Concurrent 5-fluorouracil Research Articles

A population-based analysis of the impact of 1 vs. 2 doses of mitomycin on patterns of failure of anal cancer patients treated with concurrent chemoradiotherapy

PurposeWe report the impact of 1 vs. 2 doses of mitomycin-C (MMC) based chemoradiation (CRT) on patterns of treatment failure and long-term patient outcomes in anal squamous cell carcinoma (ASCC) and the predictors for locoregional failure (LRF) and distant metastasis (DM). MethodsIn this population-based study, we identified all patients with anal cancer in our province treated radically with radiation and concurrent 5-Fluorouracil (5FU) and 1 vs. 2 doses of MMC between the years 2000-2019. The primary outcomes analyzed were locoregional recurrence (LRR), disease free survival (DFS), ASCC cancer-specific survival (ASCC-CSS) and overall survival (OS). Results451 patients were identified. 272 (60%) patients received 1 cycle of MMC (MMC1) and 179 (40%) received 2 cycles (MMC2) as part of the CRT regimen. The median follow-up was 57 (36-252) and 97 (38-239) months for MMC1 and MMC2, respectively. Cox Regression analysis showed stage IIIb and IIIc were associated with worse locoregional recurrence free survival (RFS) (HR=2.851, p=<0.001) and distant RFS (HR=3.391, p=<0.001). Similarly, stage IIIb and IIIc patients had poorer DFS (HR 3.439, p=<0.001), ASCC-SS (HR 3.729, p=<0.001) and OS (2.230, p=<0.001). The use of MMC2 showed a positive impact on improved ASCC-SS (HR 0.569, p=0.029) and distant RFS (HR 0.555, p=0.040) in patients with stage IIIb and IIIc. ConclusionsOur analysis showed that 1 vs. 2 cycles of MMC along with 5FU and radiation is associated with comparable treatment outcomes in general. However, in patients with stage IIIb and IIIc cancer, 2 doses of MMC were associated with improved ASCC-SS and distant DFS.

Patterns of Locoregional Pancreatic Cancer Recurrence after Total Neoadjuvant Therapy and Implications on Optimal Neoadjuvant Radiation Treatment Volumes

Neoadjuvant treatment for patients with localized pancreatic adenocarcinoma (PDAC) has improved survival duration. As survival increases, local disease control becomes even more important. We sought to understand the patterns of locoregional recurrence following total neoadjuvant therapy (TNT) and determine the impact of treatment volumes on recurrence. Patients with PDAC managed with neoadjuvant chemotherapy and chemoradiation (TNT) followed by surgery who developed an isolated locoregional or simultaneously locoregional and distant recurrence were identified. Locoregional recurrences were individually contoured utilizing commercially available software. When available, original neoadjuvant dose distributions were registered to the scans on which the locoregional recurrences were contoured. Recurrences where then classified as in-field (> 95% of prescription dose), marginal (50-95% of prescription dose), or out of field (< 50% of prescription dose). Target volumes were created using four commonly utilized PDAC contouring guidelines to characterize the relationship of the local recurrence to the RT dose distribution. Of 474 patients treated with TNT and surgery, 80 (17%) patients developed a locoregional recurrence with or without distant recurrence, visible on diagnostic imaging. Of the 80 patients, 56 (70%) had tumors in the pancreatic head; 46 (57.5%) were borderline resectable, 23 (28.8%) locally advanced, and 11 (13.6%) resectable. The most common initial neoadjuvant therapies were FOLFIRINOX (57.5%) and gemcitabine/nab-paclitaxel (18.8%). Chemoradiation included concurrent gemcitabine (47.5%) or 5-fluorouracil (26.3%). RT dose distributions were available for 38 patients; 22 (57.9%) had in-field failures, 9 (23.7%) marginal failures, and 7 (18.4%) out of field failures. Each published contouring atlas covered a relatively low percentage of recurrences, which are summarized in Table 1. Regions at particularly high likelihood of recurrence that were under covered on existing atlases included: aortic-diaphragmic junction, retro-pancreatic duodenal nodal basin, and the region to the right of the superior mesenteric artery (SMA). We present the largest series (to our knowledge) of mapped locoregional recurrences for patients being treated with TNT in PDAC. These recurrences differ substantially from established atlases and highlight anatomical regions of highest priority for RT coverage. A novel visual contouring volume highlighting these regions will be presented which will strive to advance the use of RT in the TNT setting.

“Moderately Hypofractionated” Radiotherapy with a Simultaneously Integrated Boost for Synchronous Treatment of Prostate and Anorectal Cancer

