Latha Kadalayil

Ablation with Low-Dose Radioiodine and Thyrotropin Alfa in Thyroid Cancer

BACKGROUND It is not known whether low-dose radioiodine (1.1 GBq [30 mCi]) is as effective as high-dose radioiodine (3.7 GBq [100 mCi]) for treating patients with differentiated thyroid cancer or whether the effects of radioiodine (especially at a low dose) are influenced by using either recombinant human thyrotropin (thyrotropin alfa) or thyroid hormone withdrawal. METHODS At 29 centers in the United Kingdom, we conducted a randomized noninferiority trial comparing low-dose and high-dose radioiodine, each in combination with either thyrotropin alfa or thyroid hormone withdrawal before ablation. Patients (age range, 16 to 80 years) had tumor stage T1 to T3, with possible spread to nearby lymph nodes but without metastasis. End points were the rate of success of ablation at 6 to 9 months, adverse events, quality of life, and length of hospital stay. RESULTS A total of 438 patients underwent randomization; data could be analyzed for 421. Ablation success rates were 85.0% in the group receiving low-dose radioiodine versus 88.9% in the group receiving the high dose and 87.1% in the thyrotropin alfa group versus 86.7% in the group undergoing thyroid hormone withdrawal. All 95% confidence intervals for the differences were within ±10 percentage points, indicating noninferiority. Similar results were found for low-dose radioiodine plus thyrotropin alfa (84.3%) versus high-dose radioiodine plus thyroid hormone withdrawal (87.6%) or high-dose radioiodine plus thyrotropin alfa (90.2%). More patients in the high-dose group than in the low-dose group were hospitalized for at least 3 days (36.3% vs. 13.0%, P<0.001). The proportions of patients with adverse events were 21% in the low-dose group versus 33% in the high-dose group (P=0.007) and 23% in the thyrotropin alfa group versus 30% in the group undergoing thyroid hormone withdrawal (P=0.11). CONCLUSIONS Low-dose radioiodine plus thyrotropin alfa was as effective as high-dose radioiodine, with a lower rate of adverse events. (Funded by Cancer Research UK; ClinicalTrials.gov number, NCT00415233.).

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.

Chemoradiotherapy for locally advanced head and neck cancer: 10-year follow-up of the UK Head and Neck (UKHAN1) trial.

Summary Background Between 1990 and 2000, we examined the effect of timing of non-platinum chemotherapy when combined with radiotherapy. We aimed to determine whether giving chemotherapy concurrently with radiotherapy or as maintenance therapy, or both, affected clinical outcome. Here we report survival and recurrence after 10 years of follow-up. Methods Between Jan 15, 1990, and June 20, 2000, 966 patients were recruited from 34 centres in the UK and two centres from Malta and Turkey. Patients with locally advanced head and neck cancer, and who had not previously undergone surgery, were randomly assigned to one of four groups in a 3:2:2:2 ratio, stratified by centre and chemotherapy regimen: radical radiotherapy alone (n=233); radiotherapy with two courses of chemotherapy given simultaneously on days 1 and 14 of radiotherapy (SIM alone; n=166); or 14 and 28 days after completing radiotherapy (SUB alone, n=160); or both (SIM+SUB; n=154). Chemotherapy was either methotrexate alone, or vincristine, bleomycin, methotrexate, and fluorouracil. Patients who had previously undergone radical surgery to remove their tumour were only randomised to radiotherapy alone (n=135) or SIM alone (n=118), in a 3:2 ratio. The primary endpoints were overall survival (from randomisation), and event-free survival (EFS; recurrence, new tumour, or death; whichever occurred first) among patients who were disease-free 6 months after randomisation. Analyses were by intention to treat. This trial is registered at www.Clinicaltrials.gov, number NCT00002476. Findings All 966 patients were included in the analyses. Among patients who did not undergo surgery, the median overall survival was 2·6 years (99% CI 1·9–4·2) in the radiotherapy alone group, 4·7 (2·6–7·8) years in the SIM alone group, 2·3 (1·6–3·5) years in the SUB alone group, and 2·7 (1·6–4·7) years in the SIM+SUB group (p=0·10). The corresponding median EFS were 1·0 (0·7–1·4), 2·2 (1·1–6·0), 1·0 (0·6–1·5), and 1·0 (0·6–2·0) years (p=0·005), respectively. For every 100 patients given SIM alone, there are 11 fewer EFS events (99% CI 1–21), compared with 100 given radiotherapy, 10 years after treatment. Among the patients who had previously undergone surgery, median overall survival was 5·0 (99% CI 1·8–8·0) and 4·6 (2·2–7·6) years in the radiotherapy alone and SIM alone groups (p=0·70), respectively, with corresponding median EFS of 3·7 (99% CI 1·1–5·9) and 3·0 (1·2–5·6) years (p=0·85), respectively. The percentage of patients who had a significant toxicity during treatment were: 11% (radiotherapy alone, n=25), 28% (SIM alone, n=47), 12% (SUB alone, n=19), and 36% (SIM+SUB, n=55) among patients without previous surgery; and 9% (radiotherapy alone, n=12) and 20% (SIM alone, n=24) among those who had undergone previous surgery. The most common toxicity during treatment was mucositis. The percentage of patients who had a significant toxicity at least 6 months after randomisation were: 6% (radiotherapy alone, n=13), 6% (SIM alone, n=10), 4% (SUB alone, n=7), and 6% (SIM+SUB, n=9) among patients who had no previous surgery; and 7% (radiotherapy alone, n=10) and 11% (SIM alone, n=13) among those who had undergone previous surgery. The most common toxicity 6 months after treatment was xerostomia, but this occurred in 3% or less of patients in each group. Interpretation Concurrent non-platinum chemoradiotherapy reduces recurrences, new tumours, and deaths in patients who have not undergone previous surgery, even 10 years after starting treatment. Chemotherapy given after radiotherapy (with or without concurrent chemotherapy) is ineffective. Patients who have undergone previous surgery for head and neck cancer do not benefit from non-platinum chemotherapy. Funding Cancer Research UK, with support from University College London and University College London Hospital Comprehensive Biomedical Research Centre.

