Summary Background Induction of a clinical complete response with chemoradiotherapy, followed by observation via a watch-and-wait approach, has emerged as a management option for patients with rectal ...cancer. We aimed to address the shortage of evidence regarding the safety of the watch-and-wait approach by comparing oncological outcomes between patients managed by watch and wait who achieved a clinical complete response and those who had surgical resection (standard care). Methods Oncological Outcomes after Clinical Complete Response in Patients with Rectal Cancer (OnCoRe) was a propensity-score matched cohort analysis study, that included patients of all ages diagnosed with rectal adenocarcinoma without distant metastases who had received preoperative chemoradiotherapy (45 Gy in 25 daily fractions with concurrent fluoropyrimidine-based chemotherapy) at a tertiary cancer centre in Manchester, UK, between Jan 14, 2011, and April 15, 2013. Patients who had a clinical complete response were offered management with the watch-and-wait approach, and patients who did not have a complete clinical response were offered surgical resection if eligible. We also included patients with a clinical complete response managed by watch and wait between March 10, 2005, and Jan 21, 2015, across three neighbouring UK regional cancer centres, whose details were obtained through a registry. For comparative analyses, we derived one-to-one paired cohorts of watch and wait versus surgical resection using propensity-score matching (including T stage, age, and performance status). The primary endpoint was non-regrowth disease-free survival from the date that chemoradiotherapy was started, and secondary endpoints were overall survival, and colostomy-free survival. We used a conservative p value of less than 0·01 to indicate statistical significance in the comparative analyses. Findings 259 patients were included in our Manchester tertiary cancer centre cohort, 228 of whom underwent surgical resection at referring hospitals and 31 of whom had a clinical complete response, managed by watch and wait. A further 98 patients were added to the watch-and-wait group via the registry. Of the 129 patients managed by watch and wait (median follow-up 33 months IQR 19–43), 44 (34%) had local regrowths (3-year actuarial rate 38% 95% CI 30–48); 36 (88%) of 41 patients with non-metastatic local regrowths were salvaged. In the matched analyses (109 patients in each treatment group), no differences in 3-year non-regrowth disease-free survival were noted between watch and wait and surgical resection (88% 95% CI 75–94 with watch and wait vs 78% 63–87 with surgical resection; time-varying p=0·043). Similarly, no difference in 3-year overall survival was noted (96% 88–98 vs 87% 77–93; time-varying p=0·024). By contrast, patients managed by watch and wait had significantly better 3-year colostomy-free survival than did those who had surgical resection (74% 95% CI 64–82 vs 47% 37–57; hazard ratio 0·445 95% CI 0·31–0·63; p<0·0001), with a 26% (95% CI 13–39) absolute difference in patients who avoided permanent colostomy at 3 years between treatment groups. Interpretation A substantial proportion of patients with rectal cancer managed by watch and wait avoided major surgery and averted permanent colostomy without loss of oncological safety at 3 years. These findings should inform decision making at the outset of chemoradiotherapy. Funding Bowel Disease Research Foundation.
Summary 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/m2 on day 1) or cisplatin (60 mg/m2 on days 1 and 29), with fluorouracil (1000 mg/m2 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.
Summary Background Definitive chemoradiotherapy (CRT) is an alternative to surgery for the curative treatment of oesophageal carcinoma. The SCOPE1 trial aimed to investigate the addition of cetuximab ...to cisplatin and fluoropyrimidine-based definitive CRT in patients with localised oesophageal squamous-cell cancer and adenocarcinomas to assess activity, safety, and feasibility of use. Methods In this multicentre, randomised, open-label, phase 2/3 trial, we recruited patients aged 18 years and older from UK radiotherapy centres who had non-metastatic, histologically confirmed carcinoma of the oesophagus (adenocarcinoma, squamous-cell, or undifferentiated; WHO status 0–1; stage I–III disease) and been selected to receive definitive CRT. Patients were randomly assigned (1:1) via a central computerised system using stratified minimisation (with an 80:20 random element) to receive CRT alone or CRT with cetuximab (400 mg/m2 on day 1 followed by 250 mg/m2 weekly), stratified by recruiting hospital, primary reason for not having surgery, tumour histology, and tumour stage. CRT consisted of cisplatin 60 mg/m2 (day 1) and capecitabine 625 mg/m2 twice daily (days 1–21) for four cycles; cycles three and four were given concurrently with 50 Gy in 25 fractions of radiotherapy. The primary endpoint was the proportion of patients who were treatment failure free at week 24 for the phase 2 trial and overall survival for the phase 3 trial, both measured from randomisation. We analysed data by intention to treat. This trial is an International Standard Randomised Controlled Trial, number 47718479. Findings 258 patients (129 assigned to each treatment group) from 36 UK centres were recruited between Feb 7, 2008, and Feb 22, 2012. Recruitment was stopped without continuation to phase 3 because the trial met criteria for futility, but we continued to follow-up recruited patients until all had reached at least 24-week follow-up (median follow-up of patients who survived was 16·8 months IQR 11·2–24·5). Fewer patients were treatment failure free at 24 weeks in the CRT plus cetuximab group (79 of 119 patients 66·4%, 90% CI 58·6–73·6) than in the CRT only group (93 of 121 patients 76·9%, 69·7–83·0). The CRT plus cetuximab group also had shorter median overall survival (22·1 months 95% CI 15·1–24·5 vs 25·4 months 20·5–37·9; adjusted HR 1·53 95% CI 1·03–2·27; p=0·035). Patients who received CRT plus cetuximab had more non-haematological grade 3 or 4 toxicities (102 79% of 129 patients vs 81 63% of 129 patients; p=0·004). The most common grade 3 or 4 toxicities were low white blood cell count (14 11% in the CRT plus cetuximab group vs 21 16% in the CRT only group), low absolute neutrophil count (15 12% vs 24 19%), fatigue (26 20% vs 25 19%), and dysphagia (35 27% vs 37 29%). Interpretation The addition of cetuximab to standard chemotherapy and radiotherapy cannot be recommended for patients with oesophageal cancer suitable for definitive CRT. Funding Cancer Research UK.