Data suggest safety and efficacy of 1.8-2.0 Gy per day radiotherapy (RT) with sequential boost regimens for patients with synchronous prostate and anorectal cancers. Emergence of 25-28 fraction (fx) prostate cancer RT regimens has enabled simultaneously integrated boost techniques to treat the prostate and anorectum (HypoRT), but limited reports exist to support the safety or efficacy of this approach. We aimed to assess oncologic outcomes and patient-reported outcomes (PRO)- and physician-reported adverse effects (AEs) of HypoRT for patients with synchronous prostate and anorectal cancers. This was a retrospective cohort study of patients synchronously diagnosed with prostate and rectal cancer or anal canal squamous cell carcinoma (ASCC) treated with a HypoRT technique and concurrent chemotherapy between 2014-2022. Outcomes included prostate cancer biochemical recurrence (BCR), anorectal cancer recurrence, progression-free (PFS) and overall survival (OS). Acute and late gastrointestinal (GI) and genitourinary (GU) AEs and PRO were prospectively collected using common terminology criteria for AEs (CTCAE) and PRO-CTCAE. Twelve patients were included. Patients had ECOG 0-1; median age was 71 years (51-82). Rectal cancer (n = 11) characteristics included T3 (91%), N1-2 (73%), M0 (73%); 3 had M1a disease suitable for curative-intent treatment. One patient had T2N1M0 ASCC. Prostate cancer risk groups included low (9%), intermediate (45%), and high/very high risk (46%). HypoRT included 45-50 and 67.5 Gy in 25 fx (33%), 46.8-52 and 70.2 Gy in 26 fx (17%), and 44.8-56 and 70 Gy in 28 fx (50%), to the pelvis-anorectum and prostate. Patients with rectal cancer received concurrent capecitabine. Nine (82%) patients with rectal cancer had surgical resection; 1 was R1. The patient with ASCC received concurrent 5-fluorouracil and mitomycin C. Six patients (50%) received androgen suppression. All patients completed treatment successfully but 1 patient with rectal cancer did require hospitalization with treatment break due to GI AEs. Median follow was 60 months (13-103). Oncologic outcomes and AEs are in the table. No patient experienced prostate cancer BCR or ASCC progression. Four of 11 patients with rectal cancer progressed including 3 distant metastases, each amongst initial M1a patients, and 1 local-regrowth in a patient managed non-operatively. HypoRT can effectively be utilized for patients with synchronous prostate and anorectal cancer. Physician assessed AEs compared favorably with prior data, however, further work is needed to understand differences in physician and patient experience. HypoRT may serve as another suitable option in the management of this complex clinical scenario.

A retrospective analysis of concurrent chemoradiation for squamous cell carcinoma of the anus in Johannesburg

Background: Anal cancer is a major cause of mortality and morbidity in low- and middle-income countries (LMICs).Aim: A retrospective analysis to understand presentation and outcomes of patients with anal cancer, who were treated with a curative intent.Setting: A radiation oncology unit in quaternary level hospital in South Africa.Methods: Medical records of patients with invasive squamous cell carcinoma (SCC) of the anal canal who were treated between 2014 and 2019 were reviewed with follow-up until June 2021. The 2D-radiotherapy planning and delivery techniques were used to a dose of 50 Gy, with a boost dose of 6 Gy – 10 Gy for patients with residual disease and concurrent chemotherapy.Results: Eighty-four patients were included in the analysis. Median age was 45 years (range: 25–73 years), 75% were female patients, 80% of the cohort was human immunodeficiency virus (HIV)-positive, and 17% with a CD4 count below 200 cells/mm3. Eighty-seven percent had locally advanced stage three disease. Concurrent 5-fluorouracil (5-FU) and mitomycin C-based chemotherapy was given in four patients, while 50% had 5-FU plus cisplatin and 16% had radiotherapy alone. Complete clinical response was observed in 54 out of 66 evaluable patients (81.8%) at 6 months post-chemoradiation. Overall survival at 2 years could not be determined because of a significant loss to follow-up rate.Conclusion: A high HIV-postive rate and an advanced disease stage were observed among cohorts with anal canal SCC treated with a definitive curative intent. Tumour response rates at 6 months were favourable although the 2-year overall survival could not be established.Contribution: This study contributes to the growing body of research on anal cancer outcomes in LMICs.

Evaluation of dosimetric predictors of toxicity after IMRT with concurrent chemotherapy for anal cancer

BackgroundThis study investigates the impact of dosimetric parameters on acute and late toxicity for patients with anal squamous cell carcinoma (SCC) treated with image-guided intensity modulated radiation therapy (IG-IMRT) and concurrent chemotherapy. Materials and MethodsPatients were enrolled in an observational cohort study between 2008 and 2013 (median follow-up 3.4 years). They were treated with standardized target and organ-at-risk (OAR) contouring, planning, and IG-IMRT. Radiotherapy dose, based on clinicopathologic features, ranged from 45 Gy to 63 Gy to gross targets and 27 Gy to 36 Gy to elective targets. Chemotherapy was concurrent 5-fluorouracil and mitomycin C (weeks 1&5). Toxicity was prospectively graded using NCI CTCAE v.3 and RTOG scales. Logistic regression was used to assess the association between dose/volume parameters (e.g small bowel V5) and corresponding grade 2 + and 3+ (G2+/3 + ) toxicities (e.g. diarrhea). ResultsIn total, 87 and 79 patients were included in the acute and late toxicity analyses, respectively. The most common acute G2 + toxicities were skin (dermatitis in 87 % [inguino-genital skin], 91 % [perianal skin]) and hematologic in 58 %. G2 + late anal toxicity (sphincter dysfunction), gastrointestinal toxicity, and skin toxicity were respectively experienced by 49 %, 38 %, and 44 % of patients. Statistically significant associations were observed between: G2 + acute diarrhea and small bowel V35; G2 + acute genitourinary toxicity and bladder D0.5cc; G2 + inguino-genital skin toxicity and anterior skin V35; G2 + perianal skin toxicity and posterior skin V15; G2 + anemia and lower pelvis bone V45. D0.5 cc was significantly predictive of late toxicity (G2 + anal dysfunction, intestinal toxicity, and inguino-genital/perianal dermatitis). Maximum skin toxicity grade was significantly correlated with the requirement for a treatment break. ConclusionStatistically significant dose-volume parameters were identified and may be used to offer individualized risk prediction and to inform treatment planning. Additional validation of the results is required.

Acute Gastrointestinal Toxicity Results from a Multi-Institution, Phase 2, Randomized Controlled Trial Comparing 3D-Conformal Radiotherapy (3DCRT) Versus Intensity Modulated Radiotherapy (IMRT) for Locally-Advanced Rectal Cancer (TRI-LARC).

