAT plans were able to mimic the HDR-BT dose distribution, showing a successful capability of highly conformal dose distribution, EUD values similar to HDR-BT, and steep dose-gradient outside PTV, then providing a reasonable alternative to brachytherapy.

[Use of the Lean methodology in the management of cancer patients in a University Hospital, Italy: First results]. / Applicazione di logiche lean nella gestione del paziente oncologico: primi risultati della sperimentazione in un policlinico universitario.

AIM: The aim of this study was to map a patient's journey along all stages of his daily care path in an Oncology outpatient department, to identify and eliminate "bottleneck" situations that interfere with the patient's flow of care. The main key performance indicators used in the study were: waiting times for each stage of the care process, time required for each activity, and resources used. METHODS: The study was conducted from 17-30 January 2018 at the medical oncology clinic of a large university teaching and research hospital in Italy. We analyzed all the healthcare services provided during the monitoring period, dividing them into: first appointments, therapy, visits for adjustments of the therapeutic plan, visits for i.v. therapy, visits for oral therapy, follow-up visits, other visits (e.g. for positioning of peripherally inserted central catheter). Data collection was performed by administering two questionnaires: a Patient Journey (PJ) questionnaire to patients and a Medical Journey (MJ) questionnaire to clinicians. This project employed Lean principles in order to: view the process and specify value through the patient's point of view, identify waste in processes and eliminate any steps lacking any added value, reduce variation of and leveling workload to improve quality and ?ow of care, engage patients and staff to redesign the process. RESULTS: The response rate in 1351 outpatients who were invited to participate was 63%; for doctors it was 81%. The mean waiting time for first visits and follow up visits performed in a single day was 50 minutes. An audit process was thus performed and a series of quality improvement measures were defined and shared with health professionals. CONCLUSIONS: The Lean methodology could provide a robust framework for improved understanding and management of complex system constraints in outpatient oncology clinics, and could result in improved access to treatment and reduced waiting times for patients.

Hypofractionated Postoperative IMRT in Prostate Carcinoma: A Phase I/II Study.

AIM: To report the outcome of hypofractionated radiotherapy after radical prostatectomy (RP) for prostate cancer (PCa) using simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT). PATIENTS AND METHODS: A total of 124 patients with PCa at high risk of relapse after RP or diagnosis of biochemical relapse were included. Patients received 62.5 Gy to the prostate bed and 45 Gy to pelvic nodes in 25 fractions. Androgen-suppressive therapy was prescribed based on National Comprehensive Cancer Network risk categories. RESULTS: Median follow-up was 30 months. Only two patients (1.6%) developed grade 3 or more acute toxicity: one grade 3 skin toxicity (0.8%) and one grade 4 genitourinary toxicity (0.8%). Grade 2 acute gastrointestinal and genitourinary toxicity was recorded in 24.2% and 17.7% of patients, respectively. Five-year grade 2 or more gastrointestinal and genitourinary toxicity was 1.1% and 7.3%, respectively. Five-year biochemical relapse-free survival was 86.5%. CONCLUSION: After RP, hypofractionated IMRT-SIB demonstrated a favorable toxicity profile and encouraging results in terms of relapse-free survival.

Intensity-modulated extended-field chemoradiation plus simultaneous integrated boost in the pre-operative treatment of locally advanced cervical cancer: a dose-escalation study.

