Concomitant 5-fluorouracil Research Articles

"Defendit Numerus": A Pooled Analysis of 6145 Locally Advanced Rectal Cancer Treated with Preoperative Chemoradiotherapy.

Objective: The optimal management of rectal cancer remains a subject of ongoing research. This meta-analysis of individual patient data assessed the benefit of chemoradiotherapy (fluorouracil-based) in local advanced rectal cancer: disease-free survival and overall survival. Methods: We pooled the data of 6145 patients from 24 studies of rectal cancer who received neoadjuvant radiotherapy with concomitant fluorouracil or capecitabine and surgery. The PRISMA 2020 abstract checklist was followed. Individual participant survival was reconstructed with an algorithm from published Kaplan-Meier curves. Results: The median OS was not reached; the mean survival time was 135.4 months (127.9-141.5). The median DFS was 176.9 months, and the mean disease-free survival time was 122.6 months (111.7-131.9). Conclusions: We provided a benchmark for future studies on rectal cancer treatment. The present results can be used in decision-making for locally advanced rectal cancer patients.

Long-Term Total Neoadjuvant Therapy Leads to Impressive Response Rates in Rectal Cancer: Results of a German Single-Center Cohort.

Intensified preoperative chemotherapy after (chemo)radiotherapy, (Total Neoadjuvant Therapy-TNT), increases pathological complete response (pCR) rates and local control. In cases of clinically complete response (cCR) and close follow-up, non-operative management (NOM) is feasible. We report early outcomes and toxicities of a long-term TNT regime in a single-center cohort. Fifteen consecutive patients with distal or middle-third locally advanced rectal cancer (UICC stage II-III) were investigated, who received neoadjuvant chemoradiotherapy (total adsorbed dose: 50.4 Gy in 28 fractions and two concomitant courses 5-fluorouracil (250 mg/m2/d)/oxaliplatin (50 mg/m2), followed by consolidating chemotherapy (nine courses of FOLFOX4). NOM was offered if staging revealed cCR 2 months after TNT, with resection performed otherwise. The primary endpoint was complete response (pCR + cCR). Treatment-related side effects were quantified for up two years after TNT. Ten patients achieved cCR, of whom five opted for NOM. Ten patients (five cCR and five non-cCR) underwent surgery, with pCR confirmed in the five patients with cCR. The main toxicities comprised leukocytopenia (13/15), fatigue (12/15) and polyneuropathy (11/15). The most relevant CTC °III + IV events were leukocytopenia (4/15), neutropenia (2/15) and diarrhea (1/15). The long-term TNT regime resulted in promising response rates that are higher than the response rates of short TNT regimes. Overall tolerability and toxicity were comparable with the results of prospective trials.

Quality of Life Analysis of a Phase II Randomized Controlled Trial Comparing 3D-Conformal Radiotherapy (3D-CRT) and Intensity Modulated Radiotherapy (IMRT) in Locally Advanced Rectal Cancer (TRI-LARC)

<h3>Purpose/Objective(s)</h3> The aim of the study was to compare the use of 3D-CRT and IMRT in pre-operative long course chemo-radiotherapy for locally advanced rectal cancer. We herein evaluate the impact of the two treatment modalities on quality of life (QOL), a secondary objective of the study. <h3>Materials/Methods</h3> 94 patients with rectal adenocarcinoma were enrolled in a prospective randomized phase II trial across three institutions between 2014 and 2020. Eligible patients had stage T3-4, N(any) or circumferential resection margin at risk with no evidence of metastatic disease. All patients were prescribed 50.4Gy in 28 fractions with concomitant 5-fluorouracil or capecitabine. Patients were randomly assigned (1:1) to 3D-CRT and IMRT planning techniques. QOL was assessed using the EORTC QLQ C30 and QLQ CR29 questionnaires at baseline, during the final week of radiotherapy and at six and twelve months after radiotherapy. A paired sample t test was used to compare differences in QOL from baseline to each follow-up. One-way between-group analyses of covariance (ANCOVA) were conducted to compare the effect of the trial arms on each QOL score. <h3>Results</h3> At a median follow-up of 14 months, the trial was terminated early due to failure to establish efficacy in the primary outcome, acute gastrointestinal toxicity. The median age was 59 years and 72/94 (77%) were male. 86/94 (91%) patients completed the baseline and at least one other QOL assessments. QOL data at one year was available in 55/94(58%). At baseline, there was no difference in QOL scores between trial arms. Overall, emotional functioning had improved at six months but physical, cognitive, role and social functioning had declined. At six months, there was a significant improvement in constipation, blood and mucous in stool, bloating, urinary frequency, buttock pain and anxiety scores compared to baseline. There was a significant deterioration in dyspnea, fatigue, nausea/vomiting, taste, hair loss, erectile dysfunction, body image and global health scores from baseline to 6-month follow-up. After adjusting for pre-intervention score, the IMRT arm had better physical functioning (p=0.038) and role functioning (p=0.014) during the final week of radiotherapy compared to the 3DCRT arm. The end of radiotherapy embarrassment score, for those without a stoma, was significantly worse in the IMRT arm (p=0.032). There was no other significant difference in QOL scores between the two arms, at either the final week of radiotherapy or at 6 months, after adjustment for pre-intervention scores. The limitations of the study include its early termination, the potential for type 1 error and the possible influence of other factors on QOL data such as chemotherapy and postoperative complications. <h3>Conclusion</h3> There are limited QOL benefits of IMRT compared to 3D-CRT in the neoadjuvant setting for rectal cancer.