<h3>Purpose/Objective(s)</h3> The primary aim of this trial was to compare the incidence of grade 2 or above acute gastrointestinal (GI) toxicity for patients undergoing 3DCRT versus IMRT in the preoperative setting for locally-advanced rectal cancer. Secondary objectives included quality of life and other acute and late toxicity. <h3>Materials/Methods</h3> The trial was designed to have 80% power to detect a difference between a hypothesized 37% acute toxicity rate in the 3DCRT arm (Bosset et al, 2006) and 20% in the IMRT arm, with a sample size of 120 per arm, and a 0.05 two-sided level of significance. Eligible participants were adults aged 18 or over scheduled to receive pre-operative pelvic chemo-radiotherapy for histologically-confirmed rectal adenocarcinoma. Exclusion criteria included prior pelvic radiotherapy, inflammatory bowel disease, hip replacements, and previous bowel surgery. Prescription dose was 50.4 Gray in 28 fractions over 5.5 weeks with concurrent 5-fluorouracil or capecitabine chemotherapy. Participants were centrally randomized 1:1 to receive 3DCRT or IMRT. Each individual radiotherapy volume and plan was reviewed centrally to ensure compliance with the trial's RTQA specifications. Toxicity was graded and reported according to CTCAE version 4.0 (National Institutes of Health National Cancer Institute). Acute toxicity was assessed weekly during radiotherapy, and at 2- and 4-weeks post-treatment. <h3>Results</h3> 94 patients were enrolled. 77% were male and median age was 59.4. Two participants from the 3DCRT arm did not complete radiotherapy as planned and were excluded from analysis. 25 (56%) of participants from the 3dCRT arm and 23 (49%) from the IMRT arm experienced acute grade 2 or above GI toxicity (p=.670). Rates for grade 3 GI toxicity were 8 (18%) and 5 (11%) for 3dCRT and IMRT, respectively (p=.494). Grade 3 GI events included diarrhea (n=11), nausea (n=2), intestinal obstruction (n=1), oral mucositis (n=1), and rectal pain (n=1). The study closed early due to absence of evidence of a difference between arms at the interim analysis. <h3>Conclusion</h3> No significant difference in rates of acute GI toxicity with IMRT versus 3DCRT for locally advanced rectal cancer was seen. Although IMRT can reduce dose to organs at risk, it appears to be similarly safe in terms of acute GI toxicity to deliver this treatment with 3DCRT.

Outcomes Associated with Total Neoadjuvant Therapy (TNT) with Non-Operative Intent for Rectal Adenocarcinoma

<h3>Purpose/Objective(s)</h3> To evaluate surgery- and permanent ostomy-free survival in patients treated with total neoadjuvant therapy (TNT) with intent for non-operative management of rectal adenocarcinoma. <h3>Materials/Methods</h3> A retrospective review was conducted of patients treated with TNT for stage II-IV rectal adenocarcinoma (n=45) at our institution between 2013-2021. All patients received radiation with concurrent capecitabine or 5-fluorouracil and additional chemotherapy, either prior to or following chemoradiation (CRT), with intent for non-operative management. Clinical complete response rates were determined based on post-treatment MRI or endoscopy. Kaplan-Meier method was utilized to estimate the 1- and 2-year surgery- and permanent ostomy-free survivals. Cox regression analysis was used to evaluate associations between surgery- and permanent ostomy-free survivals and various factors of interest, including patient and tumor characteristics and clinical response. Institutional results on patient outcomes treated from 2013-2018 (n=28) has been reported previously, which have been updated with more patients and longer-term follow-up. <h3>Results</h3> 45 patients were identified with a median follow up of 28 months. 66.7% (n=30) achieved a clinical complete response (cCR). 17 patients (37.8%) underwent surgical resection while only 13.3% (n=4) of patients who achieved a cCR ultimately required surgery. 2 clinical incomplete responders did not have surgery; one patient refused APR and has been stable on maintenance chemotherapy, and one patient continued on surveillance and failed distantly. At 12 months, permanent ostomy free survival was 90.8% and 80.3% at 24 months. Surgery free survival was 76.9% and 65.7%, at 12 and 24 months, respectively. On Cox regression multivariate analysis, 6-month, but not 1-month, post treatment endoscopy was associated with surgery free survival (p=0.006) and permanent ostomy free survival (p=0.033). <h3>Conclusion</h3> Our institutional results support evidence that TNT may be a non-surgical option for select patients with rectal adenocarcinoma. 6-month, but not 1-month post treatment endoscopy was associated with surgery- and permanent ostomy-free survival suggesting continued tumor regression after 1 month. This is consistent with National Comprehensive Cancer Network (NCCN) guidelines to restage rectal cancer patients after at least 8 weeks following RT. Identification of reliable predictors of tumor regression after TNT for patient treatment planning is warranted.

Descriptive Statistics for Patients with Glioblastoma Associated with Germline Mismatch Repair Gene Mutation