OBJECTIVE: To investigate the feasibility and determine the recommended pre-operative intensity-modulated radiotherapy (IMRT) dose of extended-field chemoradiation along with simultaneous integrated boost (SIB) dose escalation. METHODS: A radiation dose of 40 Gy over 4 weeks, 2 Gy/fraction, was delivered to the tumour and the lymphatic drainage (planning target volume, PTV3), which encompassed a volume larger than standard (common iliac lymphatic area up to its apex, in front of the L3 vertebra), concurrently with chemotherapy (cisplatin and 5-fluorouracil). Radiation dose was escalated to the pelvis (PTV2) and to the macroscopic disease (PTV1) with the SIB-IMRT strategy. Three dose levels were planned: Level 1 (PTV3: 40/2 Gy; PTV2: 40/2 Gy; PTV1: 45/2.25 Gy), Level 2 (PTV3: 40/2 Gy; PTV2: 45/2.25 Gy; PTV1: 45/2.25 Gy) and Level 3 (PTV3: 40/2 Gy; PTV2: 45/2.25 Gy; PTV1: 50/2.5 Gy). All treatments were delivered in 20 fractions. Patients were treated in cohorts of between three and six per group using a Phase I study design. The recommended dose was exceeded if two of the six patients in a cohort experienced dose-limiting toxicity within 3 months from treatment. RESULTS: 19 patients [median age: 46 years; The International Federation of Gynecology and Obstetrics (FIGO) stage IB2: 3, IIB: 10, IIIA-IIIB: 6] were enrolled. Median follow-up was 24 months (9-60 months). The most common grade 3/4 toxicity was gastrointestinal (GI) (diarrhoea, mucous discharge, rectal/abdominal pain). At Levels 1 and 2, only one grade 3 GI toxicity per level was recorded, whereas at Level 3, two grade 3 GI toxicities (diarrhoea, emesis and nausea) were recorded. CONCLUSION: The SIB-IMRT technique was found to be feasible and safe at the recommended doses of 45 Gy to PTV1 and PTV2 and 40 Gy to PTV3 in the pre-operative treatment of patients with locally advanced cervical cancer. Unfortunately, this complex technique was unable to safely escalate dose beyond levels already achieved with three-dimensional conformal radiotherapy technique given acute GI toxicity. ADVANCES IN KNOWLEDGE: A Phase I radiotherapy dose-escalation trial with SIB-IMRT technique is proposed in cervical cancer. This complex technique is feasible and safe at the recommended doses.

No benefit of adjuvant Fluorouracil Leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): Long term results of a randomized trial (I-CNR-RT).

BACKGROUND AND PURPOSE: To evaluate the effect of adjuvant chemotherapy (ACT) in locally advanced rectal cancer (LARC) after neoadjuvant chemoradiation (NACT-RT). The study was funded by the Italian National Research Council (CNR). METHODS: From September 1992 to January 2001, 655 patients with LARC (clinically T3-4, any N) treated with NACT-RT and surgery, were randomized in two arms: follow-up (Arm A) or 6 cycles of ACT with 5 fluorouracil (5FU)-Folinic Acid (Arm B). NACT-RT consisted of 45Gy/28/ff concurrent with 5FU (350mg/sqm) and Folinic Acid (20mg/sqm) on days 1-5 and 29-33; surgery was performed after 4-6weeks. Median follow up was 63·7months. Primary end point was overall survival (OS). RESULTS: 634/655 patients were evaluable (Arm A 310, Arm B 324); 92·5% of Arm A and 91% of Arm B patients received the preoperative treatment as in the protocol; 294 patients of Arm A (94·8%) and 296 of Arm B (91·3%) underwent a radical resection; complete pathologic response and overall downstaging rates did not show any significant difference in the two arms. 83/297 (28%) patients in Arm B, never started ACT. Five year OS and DFS did not show any significant difference in the two treatment arms. Distant metastases occurred in 62 patients (21%) in Arm A and in 58 (19·6%) in Arm B. CONCLUSIONS: In patients with LARC treated with NACT-RT, the addition of ACT did not improve 5year OS and DFS and had no impact on the distant metastasis rate.

Completion surgery after concomitant chemoradiation in locally advanced cervical cancer: a comprehensive analysis of pattern of postoperative complications.

