The neoadjuvant rectal score and a novel magnetic resonance imaging based neoadjuvant rectal score are stage independent predictors of long-term outcome in locally advanced rectal cancer.

AIM: Neoadjuvant rectal (NAR) score is an early surrogate for longer-term outcomes in rectal cancer undergoing radiotherapy and resection. In an era of increasing organ preservation, resection specimens are not always available to calculate the NAR score. Post-treatment magnetic resonance imaging (MRI) re-staging of regression is subjective, limiting reproducibility. We explored the potential for a novel MRI-based NAR score (mrNAR) adapted from the NAR formula. METHODS: Locally advanced rectal cancer patients undergoing neoadjuvant therapy (nCRT) and surgery were retrospectively identified between 2008 and 2020 in a single cancer network. mrNAR was calculated by adapting the NAR formula, replacing pathological (p) stages with post-nCRT MR stages (ymr). Cox regression assessed relationships between clinicopathological characteristics, NAR and mrNAR with overall survival (OS) and recurrence-free survival (RFS). RESULTS: In total, 381 NAR and 177 mrNAR scores were calculated. On univariate analysis NAR related to OS (hazard ratio [HR] 2.05, 95% confidence interval [CI] 1.33-3.14, p = 0.001) and RFS (HR 2.52, 95% CI 1.77-3.59, p = 0.001). NAR 3-year OS <8 was 95.3%, 8-16 was 88.6% and >16 was 80%. mrNAR related to OS (HR 2.96, 95% CI 1.38-6.34, p = 0.005) and RFS (HR 2.99, 95% CI 1.49-6.00, p = 0.002). 3-year OS for mrNAR <8 was 96.2%, 8-16 was 92.4% and >16 was 78%. On multivariate analysis, mrNAR was a stage-independent predictor of OS and RFS. mrNAR corresponded to NAR score category in only 15% (positive predictive value 0.23) and 47.5% (positive predictive value 0.48) of cases for categories <8 and >16, respectively. CONCLUSIONS: Neoadjuvant rectal score is validated as a surrogate end-point for long-term outcomes. mrNAR categories do not correlate with NAR but have stage-independent prognostic value. mrNAR may represent a novel surrogate end-point for future neoadjuvant treatments that focus on organ preservation.

Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. METHODS: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m2 oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. FINDINGS: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group. INTERPRETATION: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK.

Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial.

BACKGROUND: In the UK, chemotherapy is the standard treatment for inoperable, locally advanced, non-metastatic pancreatic cancer. Chemoradiotherapy is also an acceptable treatment option, for which gemcitabine, fluorouracil, or capecitabine can be used as concurrent chemotherapy agents. We aimed to assess the activity, safety, and feasibility of both gemcitabine-based and capecitabine-based chemoradiotherapy after induction chemotherapy for patients with locally advanced pancreatic cancer. METHODS: In this open-label, randomised, two-arm, phase 2 trial, patients aged 18 years or older with histologically proven, locally advanced pancreatic cancer (with a tumour diameter of 7 cm or less) were recruited from 28 UK centres between Dec 24, 2009 and Oct 25, 2011. After 12 weeks of induction gemcitabine and capecitabine chemotherapy (three cycles of gemcitabine [1000 mg/m(2) on days 1, 8, 15 of a 28-day cycle] and capecitabine [830 mg/m(2) twice daily on days 1-21 of a 28-day cycle]), patients with stable or responding disease, tumour diameter of 6 cm or less, and WHO performance status 0-1 were randomly assigned to receive a further cycle of gemcitabine and capecitabine chemotherapy followed by either gemcitabine (300 mg/m(2) once per week) or capecitabine (830 mg/m(2) twice daily, Monday to Friday only), both in combination with radiation (50·4 Gy in 28 fractions). Randomisation (1:1) was done via a central computerised system and used stratified minimisation. The primary endpoint was 9-month progression-free survival, analysed by intention to treat including only those patients with valid CT assessments. This trial is registered with ISRCTN, number 96169987. FINDINGS: 114 patients were registered and 74 were randomly allocated (38 to the gemcitabine group and 36 to the capecitabine group). After 9 months, 22 of 35 assessable patients (62·9%, 80% CI 50·6-73·9) in the capecitabine group and 18 of 35 assessable patients (51·4%, 39·4-63·4) in the gemcitabine group had not progressed. Median overall survival was 15·2 months (95% CI 13·9-19·2) in the capecitabine group and 13·4 months (95% CI 11·0-15·7) in the gemcitabine group (adjusted hazard ratio [HR] 0·39, 95% CI 0·18-0·81; p=0·012). 12-month overall survival was 79·2% (95% CI 61·1-89·5) in the capecitabine group and 64·2 (95% CI 46·4-77·5) in the gemcitabine group. Median progression-free survival was 12·0 months (95% CI 10·2-14·6) in the capecitabine group and 10·4 months (95% CI 8·9-12·5) in the gemcitabine group (adjusted HR 0·60, 95% CI 0·32-1·12; p=0·11). Eight patients in the capecitabine group had an objective response at 26 weeks, as did seven in the gemcitabine group. More patients in the gemcitabine group than in the capecitabine group had grade 3-4 haematological toxic effects (seven [18%] vs none, p=0·008) and non-haematological toxic effects (ten [26%] vs four [12%], p=0·12) during chemoradiation treatment; the most frequent events were leucopenia, neutropenia, and fatigue. Two patients in the capecitabine group progressed during the fourth cycle of induction chemotherapy. Of the 34 patients in the capecitabine group who received chemoradiotherapy, 25 (74%) received the full protocol dose of radiotherapy, compared with 26 (68%) of 38 patients in the gemcitabine group. Quality-of-life scores were not significantly different between the treatment groups. INTERPRETATION: Our results suggest that a capecitabine-based regimen might be preferable to a gemcitabine-based regimen in the context of consolidation chemoradiotherapy after a course of induction chemotherapy for locally advanced pancreatic cancer. However, these findings should be interpreted with caution because the difference in the primary endpoint was non-significant and the number of patients in the trial was small. FUNDING: Cancer Research UK.

Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial.

BACKGROUND: Chemoradiation became the standard of care for anal cancer after the ACT I trial. However, only two-thirds of patients achieved local control, with 5-year survival of 50%; therefore, better treatments are needed. We investigated whether replacing mitomycin with cisplatin in chemoradiation improves response, and whether maintenance chemotherapy after chemoradiation improves survival. METHODS: In this 2 × 2 factorial trial, we enrolled patients with histologically confirmed squamous-cell carcinoma of the anus without metastatic disease from 59 centres in the UK. Patients were randomly assigned to one of four groups, to receive either mitomycin (12 mg/m(2) on day 1) or cisplatin (60 mg/m(2) on days 1 and 29), with fluorouracil (1000 mg/m(2) per day on days 1-4 and 29-32) and radiotherapy (50.4 Gy in 28 daily fractions); with or without two courses of maintenance chemotherapy (fluorouracil and cisplatin at weeks 11 and 14). The random allocation was generated by computer and patients assigned by telephone. Randomisation was done by minimisation and stratified by tumour site, T and N stage, sex, age, and renal function. Neither patients nor investigators were masked to assignment. Primary endpoints were complete response at 26 weeks and acute toxic effects (for chemoradiation), and progression-free survival (for maintenance). The primary analyses were done by intention to treat. This study is registered at controlled-trials.com, number 26715889. FINDINGS: We enrolled 940 patients: 472 were assigned to mitomycin, of whom 246 were assigned to no maintenance, 226 to maintenance; 468 were assigned to cisplatin, of whom 246 were assigned to no maintenance, 222 to maintenance. Median follow-up was 5.1 years (IQR 3.9-6.9). 391 of 432 (90.5%) patients in the mitomycin group versus 386 of 431 (89.6%) in the cisplatin group had a complete response at 26 weeks (difference -0.9%, 95% CI -4.9 to 3.1; p=0.64). Overall, toxic effects were similar in each group (334/472 [71%] for mitomycin vs 337/468 [72%] for cisplatin). The most common grade 3-4 toxic effects were skin (228/472 [48%] vs 222/468 [47%]), pain (122/472 [26%] vs 135/468 [29%]), haematological (124/472 [26%] vs 73/468 [16%]), and gastrointestinal (75/472 [16%] vs 85/468 [18%]). 3-year progression-free survival was 74% (95% CI 69-77; maintenance) versus 73% (95% CI 68-77; no maintenance; hazard ratio 0.95, 95% CI 0.75-1.21; p=0.70). INTERPRETATION: The results of our trial--the largest in anal cancer to date--show that fluorouracil and mitomycin with 50.4 Gy radiotherapy in 28 daily fractions should remain standard practice in the UK. FUNDING: Cancer Research UK.

The in-silico feasibility of dose escalated, hypofractionated radiotherapy for rectal cancer.