Exome sequence read depth methods for identifying copy number changes

Copy number variants (CNVs) play important roles in a number of human diseases and in pharmacogenetics. Powerful methods exist for CNV detection in whole genome sequencing (WGS) data, but such data are costly to obtain. Many disease causal CNVs span or are found in genome coding regions (exons), which makes CNV detection using whole exome sequencing (WES) data attractive. If reliably validated against WGS-based CNVs, exome-derived CNVs have potential applications in a clinical setting. Several algorithms have been developed to exploit exome data for CNV detection and comparisons made to find the most suitable methods for particular data samples. The results are not consistent across studies. Here, we review some of the exome CNV detection methods based on depth of coverage profiles and examine their performance to identify problems contributing to discrepancies in published results. We also present a streamlined strategy that uses a single metric, the likelihood ratio, to compare exome methods, and we demonstrated its utility using the VarScan 2 and eXome Hidden Markov Model (XHMM) programs using paired normal and tumour exome data from chronic lymphocytic leukaemia patients. We use array-based somatic CNV (SCNV) calls as a reference standard to compute prevalence-independent statistics, such as sensitivity, specificity and likelihood ratio, for validation of the exome-derived SCNVs. We also account for factors known to influence the performance of exome read depth methods, such as CNV size and frequency, while comparing our findings with published results.

Best time to assess complete clinical response after chemoradiotherapy in squamous cell carcinoma of the anus (ACT II): a post-hoc analysis of randomised controlled phase 3 trial