BACKGROUND: We provided a comprehensive analysis of rate, pattern, and severity of early and late postoperative complications in a very large, single-institution series of locally advanced cervical cancer (LACC) patients administered CT/RT plus radical surgery (RS). METHODS: A total of 362 consecutive LACC (FIGO stage IB2-IVA) patients were submitted to RS after CT/RT at the Gynecologic Oncology Unit of the Catholic University (Rome/Campobasso). At 4 weeks after CT/RT, patients were evaluated for objective response and triaged to radical hysterectomy and pelvic ± aortic lymphadenectomy. Surgical morbidity was classified according to the Chassagne's grading system. RESULTS: Most cases underwent type III-IV radical hysterectomy (N = 313, 86.5 %); pelvic lymphadenectomy was performed in all patients, while 116 patients (32.1 %) were also submitted to aortic lymphadenectomy. A total of 93 patients (25.7 %) experienced any grade postoperative complications, and 60 (16.6 %) had ≥grade 2 complications; grade 3-4 complications occurred in 21 patients (5.8 %). Of all early postoperative complications (N = 100), 31 (31.0 %) were urinary, 9 (9.0 %) were gastrointestinal, and 45 (45.0 %) were vascular. Of all late complications (N = 31), 20 (64.5 %) were urinary, 7 (22.6 %) gastrointestinal, and 2 (6.4 %) were vascular. Multivariate analysis showed that not complete clinical response to treatment retained an independent, unfavorable association with risk of development of postoperative morbidity, while advanced stage, and aortic lymphadenectomy showed only a borderline value. CONCLUSIONS: Failure to achieve clinical complete response to treatment and, to a lesser extent, more advanced stage, and aortic lymphadenectomy, were associated with a higher risk of developing any grade as well as ≥grade 2 complications.

Chemoradiation with concomitant boosts followed by radical surgery in locally advanced cervical cancer: long-term results of the ROMA-2 prospective phase 2 study.

PURPOSE: This prospective, phase 2 study aimed at assessing the efficacy of accelerated fractionation radiation therapy by concomitant boosts (CBs) associated with chemoradiation therapy (CRT) of the whole pelvis, in improving the rate of pathological complete response (pCR) to treatment in patients with International Federation of Gynaecology and Obstetrics (FIGO) stage IB2-IVA locally advanced cervical cancer. METHODS AND MATERIALS: Neoadjuvant CRT included conformal irradiation of the whole pelvis with a total dose of 39.6 Gy (1.8 cGy/fraction, 22 fractions), plus additional irradiation of primary tumor and parametria with 10.8 Gy administered with CBs (0.9 cGy/fraction, 12 fractions, every other day). Concomitant chemotherapy included cisplatin (20 mg/m(2), days 1-4 and 26-30 of treatment), and capecitabine (1300 mg/m(2)/daily, orally) during the first 2 and the last 2 weeks of treatment. Radical hysterectomy plus pelvic with or without aortic lymphadenectomy was performed within 6 to 8 weeks from CRT. Toxicity was recorded according to Radiation Therapy Oncology Group toxicity criteria and Chassagne grading system. Based on the Simon design, 103 cases were required, and the regimen would be considered active if >45 pCR were registered (α error = 0.05; ß error = 0.1). RESULTS: pCR was documented in 51 cases (50.5%), and the regimen was considered active, according to the planned statistical assumptions. At median follow-up of 36 months (range: 7-85 months), the 3-year local failure rate was 7%, whereas the 3-year disease-free and overall survival rates were 73.0% and 86.1%, respectively. Grade 3 leukopenia and neutropenia were reported in only 1 and 2 cases, respectively. Gastrointestinal toxicity was always grade 1 or 2. CONCLUSIONS: Addition of CBs in the accelerated fractionation modality to the whole pelvis chemoradiation followed by radical surgery results in a high rate of pathologically assessed complete response to CRT and a very encouraging local control rate, with acceptable toxicity.

Postoperative 5-FU based radiochemotherapy in rectal cancer: retrospective long term results and prognostic factors of a pooled analysis on 1,338 patients.

AIM: To evaluate survival outcomes of patients in pStage II-III rectal cancer treated with adjuvant 5-fluorouracil-based radiochemotherapy and to retrospectively analyze the impact of prognostic variables on local control, metastasis-free survival and cause-specific survival. PATIENTS AND METHODS: A total of 1,338 patients, treated between 1985-2005 for locally advanced rectal cancer, who underwent surgery and postoperative 5-fluorouracil-based chemoradiation, were selected. RESULTS: The actuarial 5- and 10-year outcomes were: local control 87.0%-84.1%, disease-free survival 61.6%-52.1%, metastasis-free survival 72.0%-67.2%, cause-specific survival 70.4%-57.5%, and overall survival 63.8%-53.4%. Better outcomes were observed in patients with IIA, IIIA stage. Multivariate analyses showed that variables significantly affecting metastasis-free survival were pT4 and pN2, while for cancer-specific survival those variables were age >65 years, pT4, pN1, pN2, distal tumors and number of lymph nodes removed ≤ 12. CONCLUSION: This study confirmed that among stage II-III rectal cancer patients there are subgroups of patients with different clinical outcomes.