<h3>Purpose/Objective(s)</h3> Hereditary Nonpolyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, is a genetic mismatch repair mutation associated with increased risk for development of glioblastoma (GBM). There is a paucity of data describing the clinical outcomes of GBM patients with HNPCC. We aim to describe tumor characteristics, treatment patterns, and outcomes. <h3>Materials/Methods</h3> IRB approved retrospective review of consecutive patients with a diagnosis of both HNPCC and GBM at a single institution. <h3>Results</h3> Nine patients with a diagnosis of HNPCC and GBM were treated at a single institution from 2001-2022. Six patients were male. Median age at GBM diagnosis was 61 (range 21-84). Median follow up from the time of GBM diagnosis was 7.83 months. Eight patients had prior malignancies: n=7 with colon adenocarcinoma, n=1 with Burkitt lymphoma. Two patients had active synchronous cancers with GBM. The most common presenting symptoms were facial droop (n=3) and cognitive changes (n=2). Others include headache, gait change, visual field defect, and seizures with n=1 each. All patients underwent surgery: n=2 gross total resection, n=4 subtotal resection, and n=3 biopsy alone. There were 3 temporal lobe, 3 parietal lobe, 2 frontal lobe, and 1 frontoparietal lobe tumors. Two patients had multifocal disease at diagnosis. One patient had a giant cell variant GBM. Seven patients had MSH6 mutations and 2 had MSH2 mutations. Two patients progressed rapidly after surgery and were unable to receive RT. Seven patients received adjuvant radiation therapy (RT): n=5 received concurrent TMZ- 1 with concurrent bevacizumab, 5-fluorouracil, and leucovorin due to synchronous metastatic colon cancer, 1 received no chemotherapy. The most common dose and fractionation schedules were 60 Gy in 30 fractions (fx) (n=3), 40.05 Gy in 15 fx (n=3), and n=1 received 30 Gy in 10 fx due to poor performance status and large tumor volume. One patient received proton therapy for active MS, n=8 received IMRT. Two patients initiated tumor treating fields following RT completion. The median time to progression after RT was 3.35 months, and all progressed within the radiation field. Median survival from diagnosis was 6.5 months (range 1.2-15.5). No patients received immune checkpoint inhibitors. One patient was alive at the time of data collection. Seven died due to GBM progression, and n=1 died from progression of a synchronous malignancy. <h3>Conclusion</h3> In this small series, patients with mismatch repair mutation associated glioblastoma had especially poor outcomes and a rapidly progressive disease course.

Bladder preservation in older adults with muscle-invasive bladder cancer: A retrospective study with concurrent chemotherapy and twice-daily hypofractionated radiotherapy schedule

IntroductionBladder cancer occurs mainly in older adults and surgery is not always possible when there are geriatric conditions and comorbidities. Trimodal treatment (TMT) combining trans-urethral resection of bladder tumour (TURBT) followed by concurrent chemoradiation (CRT) would be a curative alternative in such patients. Materials and MethodsAll consecutive patients 75 years of age and older with non-metastatic muscle-invasive bladder cancer (MIBC) treated with TMT by Georges Pompidou European Hospital team were retrospectively analysed. Induction CRT combined hypofractionated twice-daily radiotherapy targeting bladder and pelvis to a total dose of 24 Gy (Gy) with concurrent platinum salt and 5-fluorouracil. Consolidation CRT to a total dose of 44 Gy was proposed to patients with biopsy-proven complete response after induction phase and those with persistent tumour underwent salvage cystectomy. We assessed using Kaplan-Meier method overall survival (OS), cancer specific survival (CSS), invasive recurrence-free survival (IRFS), metastasis-free survival (MFS), survival with bladder preserved (SBP), and toxicities. With a Cox model for OS and the Fine Gray method of competing risk for secondary endpoints, we analysed in univariate (u) and multivariate (m) analysis the impact of tumour characteristics and patient profiles: gender, age, age-adjusted Charlson comorbidity index, polypharmacy, and malnutrition. ResultsFrom 1988 to 2017, 85 patients were included. After induction, complete response rate was 83.5%. With a median follow-up of 63 months, 5 year-OS, CSS, IRFS, MFS and SBP were 61.0%, 77.6%, 71%, 82.9%, and 70.2% respectively. A persistent tumour after induction impacted SBP (SHRm 3.61; p = 0.004), CSS (SHRm 3.27; p = 0.023), and MFS (SHRm 3.68; p = 0.018). Late grade 3 urinary and gastrointestinal toxicities were 3.5% and 1.2%. DiscussionWe report here the largest series of bladder preservation over 75 years in a curative intent. Outcomes and tolerance in selected older adults compared favourably with surgical series and with CRT studies using classical fractionation.

Survival outcome and treatment response of patients with young-onset locally advanced rectal cancer (YO-LARC) receiving total neoadjuvant therapy (TNT).

44 Background: Despite an alarming rise in incidence, data on survival outcome and treatment response of young-onset (age &lt; 50 years) locally advanced rectal cancer (YO-LARC) patients receiving total neoadjuvant therapy (TNT) are sparse. We retrospectively compared the outcome between YO-LARC and later-onset (aged 50 years or older) LARC (LO-LARC) patients treated with TNT. Methods: After the institutional review board approval, electronic medical records of the LARC (T3/T4 or node-positive) patients treated with TNT at a tertiary care cancer center between January 1, 2015, and June 30, 2020, were reviewed for data collection. TNT consisted of systemic chemotherapy with oxaliplatin-based regimens for 16 weeks followed by long-course radiation with concurrent capecitabine or 5-fluorouracil (CRT). Patients receiving only preoperative CRT were excluded. Most patients underwent surgical resection following the TNT. Non-operative management was offered to patients if TNT resulted in clinical complete response (cCR). The following comparisons between the YO-LARC and the LO-LARC patients were performed: patient characteristics, pathological complete response (pCR) rate, combined pCR + cCR rate, disease-free survival (DFS), and overall survival (OS). Results: Of 72 patients included in the analysis, 44(61%) were male, 49 (68%) were Caucasian, and 62 (86%) had clinical stage III disease. The study included 26 (36%) patients with YO-LARC (median age, 43 years) and 46 (64%) patients with LO-LARC (median age, 64 years). The comparison of patient characteristics that included gender, clinical stage, baseline carcinoembryonic antigen level, the distance of the tumor from the anal verge, presence of high-risk features, and histologic grade did not differ significantly between the groups. There were no statistically significant differences in pCR and combined pCR+cCR rates (p = 0.16) between the groups: YO-LARC, 12 % (3/26) and 15 % (4/26), respectively; LO-LARC, 22% (10/46) and 30% (14/46), respectively. Either group did not reach median DFS and OS after a median follow-up of 38 months for survivors. The estimated 5-year OS rates in patients with YO-LARC and LO-LARC were 86 % (95% confidence interval [CI], 69% to 100%) and 84% (95% CI, 68% to 100%), respectively (p = 0.92). The estimated 3-year DFS rates in patients with YO-LARC and LO-LARC were 67 % (95% CI, 50% to 89%) and 83% (95% CI, 72% to 95%), respectively (p = 0.19). Conclusions: The current retrospective analysis did not demonstrate significant differences in the pCR rates, combined pCR +cCR rates, DFS, or OS between the YO-LARC and LO-LARC patients treated with TNT.