Pre-analytical factors can significantly affect circulating cell-free DNA (cfDNA) analysis. However, there are few robust methods to rapidly assess sample quality and the impact of pre-analytical ...processing. To address this gap and to evaluate effects of DNA extraction methods and blood collection tubes on cfDNA yield and fragment size, we developed a multiplexed droplet digital PCR (ddPCR) assay with 5 short and 4 long amplicons targeting single copy genomic loci. Using this assay, we compared 7 cfDNA extraction kits and found cfDNA yield and fragment size vary significantly. We also compared 3 blood collection protocols using plasma samples from 23 healthy volunteers (EDTA tubes processed within 1 hour and Cell-free DNA Blood Collection Tubes processed within 24 and 72 hours) and found no significant differences in cfDNA yield, fragment size and background noise between these protocols. In 219 clinical samples, cfDNA fragments were shorter in plasma samples processed immediately after venipuncture compared to archived samples, suggesting contribution of background DNA by lysed peripheral blood cells. In summary, we have described a multiplexed ddPCR assay to assess quality of cfDNA samples prior to downstream molecular analyses and we have evaluated potential sources of pre-analytical variation in cfDNA studies.
Colorectal cancer is the third most common cancer in the world. Despite surgery, up to 50% of patients relapse with incurable disease. First-line chemotherapy uses the topoisomerase 1 (TOP1) poison ...irinotecan, which triggers cell death by trapping TOP1 on DNA. The removal of TOP1 peptide from TOP1-DNA breaks is conducted by tyrosyl-DNA phosphodiesterase 1 (TDP1). Despite putative roles for TDP1 and TOP1 in colorectal cancer, their role in cellular and clinical responses to TOP1-targeting therapies remains unclear. Here, we show varying expression levels of TOP1 and TDP1 polypeptides in multiple colorectal cancer cell lines and in clinical colorectal cancer samples. TDP1 overexpression or TOP1 depletion is protective. Conversely, TDP1 depletion increases DNA-strand breakage and hypersensitivity to irinotecan in a TOP1-dependent manner, presenting a potential therapeutic opportunity in colorectal cancer. TDP1 protein levels correlate well with mRNA and with TDP1 catalytic activity. However, no correlation is observed between inherent TDP1 or TOP1 levels alone and irinotecan sensitivity, pointing at their limited utility as predictive biomarkers in colorectal cancer. These findings establish TDP1 as a potential therapeutic target for the treatment of colorectal cancer and question the validity of TOP1 or TDP1 on their own as predictive biomarkers for irinotecan response.
Summary Background When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve ...both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim. Methods COIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1·162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448. Findings 1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15·8 months (IQR 9·4–26·1) in arm A and 14·4 months (8·0–24·7) in arm C (hazard ratio HR 1·084, 80% CI 1·008–1·165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19·6 months (13·0–28·1) in arm A and 18·0 months (12·1–29·3) in arm C (HR 1·087, 0·986–1·198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400 000 per μL or higher (271 28% of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0·96 (95% CI 0·80–1·15, p=0·66), versus 1·54 (1·17–2·03, p=0·0018) in patients with a raised platelet count (p=0·0027 for interaction). In the per-protocol population, more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects (72 15% vs 60 12%), whereas nausea and vomiting were more common on intermittent treatment (11 2% vs 43 8%). Grade 3 or worse peripheral neuropathy (126 27% vs 25 5%) and hand–foot syndrome (21 4% vs 15 3%) were more frequent on continuous than on intermittent treatment. Interpretation Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life. Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break. Funding Cancer Research UK.
The role of prophylactic antibacterial agents after chemotherapy remains controversial.