Summary Background Guidelines for anal cancer recommend assessment of response at 6–12 weeks after starting treatment. Using data from the ACT II trial, we determined the optimum timepoint to assess clinical tumour response after chemoradiotherapy. Methods The previously reported ACT II trial was a phase 3 randomised trial of patients of any age with newly diagnosed, histologically confirmed, squamous cell carcinoma of the anus without metastatic disease from 59 centres in the UK. We randomly assigned patients (by minimisation) to receive either intravenous mitomycin (one dose of 12 mg/m2 on day 1) or intravenous cisplatin (one dose of 60 mg/m2 on days 1 and 29), with intravenous fluorouracil (one dose of 1000 mg/m2 per day on days 1–4 and 29–32) and radiotherapy (50·4 Gy in 28 daily fractions); and also did a second randomisation after initial therapy to maintenance chemotherapy (fluorouracil and cisplatin) or no maintenance chemotherapy. The primary outcome was complete clinical response (the absence of primary and nodal tumour by clinical examination), in addition to overall survival and progression-free survival from time of randomisation. In this post-hoc analysis, we analysed complete clinical response at three timepoints: 11 weeks from the start of chemoradiotherapy (assessment 1), 18 weeks from the start of chemoradiotherapy (assessment 2), and 26 weeks from the start of chemoradiotherapy (assessment 3) as well as the overall and progression-free survival estimates of patients with complete clinical response or without complete clinical response at each assessment. We analysed both the overall trial population and a subgroup of patients who had attended each of the three assessments by modified intention-to-treat. This study is registered at controlled-trials.com, ISRCTN 26715889. Findings We enrolled 940 patients from June 4, 2001, until Dec 16, 2008. Complete clinical response was achieved in 492 (52%) of 940 patients at assessment 1 (11 weeks), 665 (71%) of patients at assessment 2 (18 weeks), and 730 (78%) of patients at assessment 3 (26 weeks). 691 patients attended all three assessments and in this subgroup, complete clinical response was reported in 441 (64%) patients at assessment 1, 556 (80%) at assessment 2, and 590 (85%) at assessments 3. 151 (72%) of the 209 patients who had not had a complete clinical response at assessment 1 had a complete clinical response by assessment 3. In the overall trial population of 940 patients, 5 year overall survival in patients who had a clinical response at assessments 1, 2, 3 was 83% (95% CI 79–86), 84% (81–87), and 87% (84–89), respectively and was 72% (66–78), 59% (49–67), and 46% (37–55) for patients who did not have a complete clinical response at assessments 1, 2, 3, respectively. In the subgroup of 691 patients, 5 year overall survival in patients who had a clinical response at assessment 1, 2, 3 was 85% (81–88), 86% (82–88), and 87% (84–90), respectively, and was 75% (68–80), 61% (50–70), and 48% (36–58) for patients who did not have a complete clinical response at assessment 1, 2, 3, respectively. Similarly, progression-free survival in both the overall trial population and the subgroup was longer in patients who had a complete clinical response, compared with patients who did not have a complete clinical response, at all three assessments. Interpretation Many patients who do not have a complete clinical response when assessed at 11 weeks after commencing chemoradiotherapy do in fact respond by 26 weeks, and the earlier assessment could lead to some patients having unnecessary surgery. Our data suggests that the optimum time for assessment of complete clinical response after chemoradiotherapy for patients with squamous cell carcinoma of the anus is 26 weeks from starting chemoradiotherapy. We suggest that guidelines should be revised to indicate that later assessment is acceptable. Funding Cancer Research UK.

Tumour- and treatment-related colostomy rates following mitomycin C or cisplatin chemoradiation with or without maintenance chemotherapy in squamous cell carcinoma of the anus in the ACT II trial

BACKGROUND Squamous cell carcinoma of the anus (SCCA) is highly sensitive to chemoradiation (CRT) which achieves good loco-regional control and preserves anal function. However, some patients require permanent stoma formation either as a result of surgery on relapse, poor anal function or treatment-related symptoms. Our aim was to determine patient, tumour and treatment-related colostomy rates following CRT and maintenance chemotherapy in the ACT II trial. PATIENTS AND METHODS The ACT II trial recruited 940 patients comparing 5FU-based CRT using cisplatin (CisP) or mitomycin C (MMC) with or without additional maintenance chemotherapy. We investigated the association between colostomy-free survival (CFS) and progression-free survival (PFS) with age, gender, T-stage, N-stage, treatment and baseline haemoglobin. RESULTS The median follow-up was 5.1 years (n = 884 evaluable/940); tumour site canal (84%), margin (14%); stage T1/T2 (52%), T3/T4 (46%); N+ (32%), N0 (62%). Twenty out of 118 (17%) colostomies fashioned before CRT were reversed within 8 months. One hundred and twelve patients had a post-treatment colostomy due to persistent disease (98) or morbidity (14). Fifty-two per cent (61/118) of all pre-treatment colostomies were never reversed. The 5-year CFS rates were 68% MMC/Maint, 70% CisP/Maint, 68% MMC/No-maint and 65% CisP/No-maint. CRT with CisP did not improve CFS when compared with MMC (hazard ratio: 1.04, 95% confidence interval: 0.82-1.31, P = 0.74). The 5-year CFS rates were higher for T1/T2 (79%) than T3/T4 (54%) tumours and higher for node-negative (72%) than node-positive (60%) patients. Significant predictors of CFS were gender, T-stage and haemoglobin, while treatment factors had no impact on outcome. Similar associations were found between PFS and tumour/treatment-related factors. CONCLUSIONS The majority (52%) of pre-treatment colostomies were never reversed. Neither CRT with 5FU/CisP nor maintenance chemotherapy impacted on CFS. The low risk of colostomy for late effects (1.7%) is likely to be associated with the modest total radiotherapy dose. The predictive factors for CFS were T-stage, gender and baseline haemoglobin. CLINICAL TRIAL REGISTRATION NUMBER ISRCTN 26715889.