Background and purpose: Short course radiotherapy (SCRT) has a low biological prescription dose. Rectal cancer has a dose response relationship and moderate α/ß ratio (∼5). We hypothesise hypofractionated dose escalation has radiobiological advantages. We assessed in-silico dose escalation to the primary tumour using a simultaneous integrated boost (SIB) technique. Materials and methods: Patients who had received 25 Gy/5# were enrolled. GTV was macroscopic tumour including lumen. CTVA was GTV + 10 mm. CTVB included elective nodes. PTV_Low was created from CTVF (CTVA + CTVB) + 7 mm. PTV_High (SIB) was GTV + 5 mm margin. OAR were as per RTOG guidelines. Each patient had 4 plans created at increasing dose levels (27.5 Gy, 30 Gy, 32.5 Gy and 35 Gy) to PTV_High. PTV_Low was 25 Gy/5#.5 test plans were created for each patient in Eclipse™ v15.5 and consisted of 2 VMAT full arcs (6 MV), Varian Truebeam (2.7). Planning objectives were set in the Photon optimiser (PO) and recalculated using Acuros v15.5. A priori feasibility was defined as 90% of plans achieving the planning objectives at 32.5 Gy dose level (EqD2 53.4 Gy). Results: 20 SCRT patients median age 70, F (n = 5), M (n = 15). Rectum level; low (n = 12), mid (n = 3) and upper (n = 5). 100 plans were analysed. Mean volume of PTV_High was 130 cm3 (SD 81.5) and PTV_Low 769.6 cm3 (SD 241.1). 100% plans complied with mandatory planning dose metrics for each structure at the 25 Gy/5# plan and each dose level. Conclusion: Hypofractionated dose escalation to the primary tumour up to 35 Gy/5# is technically feasible in rectal cancer radiotherapy.

Adjuvant chemotherapy for resected colon cancer: comparison of the prognostic value of tumour and patient related factors.

PURPOSE: Despite proven benefits of adjuvant chemotherapy in colon cancer, outcomes remain heterogeneous. Several non-validated prognostic factors have been proposed. This study examines the prognostic value of tumour and patient factors currently included in the Numeracy and Adjuvant! models together with measures of the local and systemic inflammatory responses in patients receiving adjuvant chemotherapy for colon cancer. METHODS: Three hundred and forty-eight patients underwent resection between 1997 and 2007. Of these, 76 received adjuvant chemotherapy. Chemotherapy was 5-FU based (single or combination). Variables from the Numeracy and Adjuvant! calculators were examined. The Petersen Index was used to assess other tumour characteristics considered high risk for recurrence (venous invasion, serosal involvement, surgical margin involvement and perforation through the tumour). Local inflammatory infiltrate was scored by the Jass and Klintrup criteria; the systemic inflammatory response by the Glasgow Prognostic Score (mGPS). RESULTS: Median follow-up was 78 months. Chemotherapy prescription was higher in younger patients with less comorbidity or tumours with higher nodal involvement, increasing T stage and high-risk characteristics (all P < 0.05). On univariate analysis, high-risk tumour characteristics such as T stage and high-risk Petersen Index in addition to the mGPS related to survival. Only the GPS retained prognostic significance on multivariate analysis (P < 0.005). CONCLUSION: The results of the present study showed that the components of Numeracy and Adjuvant! models and the tumour inflammatory infiltrate had inferior prognostic value compared with that of the systemic inflammatory response, as evidenced by the mGPS, in patients receiving adjuvant chemotherapy for colon cancer.

A bilateral cicatricial ectropion and bilateral upper lid shortening caused by 5-fluorouracil toxicity in a patient with dihydropyrimidine dehydrogenase deficiency.

CONTEXT: Well-known causes of a cicatrizing ectropion are chemical/thermal injuries, dermatitis, cutaneous diseases, malignancies, and trauma. We add to this preceding list a systemic cause of a cicatrizing ectropion as a result of a rare side effect of 5-fluorouracil (5-FU), a common and frequently used chemotherapeutic agent. METHODS: A case report demonstrating the clinical presentation of a cicatricial ectropion caused by (5-FU) chemotherapy toxicity in a patient with dihydropyrimidine dehydrogenase deficiency. We also describe the subsequent investigations and management of this case. RESULTS: A bilateral cicatrizing lower lid ectropion, bilateral upper lid shortening, cicatrizing and sclerosing facial skin changes occurred in an 80-year-old male, undergoing preoperative chemoradiotherapy, incorporating Capecitabine, an oral 5-FU prodrug for a locally advanced rectal carcinoma. Severe 5-FU toxicity ultimately proved fatal but in addition to typical 5-FU related adverse effects, the patient developed bilateral incomplete lid closure, secondary corneal exposure and keratopathy. Due to the patient's extreme ill health, he was managed conservatively with a moist chamber. CONCLUSION: 5-fluorouracil chemotherapy in patients with dihydropyrimidine dehydrogenase deficiency, can give rise to ocular and cutaneous toxicity. We also present the complex management problems that have to be anticipated in treating such systemically compromised patients.