Chemoradiotherapy in Muscle-invasive Bladder Cancer: 10-yr Follow-up of the Phase 3 Randomised Controlled BC2001 Trial

BackgroundBC2001, the largest randomised trial of bladder-sparing treatment for muscle-invasive bladder cancer (MIBC), demonstrated improvement in locoregional control by adding fluorouracil and mitomycin C to radiotherapy (James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477–88). There are limited data on long-term recurrence risk. ObjectiveTo determine whether benefit of adding chemotherapy to radiotherapy for MIBC is maintained in the long term. Design, setting, and participantsA phase 3 randomised controlled 2 × 2 factorial trial was conducted. Between 2001 and 2008, 458 patients with T2-T4a N0M0 MIBC were enrolled; 360 were randomised to radiotherapy (178) or chemoradiotherapy (182), and 218 were randomised to standard whole-bladder radiotherapy (108) or reduced high-dose-volume radiotherapy (111). The median follow-up time was 9.9 yr. The trial is registered (ISRCTN68324339). InterventionRadiotherapy: 55 Gy in 20 fractions over 4 wk or 64 Gy in 32 fractions over 6.5 wk; concurrent chemotherapy: 5-fluorouracil and mitomycin C. Outcome measurements and statistical analysisLocoregional control (primary endpoint), invasive locoregional control, toxicity, rate of salvage cystectomy, disease-free survival (DFS), metastasis-free survival (MFS), bladder cancer–specific survival (BCSS), and overall survival. Cox regression was used. The analysis of efficacy outcomes was by intention to treat. Results and limitationsChemoradiotherapy improved locoregional control (hazard ratio [HR] 0.61 [95% confidence interval {CI} 0.43–0.86], p = 0.004) and invasive locoregional control (HR 0.55 [95% CI 0.36–0.84], p = 0.006). This benefit translated, albeit nonsignificantly, for disease-related outcomes: DFS (HR 0.78 [95% CI 0.60–1.02], p = 0.069), MFS (HR 0.78, [95% CI 0.58–1.05], p = 0.089), overall survival (HR = 0.88 [95% CI 0.69–1.13], p = 0.3), and BCSS (HR 0.79 [95% CI 0.59–1.06], p = 0.11). The 5-yr cystectomy rate was 14% (95% CI 9–21%) with chemoradiotherapy versus 22% (95% CI 16–31%) with radiotherapy alone (HR 0.54, [95% CI 0.31–0.95], p = 0.034). No differences were seen between standard and reduced high-dose-volume radiotherapy. ConclusionsLong-term findings confirm the benefit of adding concomitant 5-fluorouracil and mitomycin C to radiotherapy for MIBC. Patient summaryWe looked at long-term outcomes of a phase 3 clinical trial testing radiotherapy with or without chemotherapy for patients with invasive bladder cancer. We concluded that the benefit of adding chemotherapy to radiotherapy was maintained over 10 yr.

Neoadjuvant Chemoradiotherapy for Oral Cavity Cancer: Predictive Factors for Response and Interim Analysis of the Prospective INVERT-Trial.

BackgroundTo study neoadjuvant chemoradiotherapy (nCRT) and potential predictive factors for response in locally advanced oral cavity cancer (LA-OCC).MethodsThe INVERT trial is an ongoing single-center, prospective phase 2, proof-of-principle trial. Operable patients with stage III-IVA squamous cell carcinomas of the oral cavity were eligible and received nCRT consisting of 60 Gy with concomitant cisplatin and 5-fluorouracil. Surgery was scheduled 6-8 weeks after completion of nCRT. Explorative, multiplex immunohistochemistry (IHC) was performed on pretreatment tumor specimen, and diffusion-weighted magnetic resonance imaging (DW-MRI) was conducted prior to, during nCRT (day 15), and before surgery to identify potential predictive biomarkers and imaging features. Primary endpoint was the pathological complete response (pCR) rate.ResultsSeventeen patients with stage IVA OCC were included in this interim analysis. All patients completed nCRT. One patient died from pneumonia 10 weeks after nCRT before surgery. Complete tumor resection (R0) was achieved in 16/17 patients, of whom 7 (41%, 95% CI: 18-67%) showed pCR. According to the Clavien-Dindo classification, grade 3a and 3b complications were found in 4 (25%) and 5 (31%) patients, respectively; grade 4-5 complications did not occur. Increased changes in the apparent diffusion coefficient signal intensities between MRI at day 15 of nCRT and before surgery were associated with better response (p=0.022). Higher abundances of programmed cell death protein 1 (PD1) positive cytotoxic T-cells (p=0.012), PD1+ macrophages (p=0.046), and cancer-associated fibroblasts (CAFs, p=0.036) were associated with incomplete response to nCRT.ConclusionnCRT for LA-OCC followed by radical surgery is feasible and shows high response rates. Larger patient cohorts from randomized trials are needed to further investigate nCRT and predictive biomarkers such as changes in DW-MRI signal intensities, tumor infiltrating immune cells, and CAFs.