Improved outcomes for rectal cancer in the era of preoperative chemoradiation and tailored mesorectal excision: a series of 338 consecutive cases.

Neoadjuvant chemoradiation (CRT), tailored mesorectal excision, and intraoperative radiotherapy (IORT) have become the leading measures for rectal cancer treatment. The objective of this study was to evaluate early and long-term results of a multimodal treatment model for rectal cancer followed by curative surgery. Prospectively collected hospital records of 338 patients surgically treated for rectal cancer between January 1998 and December 2008 were retrospectively reviewed. Patients with high rectum level cancers and those with middle and low rectum cancers with clinical stage T1 to T2 underwent surgery, whereas those with T3 to T4 and N+ disease at the middle and low rectum received neoadjuvant CRT in 96.2 per cent of cases. Short-course neoadjuvant radiotherapy was not considered for neoadjuvant treatment. Postoperative major complications and mortality rates were 12.7 and 2.3 per cent, respectively. Overall 5-year disease-specific and disease-free survival were 80 and 73.1 per cent, respectively, whereas local recurrence rate was 6.1 per cent. At multivariate analysis, nodal status and circumferential margin status were independently associated with poor survival; local recurrence rates were independently affected by nodal and marginal status and tumor stage. The extent of mesorectal excision should be tailored depending on tumor location and the use of neoadjuvant chemotherapy, combined with IORT in advanced middle and low rectal cancer, leading to remarkable tumor downstaging with excellent prognosis in responding patients.

Concomitant boost plus large-field preoperative chemoradiation in locally advanced uterine cervix carcinoma: Phase II clinical trial final results (LARA-CC-1).

OBJECTIVE: To report the Phase II study final results in terms of pathological complete response (pCR) and complications in locally advanced cervical carcinoma (LACC) patients treated with chemoradiation (CT/RT) regimen based on accelerated fractionation, nodal extended fields and adjuvant radical surgery. METHODS: The sample size was quantified according to published data which shows that CT/RT followed by radical surgery in LACC patients provides a pCR rate above 45%. The 2-stage design by Simon was used to test the null hypothesis that the true pCR would improve by above 20%. The chemoradiation regimen was considered active if >24/43 pCRs were recorded. 40 Gy/2 Gy fraction in 4 weeks was delivered to nodal volume extending up to L3 vertebra, concurrently with chemotherapy. 45 Gy in 20 fractions with a concomitant boost strategy was delivered to the macroscopic disease only. RESULTS: 47 patients were enrolled. Median follow-up was 26 months (3-52 months). Pathological response was assessed in 44/47 patients: 17/44 (38.6%) showed a pCR to treatment, and 9/44 cases (20.5%) showed microscopic disease. Pelvic nodal metastases were documented in 9/44 cases (20.5%). 87.5% of recurrences were extra pelvic. Five patients (11%) developed acute severe gastrointestinal toxicity. The actuarial cumulative 2-year incidence of G ≥ 2 late cutaneous, gastrointestinal, and genitourinary toxicity was 10.3%, 8.3% and 24.9%, respectively. The 3-year DFS was 77.1%, while the 3-year OS was 80.5%. CONCLUSIONS: Our results confirm the high tolerability and efficacy of this accelerated regimen. However, based on the study design, 45 Gy as a concomitant boost CT/RT delivered by a 3D technique does not seem sufficient to increase pCR rate.

Diffusion-weighted MRI for selection of complete responders after chemoradiation for locally advanced rectal cancer: a multicenter study.