A Pattern of Care Report on the Management of Patients with Squamous Cell Carcinoma of the Anus-A Study by the Italian Association of Radiotherapy and Clinical Oncology (AIRO) Gastrointestinal Tumors Study Group.

Background and objectives: The diagnosis and therapy of squamous cell carcinoma of the anus may vary significantly in daily clinical practice, even if international guidelines are available. Materials and Methods: We conducted a pattern of care survey to assess the management of patients with anal cancer in Italy (38 questions). We analyzed 58 questionnaires. Results: Most of the respondents work in public and/or university hospitals (75.8%) in northern Italy (65.5%). The majority (88.0%) treat less than 20 patients/year. Common examinations for diagnosis and staging are anorectal endoscopy (84.5%), computed tomography scan (86.2%) and pelvic magnetic resonance imaging (MRI) (96.5%). The most frequently prescribed dose to primary tumor is 50–54 Gy (46.5–58.6%) for early stage disease and 54–59.4 Gy (62.1–32.8%) for locally advanced cases. Elective volumes are prescribed around 45 Gy (94.8%). Most participants use volumetric intensity modulated radiotherapy (89.7%) and a simultaneous integrated boost (84.5%). Concurrent radiotherapy, 5-fluorouracil and mitomycin is considered the standard of care (70.6%). Capecitabine is less frequently used (34.4%). Induction chemotherapy is an option for extensive localized disease (65.5%). Consolidation chemotherapy is rarely used (18.9%). A response evaluation is conducted at 26–30 weeks (63.9%) with a pelvic MRI (91.4%). Follow-up is generally run by the multidisciplinary tumor board (62.1%). Conclusions: Differences were observed for radiotherapy dose prescription, calling for a consensus to harmonize treatment strategies.

Postoperative Chemoradiotherapy With Capecitabine and Oxaliplatin vs Capecitabine for Stage II to III Rectal Cancer

Several studies have explored the efficacy and toxic effects of concurrent 5-fluorouracil (5-FU)- or capecitabine-based chemoradiotherapy (CRT) with or without oxaliplatin in the neoadjuvant setting. Addition of oxaliplatin to 5-FU or capecitabine elicited similar outcomes but with significantly increased toxic effects; however, there is a need for randomized clinical trials comparing 2 CRT regimens for patients receiving CRT in the adjuvant setting. To explore the efficacy and toxic effects of oxaliplatin combined with postoperative concurrent capecitabine and radiotherapy (RT) for pathological stage II and III rectal cancer. This multicenter randomized clinical trial enrolled patients from 7 centers in China between April 1, 2008, and December 30, 2015. Patients with pathologically confirmed stage II and III rectal cancer were randomized (1:1) to receive concurrent CRT with capecitabine or capecitabine plus oxaliplatin. Analysis was conducted from December 31, 2019, to March 15, 2020. RT comprised 45 to 50 Gy in 25 fractions of 1.8 to 2.0 Gy over 5 weeks. In the capecitabine with RT group, concurrent chemotherapy included 2 cycles of capecitabine (1600 mg/m2) on days 1 to 14 and 22 to 35. The capecitabine and oxaliplatin with RT group received identical postoperative RT to that in the capecitabine with RT group combined with capecitabine (1300 mg/m2) on days 1 to 14 and 22 to 35 and a 2-hour infusion of oxaliplatin (60 mg/m2) on weeks 1, 2, 4, and 5. Patients in both groups received adjuvant chemotherapy (capecitabine or fluorouracil and oxaliplatin) after CRT. The primary end point was 3-year disease-free survival (DFS). A total of 589 patients (median [IQR] age, 55 [47-52] years; 375 [63.7%] men and 214 [36.3%] women) were enrolled, including 294 patients randomized to the capecitabine with RT group and 295 patients randomized to the capecitabine and oxaliplatin with RT group. Median (IQR) follow-up was 68 (45-96) months. Most patients had stage III disease (574 patients [75.9%]). Three-year DFS was 76.3% for the capecitabine with RT group and 74.1% for the capecitabine and oxaliplatin with RT group, and 5-year DFS was 72.0% for the capecitabine with RT group and 71.1% for the capecitabine and oxaliplatin with RT group (hazard ratio [HR], 1.07; 95% CI, 0.79-1.44; P = .68). There was no significant difference between groups in overall survival (HR, 0.93; 95% CI, 0.64-1.34; P = .70) or local recurrence (HR, 0.61; 95% CI, 0.31-1.22; P = .16). More grade 3 and 4 acute toxic effects were observed in the capecitabine and oxaliplatin with RT group than in the capecitabine with RT group (114 patients [38.6%] vs 84 patients [28.6%]; P = .01). This randomized clinical trial found that addition of oxaliplatin to capecitabine-based postoperative CRT did not improve the efficacy of treatment but increased the risk of severe acute toxic effects. This finding highlights the basic role of postoperative capecitabine with RT for patients with locally advanced rectal cancer. ClinicalTrials.gov Identifier: NCT00714077.