Omission of the Pathologic Node-Negative Neck From Postoperative Radiation Therapy for Oral Cavity Cancer

<h3>Purpose/Objective(s)</h3> Elective neck dissection has been shown to confer a survival benefit in the setting of oral cavity squamous cell cancer (OC-SCC). Post-operative radiation therapy (RT) is recommended after primary surgical management of OC-SCC for adverse pathologic features. Current guidelines recommend coverage of the operative bed, including the pathologic node-negative (pN0) neck, which is associated with worse late toxicity and quality of life. The risk of regional failure with omission of the pN0 neck from the RT treatment volume is not well described. <h3>Materials/Methods</h3> Patients (pts) with OC-SCC who underwent primary surgical management and were treated with post-operative RT at a single institution between 2011 and 2019 were retrospectively analyzed. Intensity-modulated RT was used in all cases. Post-operative RT was delivered once daily. Post-operative chemoradiation therapy (CRT) typically consisted of concomitant fluorouracil, hydroxyurea, with or without paclitaxel in a week-on/week-off fashion with either once- or twice-daily RT. The Kaplan-Meier method was used to estimate rates of local failure-free survival (LFFS), omitted neck failure-free survival (ONFFS), distant metastasis-free survival (DMFS), and overall survival. Cox regression analysis was used to examine the relationships between clinicopathologic variables, and ONFFS. <h3>Results</h3> 47 pN0 hemi-necks in 36 pts were omitted from the post-operative RT treatment volume. The median follow-up was 53.5 months. Primary site was oral tongue in the majority (N = 16). Other subsites included floor of mouth (N = 7), alveolus (N = 6), buccal (N = 3), retromolar trigone (N = 1), and palate (N = 1). Median number of lymph nodes removed from the RT-omitted pN0 ipsilateral and contralateral hemi-neck were 24 (IQR: 19-27) and 18.5 (IQR: 9-24), respectively. Perineural invasion was present in 63% and lymphovascular invasion was present in 18%. T-stage was T1 (N = 4), T2 (N = 10), T3 (N = 7), and T4 (N = 15). Overall N-stage (including the pathologic node-positive hemi-neck, if present) was N0 (N = 23), N1 (N = 5), N2a (N = 1), N2b (N = 2), and N3b (N = 5). Median RT dose was 66 Gy (IQR: 60-66). 70% of pts received concurrent CRT. 89% of pts received once-daily RT and 11% received twice-daily RT. Overall, three hemi-necks (6%) in three pts (8%) were found to have omitted neck relapse. Two-year LFFS, ONFFS, DMFS, and OS were 97%, 91%, 94%, and 92%, respectively. Four-year LFFS, ONFFS, DMFS, and OS were 93%, 91%, 91%, and 85%, respectively. On Cox regression, floor of mouth subsite (FOM) (HR 11.1 [C.I.: 1.0-126.2], p=0.05) was associated with an increased risk of ONFFS. <h3>Conclusion</h3> In this largest reported series of OC-SCC pts treated with post-operative RT omitting the pN0 neck, low rates of regional failures occurred overall.

Dosimetric and Clinical Predictors for Acute and Late Gastrointestinal Toxicity Following Chemoradiotherapy of Locally Advanced Anal Cancer

AimsTo analyse dosimetric and clinical predictors for acute and late gastrointestinal toxicity following chemoradiotherapy of anal cancer. Materials and methodsConsecutive patients with locally advanced (T2 ≥4 cm – T4 or N+) anal cancer were selected from an institutional database (n = 114). All received intensity-modulated radiotherapy with concomitant 5-fluorouracil and mitomycin C. Gastrointestinal toxicity was retrospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and bowel cavity, small bowel and large bowel were contoured. Dosimetric and clinical variables were tested for associations with acute grade ≥3 gastrointestinal toxicity and late grade ≥2 gastrointestinal toxicity using the Mann–Whitney test, area under receiver operating characteristic curve (AUC) and logistic regression. ResultsThe median follow-up was 40 months. Acute grade ≥3 gastrointestinal toxicity was seen in 51 (44.7%) of the patients; late grade ≥2 gastrointestinal toxicity was seen in 36 of the patients (39.6% of 91 patients with >1 year recurrence-free follow-up). Bowel cavity V30Gy was the best dosimetric predictor for acute gastrointestinal toxicity (AUC 0.633; P = 0.02). Large bowel V20Gy was the best dosimetric predictor for late gastrointestinal toxicity (AUC 0.698; P = 0.001) but showed no association with acute gastrointestinal toxicity. In multivariate logistic regression, increasing age was significantly associated with acute gastrointestinal toxicity; smoking and large bowel V20Gy were significantly associated with late gastrointestinal toxicity. Patients who experienced acute grade ≥3 gastrointestinal toxicity were not at an increased risk of late grade ≥2 gastrointestinal toxicity (odds ratio 1.3; P = 0.55). ConclusionsFactors of importance for acute and late gastrointestinal toxicity were not the same. Bowel cavity V30Gy is a good metric to use for the prediction of acute gastrointestinal toxicity, but the results of our study indicate that individual large and small bowel loops need to be contoured for better prediction of late gastrointestinal toxicity. The role of the large bowel as an important organ at risk for late gastrointestinal toxicity merits further research.