Telomere length predicts progression and overall survival in chronic lymphocytic leukemia: data from the UK LRF CLL4 trial

Telomere length predicts progression and overall survival in chronic lymphocytic leukemia: data from the UK LRF CLL4 trial

Non-coding NOTCH1 mutations in chronic lymphocytic leukemia; their clinical impact in the UK CLL4 trial

Non-coding NOTCH1 mutations in chronic lymphocytic leukemia; their clinical impact in the UK CLL4 trial

Capturing Data on Colostomy Formation in Anal Cancer

TO THE EDITOR: The authors of the recent article by Peiffert et al are to be congratulated because randomized trials in anal cancer are difficult toperform.Theirprimaryendpointwascolostomy-freesurvival, which was defined as a definitive colostomy for progression, relapse, or complicationatthetimeofanalysis,andtheydidnotincludepatientswho had undergone a colostomy that was eventually reversed. Therefore, we are surprised that, in Figure 3, which depicts actuarial colostomy-free survival, the y-axis starts at 100%. Were there no patients who had an initial colostomy for symptoms in whom this was never reversed? Current conventional descriptions of colostomy in anal cancer trials fail to capture the data accurately. Colostomy-free survival or cumulative colostomy rates are frequently reported, or the rate of colostomies at specific time-points is reported. However, several series have noted that, among patients who receive a pretreatment colostomy, despite subsequent local disease control, failure to reverse the colostomy is almost invariable. However, although this could initially be considered cause specific, the definition would seem inaccurate in patients who achieve long-term control. This difficult issue was highlighted in a recent correspondence. A baseline pretreatment colostomy that was that was fashioned because of symptoms before radiotherapy was considered by Sunesen et al as a tumor-related colostomy. It is vital to capture this information if we are to compare different treatments. The RTOG (Radiation Therapy Oncology Group) 98-11 study described persistent or recurrent anal carcinoma as being responsible for 62 of 80 patients having a colostomy (78%), but 16 patients (20%) were coded as treatment-related in patients with no evidence of disease (treatment complications or sphincter dysfunction as a result of a previous tumor invasion or destruction), and two patients were coded as having both reasons. The recent classification of Sunesen et al should be extended to include separately a third group of patients (5% to 12% of all patients, depending on the stage) who require a baseline colostomy pretreatment in anal cancer for incontinence, fistula formation, and/or pain on defecation. We recommend the following definitions: (1) a colostomy is classified as a tumor-related colostomy if the patient had evidence of anal cancer at the time of the surgery either for a defunctioning stoma to allay symptoms or a salvage APER (which clearly will not be reversed); (2) a colostomy is classified as a treatment-related colostomy if it was performed either during chemoradiotherapy or after the completion of chemoradiotherapy, and the patient had no histologic evidence of cancer; or (3) a colostomy is classified as a baseline pretreatment-colostomy if the colostomy was created before chemoradiotherapy because of a fistula or intolerable symptoms from the tumor. This may be reversed if the patient achieves local control, although in practice this is unlikely. If the tumor never goes into remission and the patient never achieves a clinical CR, this colostomy should be considered tumor-related at the 6-month time point (Fig 1). A common language according to these definitions would give greater clarity in the future.

Meta-analysis of three genome-wide association studies identifies two loci that predict survival and treatment outcome in breast cancer

The majority of breast cancers are driven by the female hormone oestrogen via oestrogen receptor (ER) alpha. ER-positive patients are commonly treated with adjuvant endocrine therapy, however, resistance is a common occurrence and aside from ER-status, no unequivocal predictive biomarkers are currently in clinical use. In this study, we aimed to identify constitutional genetic variants influencing breast cancer survival among ER-positive patients and specifically, among endocrine-treated patients. We conducted a meta-analysis of three genome-wide association studies comprising in total 3,136 patients with ER-positive breast cancer of which 2,751 had received adjuvant endocrine therapy. We identified a novel locus (rs992531 at 8p21.2) associated with reduced survival among the patients with ER-positive breast cancer (P = 3.77 × 10−8). Another locus (rs7701292 at 5q21.3) was associated with reduced survival among the endocrine-treated patients (P = 2.13 × 10−8). Interaction analysis indicated that the survival association of rs7701292 is treatment-specific and independent of conventional prognostic markers. In silico functional studies suggest plausible biological mechanisms for the observed survival associations and a functional link between the putative target genes of the rs992531 and rs7701292 (RHOBTB2 and RAB9P1, respectively). We further explored the genetic interaction between rs992531 and rs7701292 and found a significant, treatment-specific interactive effect on survival among ER-positive, endocrine-treated patients (hazard ratio = 6.97; 95% confidence interval, 1.79–27.08, Pinteraction = 0.036). This is the first study to identify a genetic interaction that specifically predicts treatment outcome. These findings may provide predictive biomarkers based on germ line genotype informing more personalized treatment selection.