PURPOSE: In 10-24% of patients with rectal cancer who are treated with neoadjuvant chemoradiation, no residual tumor is found after surgery (ypT0). When accurately selected, these complete responders might be considered for less invasive treatments instead of standard surgery. So far, no imaging method has proven reliable. This study was designed to assess the accuracy of diffusion-weighted MRI (DWI) in addition to standard rectal MRI for selection of complete responders after chemoradiation. METHODS: A total of 120 patients with locally advanced rectal cancer from three university hospitals underwent chemoradiation followed by a restaging MRI (1.5T), consisting of standard T2W-MRI and DWI (b0-1000). Three independent readers first scored the standard MRI only for the likelihood of a complete response using a 5-point confidence score, after which the DWI images were added and the scoring was repeated. Histology (ypT0 vs. ypT1-4) was the standard reference. Diagnostic performance for selection of complete responders and interobserver agreement were compared for the two readings. RESULTS: Twenty-five of 120 patients had a complete response (ypT0). Areas under the ROC-curve for the three readers improved from 0.76, 0.68, and 0.58, using only standard MRI, to 0.8, 0.8, and 0.78 after addition of DWI (P = 0.39, 0.02, and 0.002). Sensitivity for selection of complete responders ranged from 0-40% on standard MRI versus 52-64% after addition of DWI. Specificity was equally high (89-98%) for both reading sessions. Interobserver agreement improved from κ 0.2-0.32 on standard MRI to 0.51-0.55 after addition of DWI. CONCLUSIONS: Addition of DWI to standard rectal MRI improves the selection of complete responders after chemoradiation.

Concomitant boost dose escalation plus large-field preoperative chemoradiation in locally advanced carcinoma of the uterine cervix: results of a phase I study (LARA-CC-1).

OBJECTIVE: To determine the recommended preoperative dose of large-field chemoradiation along with concomitant boost dose escalation on the tumor in locally advanced cervical carcinoma (LACC). PATIENTS AND METHODS: A radiation dose of 40Gy over four weeks, 2Gy per fraction, was delivered to the tumor and the lymphatic drainage (planning target volume, PTV2), which encompassed a volume larger than standard (upper field border: L3 vertebra), concurrently with chemotherapy (cisplatin and 5-fluorouracil). Radiation dose was escalated to the macroscopic tumor only (PTV1) with a concomitant boost strategy. Three dose levels were planned: levels 1 (no PTV1 boost), 2 (45/2.25Gy) and 3 (50/2.5Gy). Patients were treated in cohorts of six to twelve per group using a standard phase I study design. The recommended dose was exceeded if >2 of 6 patients in a cohort experienced dose-limiting toxicity (DLT). RESULTS: 32 patients (median age: 50 years; FIGO stage IB2: 4, IIA: 3, IIB: 21, III-IVA: 4) were enrolled. Median follow-up was 18 months (3-49 months). The most common grade 3/4 toxicity was gastrointestinal (diarrhea). Since three DLTs (grade 3 diarrhea, n=2; grade 3 proctitis, n=1), were observed in 4 patients at level 3, the trial was closed and level 2 was judged as the recommended dose. CONCLUSION: Based on the data from this phase I study, 45Gy/2.25Gy to macroscopic tumor and 40Gy/2Gy to lymphatic drainage may be considered the recommended doses.

Capecitabine based postoperative accelerated chemoradiation of pancreatic carcinoma. A dose-escalation study.

UNLABELLED: The objective of this study was to evaluate the safety of escalating up to 55 Gy within five weeks, the dose of external beam radiotherapy to the previous tumor site concurrently with a fixed daily dose of capecitabine, in patients with resected pancreatic cancer. MATERIAL AND METHODS: Patients with resected pancreatic carcinoma were eligible for this study. Capecitabine was administered at a daily dose of 1600 mg/m (2). Regional lymph nodes received a total radiation dose of 45 Gy with 1.8 Gy per fractions. The starting radiation dose to the tumor bed was 50.0 Gy (2.0 Gy/fraction, 25 fractions). Escalation was achieved up to a total dose of 55.0 Gy by increasing the fraction size by 0.2 Gy (2.2 Gy/fraction), while keeping the duration of radiotherapy to five weeks (25 fractions). A concomitant boost technique was used. Dose limiting toxicity (DLT) was defined as any grade>3 hematologic toxicity, grade>2 liver, renal, neurologic, gastrointestinal, or skin toxicity, by RTOG criteria, or any toxicity producing prolonged (> 10 days) radiotherapy interruption. RESULTS AND DISCUSSION: Twelve patients entered the study (median age: 64 years). In the first cohort (six patients), no patient experienced DLT. Similarly in the second cohort, no DLT occurred. All 12 patients completed the planned regimen of therapy. Nine patients experienced grade 1-2 nausea and/or vomiting. Grade 2 hematological toxicity occurred in four patients. The results of our study indicate that a total radiation dose up to 55.0 Gy/5 weeks can be safely administered to the tumor bed, concurrently with capecitabine (1600 mg/m (2)) in patients with resected pancreatic carcinoma.