A novel approach for radiotherapy dose escalation in rectal cancer using online MR-guidance and rectal ultrasound gel filling – Rationale and first in human

IntroductionDose escalated radiotherapy has previously been investigated as a strategy to increase complete response rates in rectal cancer. However large safety margins are required using cone-beam computed tomography guided radiotherapy leading to high doses to organs at risk or insufficient target volume coverage in order to keep dose constraints. We herein present the first clinical application of a new technique for dose escalation in rectal cancer using online magnetic resonance (MR)-guidance and rectal ultrasound gel filling. MethodsA 73-year-old patient with distal cT3a cN0 cM0 rectal cancer was referred for definitive radiochemotherapy with the goal of organ preservation after multidisciplinary discussion. A dose of 45 Gy in 25 fractions with a stereotactic integrated boost to the primary tumor of 50 Gy with concomitant 5-fluorouracil was prescribed. Furthermore, a boost to the primary tumor with 3 Gy per fraction using the adapt-to-shape workflow on a 1.5 T MR-Linac was planned once weekly. For the boost fractions 100 cc of ultrasound gel was applied rectally in order to improve tumor visibility and distancing of uninvolved rectal mucosa. In order to determine the required planning target volume margin diagnostic scans of ten rectal cancer patients conducted with rectal ultrasound gel filling were studied. ResultsBased on the ten diagnostic scans an average isotropic margin of 4 mm was found to be sufficient to cover 95% of the target volume during an online adaptive workflow. Three boost fractions were applied, mean treatment duration was 22:34 min. Treatment was well tolerated by the patient with no more than PRO-CTCAE grade I° toxicity of any kind. The rectal ultrasound gel filling resulted in superior visibility of the tumor and reduced the dose to the involved mucosa especially in the high dose range compared with a boost plan calculated without any filling. A considerable tumor shrinkage was observed during treatment from 17.43 cc at baseline to 4 cc in week four. ConclusionThis novel method appears to be a simple but effective strategy for dose escalated radiotherapy in rectal cancer. Based on the encouraging observation, a prospective trial is currently under preparation.

Sarcopenia and dosimetric parameters in relation to treatment-related leukopenia and survival in anal cancer

BackgroundTreatment-related white blood cell (WBC) toxicity has been associated with an inferior prognosis in different malignancies, including anal cancer. The aim of the present study was to investigate predictors of WBC grade ≥ 3 (G3+) toxicity during chemoradiotherapy (CRT) of anal cancer.MethodsConsecutive patients with locally advanced (T2 ≥ 4 cm—T4 or N+) anal cancer scheduled for two cycles of concomitant 5-fluorouracil and mitomycin C chemotherapy were selected from an institutional database (n = 106). All received intensity modulated radiotherapy (IMRT; mean dose primary tumor 59.5 Gy; mean dose elective lymph nodes 45.1 Gy). Clinical data were extracted from medical records. The highest-grade WBC toxicity was recorded according to CTCAE version 5.0. Pelvic bone marrow (PBM) was retrospectively contoured and dose-volume histograms were generated. The planning CT was used to measure sarcopenia. Dosimetric, anthropometric, and clinical variables were tested for associations with WBC G3+ toxicity using the Mann–Whitney test and logistic regression. Cox proportional hazard regression was used to assess predictors for overall survival (OS) and anal cancer specific survival (ACSS).ResultsWBC G3+ was seen in 50.9% of the patients, and 38.7% were sarcopenic. None of the dosimetric parameters showed an association with WBC G3+ toxicity. The most significant predictor of WBC G3+ toxicity was sarcopenia (adjusted OR 4.0; P = 0.002). Sarcopenia was also associated with an inferior OS (adjusted HR 3.9; P = 0.01), but not ACSS (P = 0.07). Sensitivity analysis did not suggest that the inferior prognosis for sarcopenic patients was a consequence of reduced doses of chemotherapy or a prolonged radiation treatment time. Patients who experienced WBC G3+ toxicity had an inferior OS and ACSS, even after adjustment for sarcopenia.ConclusionsSarcopenia was associated with increased risks of both WBC G3+ toxicity and death following CRT for locally advanced anal cancer. In this study, radiation dose to PBM was not associated with WBC G3+ toxicity. However, PBM was not used as an organ at risk for radiotherapy planning purposes and doses to PBM were high, which may have obscured any dose–response relationships.