The Phase I Results of a Phase 1/2 Trial for Patients With Newly Diagnosed Anal Cancer Treated With Concurrent Radiation Therapy, 5-Fluorouracil, Mitomycin and BMX-001

<h3>Purpose/Objective(s)</h3> Radiation therapy with concurrent 5-fluorouracil and mitomycin (MMC) (CRT) for patients with locally advanced anal squamous cell carcinoma (ASCC) results in long-term disease-free survival and sphincter preservation, but often with significant toxicity. RTOG trials showed 43-87% ≥ grade (G) 3 acute toxicity. We hypothesize that BMX-001, a scavenger of O2, will decrease CRT-associated toxicity without compromising the survival outcome. The objectives of this phase I trial were to determine the maximum tolerated (MTD) BMX-001 primarily, and secondarily evaluate outcomes. <h3>Materials/Methods</h3> Eleven eligible stage II-III and pathologic confirmed ASCC patients received standard CRT. BMX-001 was given by sub-cutaneous injection, twice a week during CRT. Loading/maintenance dose escalation was as follows: 1) 7 and 3.5 mg/subject x 3; 2) 14 and 7 mg/subject x 3; 3) 28 and 14 mg/subject x 5. Endpoints (Toxicity and quality of life (QOL)) were assessed with CTCAE and EORTC QLQ-C30 questionnaires, respectively. <h3>Results</h3> All patients are free of disease with a median follow up of 17 (range 3-38) months. BMX-associated toxicity as follows: 6/11 G1 injection site erythema, 3/11 G2 sinus tachycardia, 1/11 G3 anxiety and hypertension and 1/11 G1 hypotension. All symptoms were relieved after hydrocortisone. No ≥ G 4 CRT-associated toxicities. G 1, 2 &3 CRT-associated toxicity during CRT was seen at skin (27/64/9%), gastrointestinal system (GI) (45/54/0%) and genitourinary system (GU) (64%/9/0%). All patients experienced anal pain during CRT (score 3-4/10: 44% and 5-9/10: 56%). At 1-month post-CRT, no G2 toxicity; G1 skin, GI and GU toxicity decreased to 0, 64 and 27%; Score 5-8/10 anal pain decreased to 27%. By 6 months, only 1 patient had anal pain scored 4/10 and 4 patients had G1 GI toxicity. Patients' physical, role and social functioning scores decreased to the lowest point at week 6 of CRT and returned to pre-CRT level at 1-month post-CRT. Emotional and cognitive functioning did not decrease significantly during CRT. <h3>Conclusion</h3> BMX-001 MTD was not reached. A loading dose of 28 mg and a maintenance dose of 14 mg concurrent with CRT for anal squamous cell carcinoma is feasible and safe and is recommended for phase II trial. Concurrent CRT/BMX-001 was associated with decreased acute toxicities compared to RTOG data. Patients' decreased QOL during CRT returns to pre-CRT status in 1 month. Clinical trial number NCT03386500.

Long Term Risk of Pelvic Insufficiency Fractures and Lower Extremity Edema After Definitive Chemoradiation for Squamous Cell Carcinoma of the Anal Canal

Definitive chemoradiation is the standard of care of treatment of squamous cell carcinomas (SCC) of the anal canal. While this treatment is effective, definitive chemoradiation is associated with significant acute and late toxicities. In this study, we seek to evaluate the incidence and identify risk factors of radiotherapy (RT) induced pelvic insufficiency fractures and lower extremity (LE) edema.We performed a single-institution retrospective analysis of 185 patients treated with chemoradiation for anal SCC between 2007-2019. Median age was 61 (range: 15-92); 9.8% were metastatic and 34.1% were men. All patients received concurrent chemotherapy, including 160 patients treated with concurrent 5-fluorouracil /MMC, 12 treated with 5-fluorouracil /Cisplatin, 9 patients treated with 5FU alone, 2 treated with FOLFOX alone, and 2 treated with Carboplatin/Paclitaxel. Median dose to the pelvis was 54 Gy. RT modalities included IMRT/VMAT (N = 157), pencil beam proton beam (N = 17), 3D-CRT (N = 6), and multi-modalities (N = 5). Patient medical charts and imaging were reviewed for patient/treatment characteristics, and to determine incidence of development of post-RT related insufficiency fractures and LE. Pelvic insufficiency fractures were all confirmed radiographically with CT or MRI pelvis. Patients with baseline LE edema were excluded from the analysis of post-RT related LE edema. Cox univariate analysis was performed to identify predictors of pelvic fracture.Median follow-up was 59 months. Among 185 patients, 11 (6%) patients developed pelvic insufficiency fractures at a median time of 11 months (range: 2.7-60) since completion of RT treatment (range: 2-60). Treatment for pelvic insufficiency fractures included narcotics (n = 3), and no patient required sacroplasty. All but 1 of the patients who developed pelvic insufficiency fractures were women. However, gender (P = 0.12) and menopausal status (P = 0.87) were not significant on univariate analysis. On univariate analysis, only treatment with IMRT/VMAT (HR 2.33, P = 0.02) predicted for higher risk of development of pelvic insufficiency fracture. Among patients without baseline LE edema, 5.95% of patients developed LE or pelvic edema after completion of RT at a median of 3 months post-treatment (range: 0-42). Of these, 7 patients developed LE edema, 1 developed vulvar edema, and 1 patient developed scrotal edema. All patients had grade 1+ edema.RT related pelvic insufficiency fractures and LE edema are rare after chemoradiation to the pelvis, and often are incidental findings appreciated radiographically. IMRT/VMAT may be associated with higher risk of pelvic insufficiency fractures.

The role of haematological parameters in predicting the response to radical chemoradiotherapy in patients with anal squamous cell cancer.