Patterns of Recurrence After Resection of Pancreatic Ductal Adenocarcinoma: A Secondary Analysis of the ESPAC-4 Randomized Adjuvant Chemotherapy Trial.

Importance: The patterns of disease recurrence after resection of pancreatic ductal adenocarcinoma with adjuvant chemotherapy remain unclear. Objective: To define patterns of recurrence after adjuvant chemotherapy and the association with survival. Design, Setting, and Participants: Prospectively collected data from the phase 3 European Study Group for Pancreatic Cancer 4 adjuvant clinical trial, an international multicenter study. The study included 730 patients who had resection and adjuvant chemotherapy for pancreatic cancer. Data were analyzed between July 2017 and May 2019. Interventions: Randomization to adjuvant gemcitabine or gemcitabine plus capecitabine. Main Outcomes and Measures: Overall survival, recurrence, and sites of recurrence. Results: Of the 730 patients, median age was 65 years (range 37-81 years), 414 were men (57%), and 316 were women (43%). The median follow-up time from randomization was 43.2 months (95% CI, 39.7-45.5 months), with overall survival from time of surgery of 27.9 months (95% CI, 24.8-29.9 months) with gemcitabine and 30.2 months (95% CI, 25.8-33.5 months) with the combination (HR, 0.81; 95% CI, 0.68-0.98; P = .03). The 5-year survival estimates were 17.1% (95% CI, 11.6%-23.5%) and 28.0% (22.0%-34.3%), respectively. Recurrence occurred in 479 patients (65.6%); another 78 patients (10.7%) died without recurrence. Local recurrence occurred at a median of 11.63 months (95% CI, 10.05-12.19 months), significantly different from those with distant recurrence with a median of 9.49 months (95% CI, 8.44-10.71 months) (HR, 1.21; 95% CI, 1.01-1.45; P = .04). Following recurrence, the median survival was 9.36 months (95% CI, 8.08-10.48 months) for local recurrence and 8.94 months (95% CI, 7.82-11.17 months) with distant recurrence (HR, 0.89; 95% CI, 0.73-1.09; P = .27). The median overall survival of patients with distant-only recurrence (23.03 months; 95% CI, 19.55-25.85 months) or local with distant recurrence (23.82 months; 95% CI, 17.48-28.32 months) was not significantly different from those with only local recurrence (24.83 months; 95% CI, 22.96-27.63 months) (P = .85 and P = .35, respectively). Gemcitabine plus capecitabine had a 21% reduction of death following recurrence compared with monotherapy (HR, 0.79; 95% CI, 0.64-0.98; P = .03). Conclusions and Relevance: There were no significant differences between the time to recurrence and subsequent and overall survival between local and distant recurrence. Pancreatic cancer behaves as a systemic disease requiring effective systemic therapy after resection. Trial Registration: ClinicalTrials.gov identifier: NCT00058201, EudraCT 2007-004299-38, and ISRCTN 96397434.

EXTRA--a multicenter phase II study of chemoradiation using a 5 day per week oral regimen of capecitabine and intravenous mitomycin C in anal cancer.