Patient-reported Quality of Life Outcomes in Patients Treated for Muscle-invasive Bladder Cancer with Radiotherapy ± Chemotherapy in the BC2001 Phase III Randomised Controlled Trial

BackgroundBC2001, the largest randomised trial of bladder-sparing treatment for muscle-invasive bladder cancer, demonstrated improvement of local control and bladder cancer–specific survival from the addition of concomitant 5-fluorouracil and mitomycin C to radiotherapy. ObjectiveTo determine the impact of treatment on the health-related quality of life (HRQoL) of BC2001 participants. Design, setting, and participants458 UK patients with T2-T4a N0 M0 transitional cell carcinoma of the bladder. InterventionPatients were randomised to the chemotherapy comparison (radiotherapy, 178, or chemoradiotherapy, 182); and/or to the radiotherapy comparison (standard, 108, or reduced high-dose volume radiotherapy, 111). Outcome measurements and statistical analysisPatients completed Functional Assessment of Cancer Therapy—Bladder (FACT-BL) questionnaires at baseline, end of treatment (EoT), and 6, 12, 24, 36, 48, and 60 months after radiotherapy. The primary endpoint was change from baseline in the bladder cancer subscale (BLCS) at 12 months. Results and limitationsData were available for 331 (92%) and 204 (93%) participants at baseline and for 192 (54%) and 114 (52%) at 12 months for the chemotherapy and radiotherapy comparisons, respectively. HRQoL declined at EoT (BLCS –5.06 [99% confidence interval: –6.12 to –4.00, p< 0.001]; overall FACT-B TOTAL score –8.22 [–10.76 to –5.68, p< 0.01]), recovering to baseline at 6 months and remaining similar to baseline subsequently. There was no significant difference between randomised groups at any time point. ConclusionsImmediately following (chemo)radiotherapy, a significant proportion of patients report declines in HRQoL, which improve to baseline after 6 months. Two-thirds of patients report stable or improved HRQoL on long-term follow-up. There is no evidence of impairment in HRQoL resulting from the addition of chemotherapy. Patient summaryQuality of life of bladder cancer patients treated with radiotherapy±chemotherapy deteriorates during treatment, but improves to at least pretreatment levels within 6 months. Addition of chemotherapy to radiotherapy does not affect patient-reported quality of life.

Randomized controlled trial of 8 weeks' vs 12 weeks' interval between neoadjuvant chemoradiotherapy and surgery for locally advanced rectal cancer.

The aim was to compare the pathological complete response (pCR) rate at 8 compared to 12weeks' interval between completion of neoadjuvant chemoradiotherapy (CRT) and surgery in patients with locally advanced rectal cancer. This was a randomized trial which included a total of 330 patients from two institutions. Patients with locally advanced (T3-4N0M0, TxN+M0) rectal cancer were randomized into 8- and 12-week interval groups. All the patients received long-course CRT (45Gy in 1.8Gy fractions and concomitant oral capecitabine or 5-fluorouracil infusion). Surgery was performed at either 8 or 12weeks after CRT. The primary end-point was pCR. Secondary end-points were sphincter preservation, postoperative morbidity and mortality. Two-hundred and fifty-two patients (n=125 in the 8-week group, n=127 in the 12-week group) were included. Demographic and clinical characteristics were similar between groups. The overall pCR rate was 17.9% (n=45): 12% (n=15) in the 8-week group and 23.6% (n=30) in the 12-week group (P=0.021). Sphincter-preserving surgery was performed in 107 (85.6%) patients which was significantly higher than the 94 (74%) patients in the 12-week group (P=0.016). Postoperative mortality was seen in three (1.2%) patients overall and was not different between groups (1.6% in 8weeks vs 0.8% in 12weeks, P=0.494). Groups were similar in anastomotic leak (10.8% in 8weeks vs 4.5% in 12weeks, P=0.088) and morbidity (30.4% in 8weeks and 20.1% in 12weeks, P=0.083). Extending the interval between CRT and surgery from 8 to 12weeks resulted in a 2-fold increase in pCR rate without any difference in mortality and morbidity.

Role of Adjuvant Chemoradiotherapy for Duodenal Cancer: An Updated Analysis of Long-Term Follow-Up from Single Institution.