Chemoradiation with concomitant boost followed by radical surgery in locally advanced cervical cancer: a dose-escalation study.

OBJECTIVE: Aim of this study is to evaluate the feasibility of an accelerated fractionation radiotherapy by concomitant boost in locally advanced cervical cancer patients, to explore the maximum tolerated dose (MTD) of radiation through a dose-escalation scheme, and to verify if increasing the radiation dose would result in a higher rate of pathologic complete response. METHODS: During the first and the last week of treatment, a combination of cisplatin (20 mg/mq/d, IV, days 1-4) and 5-fluorouracil (1 g/mq/d, continuous venous infusion, days 1-4) was administered. The dose escalation of external radiotherapy was delivered on the primary tumor, using the concomitant boost technique (CB, 90 cGy per fraction), delivering 3 different dose levels: (1) 1 weekly boost for a total dose of 4320 cGy; (2) 2 weekly boosts, total dose 4680 cGy; (3) 3 weekly boosts, total dose of 5040 cGy. RESULTS: Eighteen patients were submitted to a radiochemotherapeutic schedule of 3960 cGy in 22 fractions on pelvic lymph nodal stations. The MTD of radiation was not reached, being the only toxicities registered neutropenia G3 (n = 4), thrombocytopenia G3 (n = 1), stomatitis G3 (n = 1), diarrhea G3 (n = 2) easily managed. Six weeks after the end of radiochemotherapy, 17 patients were submitted to radical surgery, and are therefore evaluable for pathologic response. Among them, 15 complete remissions (88.2%, including 3 microscopical partial response), 1 partial response (5.9%), and 1 progression (5.9%) have been observed. CONCLUSIONS: These results demonstrate, even if in a small study, that this regimen of concurrent chemoradiation followed by radical surgery is well tolerated.

Intraoperative radiation therapy in resected pancreatic carcinoma: long-term analysis.

PURPOSE: The combination of external radiotherapy (RT) plus intraoperative radiotherapy (IORT) in patients with pancreatic cancer is still debated. This study presents long-term results (minimum follow-up, 102 months) for 26 patients undergoing integrated adjuvant RT (external RT+IORT). METHODS AND MATERIALS: From 1990 to 1995, a total of 17 patients with pancreatic cancer underwent IORT (10 Gy) and postoperative external RT (50.4 Gy). Preoperative "flash" RT was included for the last 9 patients. The liver and pancreatic head received 5 Gy (two 2.5-Gy fractions) the day before surgery. In the subsequent period (1996-1998), 9 patients underwent preoperative concomitant chemoradiation (39.6 Gy) with 5-fluorouracil, IORT (10 Gy), and adjuvant chemotherapy. RESULTS: Preoperative chemoradiation was completed in all patients, whereas postoperative therapy was completed in 13 of 17 patients. All 26 patients underwent pancreatectomy (25 R0 and one R1 resections). One patient died of postoperative complications (3.8%) not related to IORT. The 9 patients undergoing concomitant chemoradiation were candidates for adjuvant chemotherapy; however, only 4 of 9 underwent adjuvant chemotherapy. At last follow-up, 4 patients (15.4%) were alive and disease free. Disease recurrence was documented in 20 patients (76.9%). Sixteen patients (61.5%) showed distant metastasis, and 5 patients (19.2%) showed local recurrence. The incidence of local recurrence in R0 patients was 4 of 25 (16.0%). The overall 5-year survival rate was 15.4%. There was significant correlation with overall survival of tumor diameter (p=0.019). CONCLUSIONS: The incidence of local recurrence in this long follow-up series (19.2%) was definitely less than that reported in other studies of adjuvant RT (approximately 50%), suggesting a positive impact on local control of integrated adjuvant RT (IORT+external RT).