BackgroundHistorically, the treatment of choice for anal cancer had been abdominoperineal resection (APR). Radical radiotherapy with concurrent 5-fluorouracil plus mitomycin C chemotherapy was later established as standard therapy, although with a failure rate of 20–30%. The aim of this study was to evaluate the outcomes after radical chemoradiotherapy (CRT), prognostic and predictive factors and patterns of failure.Patients and methodsThis study included 47 patients treated with radical CRT for patohistologicaly confirmed anal squamous cell carcinoma. Analysed haematological parameters included: neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and haemoglobin level. The final logistic regression model included treatment break period. Tumour response was assessed at 24 weeks from CRT completion. Follow-up was performed every 3 months during the first two years, and every 6 months thereafter.ResultsA complete clinical response (CR) was detected in 30 patients (63.8%). Patients who did not achieve a 6-months CR and those who had a CR after 6 months but then relapsed were referred to surgical treatment. With combined CRT and surgical salvage treatment the CR rate was 80.9%. Patients with CR after 6 months had significantly longer disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS). A significant effect on the 6-month response was confirmed for PLR (p = 0.03).ConclusionsImportant prognostic factors associated with CR were baseline haemoglobin level and period of treatment interruptions. Potential haematological prognostic factors could be PLR and NLR, which can be routinely determined by low-cost and minimally invasive methods.

Neoadjuvant Chemoradiation Impacts the Prognostic Effect of Surgical Margin Status in Pancreatic Adenocarcinoma.

Many studies show significantly improved survival after R0 resection compared with R1 resection in pancreatic adenocarcinoma (PAC); however, the effect of neoadjuvant chemoradiation (NACRT) on this association is unknown. The aim of this study was to evaluate the prognostic significance of positive surgical margins (SMs) after NACRT compared with upfront surgery + adjuvant therapy in PAC. All cases of surgically resected PAC at a single institution were reviewed from 1996 to 2014; patients treated with palliative intent, metastatic disease, and biliary/ampullary tumors were excluded. The primary endpoint was overall survival (OS). Overall, 300 patients were included; 134 patients received NACRT with concurrent 5-fluorouracil or gemcitabine followed by surgery, and 166 patients received upfront surgery (+ adjuvant chemotherapy in 72% of patients and RT in 65%); 31% of both groups had a positive SM (+SM). The median OS for patients with a +SM or negative SM (-SM) was 26.6 and 31.6 months, respectively for NACRT, and 12.0 and 24.5 months, respectively, for upfront surgery. OS was significantly improved with -SM compared with +SM in both groups (p=0.006). When resection yielded +SM, NACRT patients had improved OS compared with upfront surgery patients (p<0.001). On multivariable analysis, +SM in the upfront surgery group (hazard ratio [HR] 2.94, 95% confidence interval [CI] 2.04-4.24; p<0.001) and older age (HR 1.01, 95% CI 1.00-1.03, per year; p=0.007) predicted worse OS. +SM in the NACRT group was not associated with worse OS (HR 1.09, 95% CI 0.72-1.65; p=0.70). Patients with a positive margin after NACRT and surgery had longer survival compared with patients with a positive margin after upfront surgery. NACRT should be strongly considered for patients at high risk of R1 resections.

Chemoradiotherapy for patients with locally advanced or unresectable extra-hepatic biliary cancer.

Although surgical resection is the preferred curative-intent treatment option for patients with non-metastatic, extra-hepatic biliary cancer (EBC), radiotherapy (RT) or chemoradiotherapy (CRT) may be utilized in select cases when surgical resection is not feasible. The purpose of this study is to report the efficacy and adverse events (AEs) associated with CRT for patients with locally advanced and unresectable EBC. This was a retrospective cohort study of patients with EBC, including extra-hepatic cholangiocarcinoma or gallbladder cancer, deemed inoperable who received RT between 1998 and 2018. The median RT dose was 50.4 Gy in 28 fractions and 94% received concurrent 5-fluorouracil. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS) from the start of RT. The cumulative incidence of local progression (LP), locoregional progression (LRP), and distant metastasis (DM) were reported with death as a competing risk. Cox proportional hazards regression models were used to assess for correlation between patient and treatment characteristics and outcomes. Forty-eight patients were included for analysis. The median OS was 12.0 months [95% confidence interval (CI): 2.3-73.2 months]. The 2-, 3-, and 5-year OS were 33% (95% CI: 22-50%), 20% (95% CI: 11-36%), and 7% (95% CI: 2-20%), respectively. The 2-year PFS, LP, LRP, and DM were 21% (95% CI: 12-36%), 27% (95% CI: 17-44%), 31% (95% CI: 20-48%), and 33% (95% CI: 22-50%), respectively. On univariate analysis, biologically effective dose (BED) >59.5 Gy10 was associated with improved OS [hazard ratio (HR): 0.40, 95% CI: 0.18-0.92, P=0.03] and PFS (HR: 0.37, 95% CI: 0.16-0.84, P=0.02) and primary tumor size (per 1 cm increase) was associated with worsened PFS (HR: 1.29, 95% CI: 1.02-1.63, P=0.04). BED >59.5 Gy10 remained associated with PFS on multivariate analysis (HR: 0.34, 95% CI: 0.15-0.78, P=0.01). Treatment-related grade 3+ acute and late gastrointestinal AEs occurred in 13% and 17% of patients, respectively. RT is associated with 3- and 5-year survival in a subset of patients with unresectable EBC. Further exploration of the role of RT as part of a multi-modality curative treatment strategy is warranted.

Adjuvant Chemotherapy in Two-Stage Tissue Expander/Implant Breast Reconstruction: Does it Affect Final Outcomes?