There are only limited data on the failure patterns after surgical resection for duodenal cancer, and the role of adjuvant chemoradiotherapy (CRT) also remains controversial. In this study, the treatment outcomes of surgery alone were compared to those of surgery plus adjuvant CRT for duodenal cancer. Between January 1991 and February 2013, a total of 47 patients with duodenal cancer had pancreaticoduodenectomy, and their age ranged from 31 to 80 (median 62). Twenty-five patients (53%) underwent surgery alone, while 22 (47%) underwent surgery plus adjuvant CRT. Postoperative radiotherapy with concomitant 5-fluorouracil was given to tumor bed and regional lymph nodes up to 40-55.4Gy. Median duration of follow-up was 31months (range 6-286) for all patients and 90months (range 14-286) for survivors. CRT (+) group included more patients with advanced nodal stage and overall stage group (p = 0.003 and 0.002, respectively). The 5-year overall survival rates were not different between CRT (-) and CRT (+) groups (50.1 vs. 46.7%, p = 0.794). CRT (+) group achieved a superior 5-year loco-regional relapse-free survival rate compared with CRT (-) group, but the difference did not reach a statistical significance (80.1 vs. 68.4%, p = 0.267). On multivariate analysis, however, the addition of CRT was the only favorable prognosticator predicting loco-regional relapse-free survival (p = 0.046). Two patients experienced grade 3 neutropenia during CRT. Adjuvant CRT after pancreaticoduodenectomy was correlated with an improved loco-regional control in duodenal cancer. Considering the high loco-regional recurrence in surgery alone group, CRT may be considered as adjuvant treatment.

Neoadjuvant hyperfractionated accelerated radiotherapy plus concomitant 5-fluorouracil infusion in locally advanced rectal cancer: A phase II study.

AIMTo evaluate the efficacy and tolerability of neoadjuvant hyperfractionated accelerated radiotherapy (HART) and concurrent chemotherapy in patients with locally advanced infraperitoneal rectal cancer.METHODSA total of 30 patients with histopathologically confirmed T2-3/N0+ infraperitoneal adenocarcinoma of rectum cancer patients received preoperative 42 Gy/1.5 Gy/18 days/bid radiotherapy and continuous infusion of 5-fluorouracil (325 mg/m2). All patients were operated 4-8 wk after neoadjuvant concomitant therapy.RESULTSIn the early phase of treatment, 6 patients had grade III-IV gastrointestinal toxicity, 2 patients had grade III-IV hematologic toxicity, and 1 patient had grade V toxicity due to postoperative sepsis during chemotherapy. Only 1 patient had radiotherapy-related late side effects, i.e., grade IV tenesmus. Complete pathological response was achieved in 6 patients (21%), while near-complete pathological response was obtained in 9 (31%). After a median follow-up period of 60 mo, the local tumor control rate was 96.6%. In 13 patients, distant metastasis occurred. Disease-free survival rates at 2 and 5 years were 63.3% and 53%, and corresponding overall survival rates were 70% and 53.1%, respectively.CONCLUSIONAlthough it has excellent local control and complete pathological response rates, neoadjuvant HART concurrent chemotherapy appears to not be a feasible treatment regimen in locally advanced rectal cancer, having high perioperative complication and intolerable side effects. Effects of reduced 5-fluorouracil dose or omission of chemotherapy with the aim of reducing toxicity may be examined in further studies.

Intensified Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer in Elderly Patients: Toxicity, Disease Control, and Survival Outcomes

IntroductionWe report the treatment compliance, toxicity rates, and long-term clinical outcomes of elderly patients who received intensified neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). Patients and MethodsWe identified a retrospective cohort of patients aged ≥ 70 years with LARC who received intensified neoadjuvant CRT, followed by surgery and adjuvant chemotherapy, from 2007 to 2014. Intensified neoadjuvant CRT consisted of radiotherapy (total dose, 50.4/54 Gy) with concomitant oxaliplatin (50 mg/m2/wk) and 5-fluorouracil (200 mg/m2 in 5 daily continuous infusion). ResultsA total of 26 patients were included. All patients completed the programmed CRT. Severe acute toxicity was recorded in 19.2% of cases. Conservative surgery was performed in 16 patients, and a pathologic complete response was achieved in 19.2%. Overall, 26.9% of the patients died. The 5-year overall survival and disease-free survival rates were 70.6% and 65.5%, respectively. ConclusionsIntensified neoadjuvant CRT is an efficacious and safe treatment option for LARC in elderly patients.

Image-guided IMRT with simultaneous integrated boost as per RTOG 0529 for the treatment of anal cancer.