PURPOSE: 5-Fluorouracil (5-FU) + mitomycin C (MMC)-based chemoradiotherapy is standard treatment for patients with epidermoid anal carcinoma. Clinical trials in other cancers have confirmed 5-FU can successfully be replaced by the oral fluoropyrimidine capecitabine. This phase II trial aimed to determine the feasibility, toxicity, and efficacy of capecitabine, MMC and radiotherapy (RT) in anal cancer patients. METHODS AND MATERIALS: Radiotherapy comprised the schedule of the UK Anal Cancer Trial (ACT) II trial (50.4 Gy in 28 fractions of 1.8 Gy). With MMC (12 mg/m2) on Day 1 and capecitabine on each RT treatment day in two divided doses (825 mg/m2 b.i.d). The endpoints were complete response at 4 weeks, local control at 6 months and toxicity. RESULTS: Thirty-one patients entered the trial. The median age was 61 years (range 45-86) with 14 males and 17 females. Compliance with chemotherapy with no dose interruptions or delays was 68%, and with RT was 81%. Eighteen (58%) patients completed both modalities of treatment as planned. Dose-limiting Grade 3 or 4 diarrhea was seen in 1 of 31 patients. Three patients experienced Grade 3 neutropenia. There were no treatment-related deaths. Four weeks following completion of chemoradiation, 24 patients (77%) had a complete clinical response, and 4 (16%) a partial response. With a median follow-up of 14 months, three locoregional relapses occurred. CONCLUSIONS: Capecitabine with MMC and RT in with patients anal carcinoma is well tolerated, with minimal toxicity and acceptable compliance. We recommend testing this schedule in future national Phase III studies in anal cancer.

Health-Related Quality of Life in SCALOP, a Randomized Phase 2 Trial Comparing Chemoradiation Therapy Regimens in Locally Advanced Pancreatic Cancer.

PURPOSE: Chemoradiation therapy (CRT) for patients with locally advanced pancreatic cancer (LAPC) provides survival benefits but may result in considerable toxicity. Health-related quality of life (HRQL) measurements during CRT have not been widely reported. This paper reports HRQL data from the Selective Chemoradiation in Advanced Localised Pancreatic Cancer (SCALOP) trial, including validation of the QLQ-PAN26 tool in CRT. METHODS AND MATERIALS: Patients with locally advanced, inoperable, nonmetastatic carcinoma of the pancreas were eligible. Following 12 weeks of induction gemcitabine plus capecitabine (GEMCAP) chemotherapy, patients with stable and responding disease were randomized to a further cycle of GEMCAP followed by capecitabine- or gemcitabine-based CRT. HRQL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the EORTC Pancreatic Cancer module (PAN26). RESULTS: A total of 114 patients from 28 UK centers were registered and 74 patients randomized. There was improvement in the majority of HRQL scales during induction chemotherapy. Patients with significant deterioration in fatigue, appetite loss, and gastrointestinal symptoms during CRT recovered within 3 weeks following CRT. Differences in changes in HRQL scores between trial arms rarely reached statistical significance; however, where they did, they favored capecitabine therapy. PAN26 scales had good internal consistency and were able to distinguish between subgroups of patients experiencing toxicity. CONCLUSIONS: Although there is deterioration in HRQL following CRT, this resolves within 3 weeks. HRQL data support the use of capecitabine- over gemcitabine-based chemoradiation. The QLQ-PAN26 is a reliable and valid tool for use in patients receiving CRT.

"Mind the gap"--the impact of variations in the duration of the treatment gap and overall treatment time in the first UK Anal Cancer Trial (ACT I).

PURPOSE: The United Kingdom Coordinating Committee on Cancer Research anal cancer trial demonstrated the benefit of combined modality treatment (CMT) using radiotherapy (RT), infusional 5-fluorouracil, and mitomycin C over RT alone. The present study retrospectively examines the impact of the recommended 6-week treatment gap and local RT boost on long-term outcome. METHODS AND MATERIALS: A total of 577 patients were randomly assigned RT alone or CMT. After a 6-week gap responders received a boost using either additional external beam radiotherapy (EBRT) (15 Gy) or iridium-192 implant (25 Gy). The effect of boost, the gap between initial treatment (RT alone or CMT) and boost (Tgap), and overall treatment time (OTT) were examined for their impact on outcome. RESULTS: Among the 490 good responders, 436 (89%) patients received a boost after initial treatment. For boosted patients, the risk of anal cancer death decreased by 38% (hazard ratio [HR]: 0.62, 99% CI 0.35-1.12; p=0.04), but there was no evidence this was mediated via a reduction in locoregional failure (LRF) (HR: 0.90, 99% CI 0.48-1.68; p=0.66). The difference in Tgap was only 1.4 days longer for EBRT boost, compared with implant (p=0.51). OTT was longer by 6.1 days for EBRT (p=0.006). Tgap and OTT were not associated with LRF. Radionecrosis was reported in 8% of boosted, compared with 0% in unboosted patients (p=0.03). CONCLUSIONS: These results question the benefit of a radiotherapy boost after a 6-week gap. The higher doses of a boost may contribute more to an increased risk of late morbidity, rather than local control.