In immediate two-stage implant-based breast reconstruction, adjuvant chemotherapy, when indicated, is usually conducted between the stages, which might influence the outcomes of the second-stage operation. The purpose of this study was to evaluate the potential influence of adjuvant chemotherapy on the final outcomes of two-stage implant-based reconstructions. Patients who underwent immediate tissue expander/implant breast reconstruction between 2010 and 2016, with completion of both stages, were reviewed. Cases were categorized into two groups-adjuvant chemotherapy and no adjuvant chemotherapy. The rates of adverse outcomes were compared between the groups. A total of 602 cases in 568 patients were analyzed, with a mean follow-up period of 58.5months, including 236 patients receiving adjuvant chemotherapy and 366 patients not receiving adjuvant chemotherapy. The two groups had similar baseline characteristics, except for a significantly higher rate of adjuvant radiotherapy in the former group. The adjuvant chemotherapy group showed significantly higher rates of overall complications (odds ratio [OR] 2.127, 95% confidence interval [CI] 1.231-3.676), including infections (OR 4.239, 95% CI 1.059-16.970), severe capsular contractures (OR 2.107, 95% CI 1.067-4.159), and reconstruction failures (OR 12.754, 95% CI 1.587-102.481) compared with the control group, after adjusting for other variables, including adjuvant radiotherapy. In the analysis regarding the influence of chemotherapy regimens, the use of sequential anthracycline/cyclophosphamide and taxane, and concurrent 5-fluorouracil, doxorubicin and cyclophosphamide, were associated with increased risks for adverse outcomes compared with the no chemotherapy group, while the use of other regimens, including anthracycline/cyclophosphamide alone, was not. Adjuvant chemotherapy might influence the final outcomes of two-stage implant-based reconstruction.

Patterns of Failure and the Need for Biliary Intervention in Resected Biliary Tract Cancers After Chemoradiation.

This study assessed patterns of failure and rates of subsequent biliary intervention among patients with resected biliary tract cancers (BTCs) including gallbladder carcinoma (GBC) and extra- and intrahepatic cholangiocarcinoma (eCCA and iCCA) treated with adjuvant chemoradiation therapy (CRT). In this single-institution retrospective analysis of 80 patients who had GBC (n = 29), eCCA (n = 43), or iCCA (n = 8) treated with curative-intent resection and adjuvant CRT from 2007 to 2017, the median radiation dose was 50.4Gy (range 36-65Gy) with concurrent 5-fluorouracil (5-FU) chemotherapy. All but two of the patients received adjuvant chemotherapy. The 2-year locoregional failure (LRF), 2-yearrecurrence-free survival (RFS), and 2-yearoverall survival (OS), and univariate predictors of LRF, RFS, and OSwere calculated for the entire cohort and for a subgroup excluding patients with iCCA (n = 72). The predictors of biliary interventions also were assessed. Of the 80 patients (median follow-up period, 30.5months; median OS, 33.9months), 54.4% had American Joint Committee on Cancer (AJCC) stage 1 or 2 disease, 57.1% were lymphnode-positive, and 66.3% underwent margin-negative resection. For the entire cohort,2-year LRF was 23.8%, 2-yearRFSwas 43.7%, and 2-yearOS was62.1%. When patients with iCCA were excluded, the2-year LRF was22.6%, the 2-yearRFS was 43.9%, and the 2-year OS was 59.2%. In the overall and subgroup univariate analyses, lymph node positivity was associated with greaterLRF, whereas resection margin was not. Biliary intervention was required for 12 (63.2%) of the 19 patients with LRF versus 11 (18%) of the 61 patients without LRF (P < 0.001). Of the 12 patients with LRF who required biliary intervention, 4 died of biliary complications. The LRF rates remained significant despite adjuvant CRT. Lymph node positivity may be associated with increased risk of LRF. Positive margins were not associated with greater LRF, suggesting that CRT may mitigate LRF risk for this group. An association between LRF and higher rates of subsequent biliary interventions was observed, which may yieldsignificant morbidity. Novel strategies to decrease the rates of LRF should be considered.

Abstract IA26: Targeting hypoxia and personalizing chemoradiation

Abstract There are multiple management options for muscle-invasive bladder cancer. Approaches include radical cystectomy and trimodality treatment with transurethral resection of bladder tumor and organ-preserving radiotherapy. Trials provided high-quality evidence for the superiority of multimodality treatments over radiotherapy alone. The BC2001 phase III trial showed adding concurrent 5-fluorouracil (5-FU) and mitomycin-C to radiotherapy increased 2-year locoregional control by 14%. The Gemtrans phase II trial, and a follow-on pooled analysis of eight trials, showed high survival outcomes (5-year overall survival rates of 59%) for gemcitabine-based chemoradiotherapy. The BCON phase III trial showed a 13% improvement in 3-year overall survival when hypoxia-targeting carbogen and nicotinamide (CON) were given with radiotherapy. Bladder-preserving trimodality treatments have equivalent survival outcomes to the previously considered gold-standard treatment of radical cystectomy for localized bladder cancer, and trials have shown it is not feasible to randomize to cystectomy or selective bladder preservation. Decisions for selecting primary cystectomy or bladder-sparing treatment are now governed largely by patient and clinician preferences. Given the poor survival outcomes for muscle-invasive bladder cancer and multiple options for its management, there is an unmet clinical need to validate predictive biomarkers to aid rational treatment selection and personalization. Personalization based on measuring tumor hypoxia is attractive. Approaches for measuring tumor hypoxia have been studied for many years. Although there are advantages and disadvantages to the different methods, gene expression signatures show promise for clinical application. The signatures can be applied using readily available pretreatment paraffin-embedded tumor samples. Signatures have been derived for multiple cancer types including bladder. A 24-gene signature was shown to have strong and independent prognostic and predictive value. The signature was validated in multiple cohorts and shown to identify patients likely to benefit from the addition of CON to radiotherapy. A key aspect for progressing personalized treatment is biomarker application, i.e., identifying a platform for clinical use. Ongoing work is taking the 24-gene signature forward and comparing platforms. Customized Taqman Low Density Array (TLDA) cards were used to take a head and neck signature forward for prospective testing in a trial, but other technologies (e.g., nanostring) are of interest. Work is also generating transcriptomic data for samples collected from patients enrolled in the BC2001 trial to test whether patients with hypoxic tumors do not benefit from having concurrent 5-FU plus mitomycin-C. A biomarker-driven trial is also being developed. Citation Format: Catharine West. Targeting hypoxia and personalizing chemoradiation [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA26.