To report on clinical outcomes of simultaneous integrated boost intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy as per Radiation Therapy Oncology Group (RTOG) 0529 protocol in anal cancer patients. Clinical stage T1-T4 N0-N3 anal cancer patients were submitted to concomitant chemoradiation. Patients with cT2N0 disease were prescribed 50.4Gy/28 fractions to the gross tumor planning target volume (PTV) and 42Gy/28 fractions to the elective nodal PTV. Patients staged as cT3-T4/N0-N3 were given 54Gy/30 fractions to the macroscopic anal PTV, while clinical nodes were prescribed 50.4Gy/30 fractions if<3cm or 54Gy/30 fractions if≥3cm; elective nodal PTV was prescribed 45Gy/30 fractions. Two cycles of concomitant 5-fluorouracil and mitomycin C were planned for all patients. Oncological outcomes, acute and late toxicity profiles and pattern of failure were reported. The 3-year colostomy-free survival rate was 64% (95% CI 0.52-0.75). The 3-year local control, disease-free and overall survival rates were 69% (95% CI 0.57-0.79), 71% (95% CI 0.59-0.80) and 79% (95% CI 0.66-0.87), respectively. The cumulative incidence of colostomies was 15.1% (95% CI 8.15-23.88) at 24 months. The cumulative incidence of cancer-specific deaths was 16.4% (95% CI 8.60-26.47) at 36 months. Major acute toxicity consisted of hematological (G3-G4: 26%) and cutaneous (G3-G4: 16%) events. Only one case of≥G3 late toxicity was documented. Simultaneous integrated boost IMRT and concurrent chemotherapy as per RTOG 0529 protocol seems to be safe and feasible with consistent oncological outcomes and a mild acute and late toxicity profile in anal cancer patients.

Pre- and post-surgery treatments in rectal cancer: a long-term single-centre experience.

Our study evaluated long-term survival outcomes in rectal cancer patients treated with preoperative radiotherapy, and the impact on survival of concomitant and postoperative adjuvant chemotherapy (ctx), among other prognostic factors. The study included 196 patients [median age: 58 years (range: 20-86 years); 63.0% men] with locally advanced rectal carcinoma and, in some cases, resectable liver metastasis. Rates of distant metastasis and local recurrence and of 5-year distant metastasis-free survival (dmfs) and overall survival (os) were determined. The 5-year os rate was 57.0%, with a median duration of 81.5 months (95% confidence interval: 73.7 months to 89.4 months), and the 5-year dmfs rate was 54.1%, with a median duration of 68.4 months (95% confidence interval: 40.4 months to 96.4 months). Prognostic factors for higher os and dmfs rates were downstaging (p = 0.013 and p = 0.005 respectively), radiotherapy dose (50 Gy vs. 56 Gy or 45-46 Gy, both p = 0.002), and concomitant ctx use (p = 0.004 and p = 0.001) and type (5-fluorouracil-leucovorin-folinic acid vs. tegafur-folinic acid, p = 0.034 and p = 0.043). Adjuvant ctx after neoadjuvant long-term concomitant chemoradiotherapy (ccrt) and surgery was associated with better 5-year os rates for postoperative T0-T3 disease (p = 0.003) and disease at all lymph node stages (p = 0.001). Our findings revealed a favourable survival outcome with long-term fractionated irradiation and concomitant 5-fluorouracil-based ctx, achieving 5-year os and dmfs rates of 57.0% and 54.1% respectively. Preoperative administration of radiotherapy (50 Gy) and postoperative adjuvant ctx were associated with a significant survival benefit. Radiation doses above 50 Gy and the interval between ccrt and surgery had no significant effect on survival.

The Prognostic Value of Tyrosine Kinase SRC Expression in Locally Advanced Rectal Cancer.

The cellular sarcoma gene (SRC) is a proto-oncogene encoding for a tyrosine kinase. SRC expression was determined in locally advanced rectal adenocarcinoma tissue from pretreatment biopsies and resection specimens. The expression level was correlated with clinicopathological parameters to evaluate the predictive and prognostic capacity.For this monocentric analysis 186 patients with locally advanced rectal cancer (median: 63.7 years; 130 men (69.9%), 56 women (30.1%)) were included. Patients with a carcinoma of the upper third of the rectum were treated with primary tumor resection (n=27; 14.5%). All other patients received a preoperative chemoradiotherapy (CRT) with 50.4 Gy and concomitant 5-fluorouracil (5-FU) or 5-FU+oxaliplatin followed by postoperative chemotherapy with 5-FU or 5-FU+oxaliplatin. SRC expression was determined with immunohistochemical staining from pretreatment biopsies (n=152) and residual tumor tissue from the resection specimens (n=163). The results were correlated with clinicopathological parameters and long-term follow-up.The expression of SRC was determined in pretherapeutic biopsies (mean H-Score: 229) and resection specimens (mean H-Score: 254). High SRC expression in pretherapeutic tumor samples significantly correlated with a negative postoperative nodal status (p=0.005). Furthermore an increased protein expression in residual tumor tissue was associated with fewer distant metastases (p=0.04). The overexpression of SRC in pretreatment tumor biopsies showed also a trend for a longer cancer-specific survival (CSS; p=0.05) and fewer local relapses (p=0.06) during long-term follow-up.High SRC expression in rectal cancer seems to be associated with a better long-term outcome. This finding could help in the future to stratify patients for a recurrence risk adapted postoperative treatment.