We conducted a randomized, double-blind, placebo-controlled trial in patients who were receiving cyclic ...chemotherapy for solid tumors or lymphoma and who were at risk for temporary, severe neutropenia (fewer than 500 neutrophils per cubic millimeter). Patients were randomly assigned to receive either 500 mg of levofloxacin once daily or matching placebo for seven days during the expected neutropenic period. The primary outcome was the incidence of clinically documented febrile episodes (temperature of more than 38 degrees C) attributed to infection. Secondary outcomes included the incidence of all probable infections, severe infections, and hospitalization but did not include a systematic evaluation of antibacterial resistance.
A total of 1565 patients underwent randomization (784 to placebo and 781 to levofloxacin). The tumors included breast cancer (35.4 percent), lung cancer (22.5 percent), testicular cancer (14.4 percent), and lymphoma (12.8 percent). During the first cycle of chemotherapy, 3.5 percent of patients in the levofloxacin group had at least one febrile episode, as compared with 7.9 percent in the placebo group (P<0.001). During the entire chemotherapy course, 10.8 percent of patients in the levofloxacin group had at least one febrile episode, as compared with 15.2 percent of patients in the placebo group (P=0.01); the respective rates of probable infection were 34.2 percent and 41.5 percent (P=0.004). Hospitalization was required for the treatment of infection in 15.7 percent of patients in the levofloxacin group and 21.6 percent of patients in the placebo group (P=0.004). The respective rate of severe infection was 1.0 percent and 2.0 percent (P=0.15), with four infection-related deaths in each group. An organism was isolated in 9.2 percent of probable infections.
Among patients receiving chemotherapy for solid tumors or lymphoma, the prophylactic use of levofloxacin reduces the incidence of fever, probable infection, and hospitalization.
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.
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.
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.
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.
IntroductionThe standard of care for patients with localised rectal cancer is radical surgery, often combined with preoperative neoadjuvant (chemo)radiotherapy. While oncologically effective, this ...treatment strategy is associated with operative mortality risks, significant morbidity and stoma formation. An alternative approach is chemoradiotherapy to try to achieve a sustained clinical complete response (cCR). This non-surgical management can be attractive, particularly for patients at high risk of surgical complications. Modern radiotherapy techniques allow increased treatment conformality, enabling increased radiation dose to the tumour while reducing dose to normal tissue. The objective of this trial is to assess if radiotherapy dose escalation increases the cCR rate, with acceptable toxicity, for treatment of patients with early rectal cancer unsuitable for radical surgery.Methods and analysisAPHRODITE (A Phase II trial of Higher RadiOtherapy Dose In The Eradication of early rectal cancer) is a multicentre, open-label randomised controlled phase II trial aiming to recruit 104 participants from 10 to 12 UK sites. Participants will be allocated with a 2:1 ratio of intervention:control. The intervention is escalated dose radiotherapy (62 Gy to primary tumour, 50.4 Gy to surrounding mesorectum in 28 fractions) using simultaneous integrated boost. The control arm will receive 50.4 Gy to the primary tumour and surrounding mesorectum. Both arms will use intensity-modulated radiotherapy and daily image guidance, combined with concurrent chemotherapy (capecitabine, 5-fluorouracil/leucovorin or omitted). The primary endpoint is the proportion of participants with cCR at 6 months after start of treatment. Secondary outcomes include early and late toxicities, time to stoma formation, overall survival and patient-reported outcomes (European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires QLQ-C30 and QLQ-CR29, low anterior resection syndrome (LARS) questionnaire).Ethics and disseminationThe trial obtained ethical approval from North West Greater Manchester East Research Ethics Committee (reference number 19/NW/0565) and is funded by Yorkshire Cancer Research. The final trial results will be published in peer-reviewed journals and adhere to International Committee of Medical Journal Editors guidelines.Trial registration numberISRCTN16158514.
Primary squamous cell carcinoma of the pancreas is a rare tumor with poor prognosis and is found in the literature only as case reports. The optimal management course remains poorly defined. We ...present a case of primary basaloid squamous cell carcinoma of the pancreas metastatic to the liver, which was treated with surgery and systemic chemotherapy. Our patient survived for 15 months: the longest survival reported in the literature to date.
A 70-year-old Caucasian man presented to hospital with a three-month history of weight loss, pruritus and icterus. Imaging studies confirmed the presence of an operable mass lesion in the head of the pancreas. Following a pancreaticoduodenectomy, histology results led us to make a diagnosis of squamous cell carcinoma. Postoperative restaging showed multiple metastases in the liver. He underwent palliative systemic chemotherapy with cisplatin and 5-fluorouracil achieving partial response and an excellent quality of life. He then went on to start second-line chemotherapy, but unfortunately died of sepsis soon thereafter.
This case report emphasizes that achievement of a worthwhile objective and symptomatic palliative response is possible using platinum-based chemotherapy in squamous cell carcinoma of the pancreas.
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