Disease Control, Survival, and Toxicity Outcome After Intensified Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: A Single-Institution Experience

PurposeTo report the long-term follow-up data and determine the toxicity rate concerning patients with locally advanced rectal cancer (LARC) treated with an intensified neoadjuvant treatment regimen. Patients and MethodsPatients with histologically proven stage II to III adenocarcinoma of the rectum were included and treated with a trimodal approach. Intensified neoadjuvant treatment (chemoradiotherapy [CRT]) consisted of radiotherapy (total dose 50.4/54 Gy) and concomitant oxaliplatin (50 mg/m2/week) and 5-fluorouracil (200 mg/m2/5 daily continuous infusion). Surgery was planned 7 to 9 weeks after the end of CRT. Adjuvant chemotherapy was recommended in those patients with lymph node metastasis at diagnosis. ResultsOne hundred patients (median age, 64 years) were eligible. Overall, the 5-year overall survival and disease-free survival (DFS) were 76.4% and 74.5%, respectively. CRT was well tolerated, with only 17% grade 3/4 acute toxicity. Twenty-four patients (24%) had a pathologic complete response (pCR), and only 1 patient had perioperative metastasis. The 5-year DFS were 95.7% and 66.7% for pCR and no-pCR tumor histology, respectively (P = .0275). ConclusionAlthough oxaliplatin is not considered to be a standard treatment, the high 5-year rate of overall survival and DFS, the low severe toxicity rates, and the effective benefit on pCR and perioperative metastasis support an intensified treatment regimen for LARC.

708P - Resection Rate with Folfirinox-Based Neoadjuvant Therapy in Locally Advanced/Borderline Resectable Pancreatic Cancer: a Pooled Analysis of Published Data

ABSTRACT Aim: Borderline resectable or unresectable pancreatic cancer (PC) could potentially be converted to surgery after neoadjuvant chemotherapy with or without radiotherapy (RT). We have systematically reviewed the published literature with 5-fluorouracil + leucovorin + irinotecan + oxaliplatin (FOLFIRINOX)-based neoadjuvant chemotherapy in unresectable or borderline resectable PC. Methods: Studies were identified using searches of PubMed, EMBASE, SCOPUS, Web of Science and Cochrane Central Register of Controlled Trials. Primary outcome measures were rate of resection and rate of radical (R0) resection. Pooled proportions and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies. Results: 13 papers were included (n = 2 phase 2 trials, and n = 11 retrospective series) for a total of 253 patients analyzed. Borderline resectable and unresectable PC ranged from 17% to 100% and from 52% to 100% of cases, respectively. Chemoradiotherapy (CTRT) following FOLFIRINOX was integrated into treatment strategy in 15-100% of these patients, mainly with concomitant gemcitabine, capecitabine or 5-fluorouracil. Overall resection rate was 43% (95% CI 32.8%–53.3%) and R0 resection rate (in 9 trials with available data) was 39.4% (95% CI 32.4%–46.9%). Rate of R0/resected patients was 86.1% (95% CI 78.2%–91.5%). Compared with 2 meta-analyses of published studies that did not consider FOLFOXIRI regimens (Gillen et al., PLOS 2010; Assifi et al., Surgery 2011) the rate of R0 resection among initially not resectable PC patients seems increased (from 26.2% and 19.6%, respectively, to 39.4%). Among borderline resectable PCs rate of R0 resection was 63.5% (95%CI 49-76%); in unresectable PCs it was 22.5% (95% CI 13.3-35.4%). Only seven articles contain information about overall RR. The pooled RR was 35.4% (95%CI 27.7-43.9%). Conclusions: FOLFOXIRI plus or minus CTRT is associated with an interesting rate of resection and R0 resection in borderline resectable or unresectable PC. Compared with historical data published in the Gillen metanalysis the rate of R0 resection seems increased by 50%. Disclosure: All authors have declared no conflicts of interest.

Cetuximab and platinum-based chemoradio- or chemotherapy of patients with epidermal growth factor receptor expressing adenoid cystic carcinoma: a phase II trial

Background:Epidermal growth factor receptor (EGFR) is highly expressed in adenoid cystic carcinoma (ACC). The efficacy and toxicity of cetuximab with concomitant platinum-based chemoradio- or chemotherapy in patients with locally advanced or metastatic ACC, respectively, was evaluated.Methods:Eligible patients (9 with locally advanced tumour and 12 with metastases) had positive tumour EGFR expression. The cetuximab loading dose (400 mg m−2) was followed by 250 mg m−2 per week. Locally advanced tumours were irradiated (mean dose 65 Gy) and treated with concomitant cisplatin (75 mg m−2, intravenously). Patients with metastases received concomitant cisplatin and 5-fluorouracil (4 × 1000 mg m−2).Results:For patients with locally advanced disease (median follow-up: 52 months), the median progression-free survival (PFS) was 64 months and the 2-year overall survival (OS) rate was 100%. For patients with metastases (median follow-up: 72 months), the median PFS and OS were 13 and 24 months, respectively. In both groups the objective response rate was >40%. Skin rash, in-field dermatitis, mucositis and vomiting were the most frequent grade 3/4 adverse events.Conclusion:In this single-arm study, the efficacy of cetuximab plus chemoradio- or chemotherapy appeared favourable as compared with historical controls. All side effects were manageable and did not hamper the treatment.