David Sebag-Montefiore

Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial

Summary Background Preoperative or postoperative radiotherapy reduces the risk of local recurrence in patients with operable rectal cancer. However, improvements in surgery and histopathological assessment mean that the role of radiotherapy needs to be reassessed. We compared short-course preoperative radiotherapy versus initial surgery with selective postoperative chemoradiotherapy. Methods We undertook a randomised trial in 80 centres in four countries. 1350 patients with operable adenocarcinoma of the rectum were randomly assigned, by a minimisation procedure, to short-course preoperative radiotherapy (25 Gy in five fractions; n=674) or to initial surgery with selective postoperative chemoradiotherapy (45 Gy in 25 fractions with concurrent 5-fluorouracil) restricted to patients with involvement of the circumferential resection margin (n=676). The primary outcome measure was local recurrence. Analysis was by intention to treat. This study is registered, number ISRCTN 28785842. Findings At the time of analysis, which included all participants, 330 patients had died (157 preoperative radiotherapy group vs 173 selective postoperative chemoradiotherapy), and median follow-up of surviving patients was 4 years. 99 patients had developed local recurrence (27 preoperative radiotherapy vs 72 selective postoperative chemoradiotherapy). We noted a reduction of 61% in the relative risk of local recurrence for patients receiving preoperative radiotherapy (hazard ratio [HR] 0·39, 95% CI 0·27–0·58, p<0·0001), and an absolute difference at 3 years of 6·2% (95% CI 5·3–7·1) (4·4% preoperative radiotherapy vs 10·6% selective postoperative chemoradiotherapy). We recorded a relative improvement in disease-free survival of 24% for patients receiving preoperative radiotherapy (HR 0·76, 95% CI 0·62–0·94, p=0·013), and an absolute difference at 3 years of 6·0% (95% CI 5·3–6·8) (77·5% vs 71·5%). Overall survival did not differ between the groups (HR 0·91, 95% CI 0·73–1·13, p=0·40). Interpretation Taken with results from other randomised trials, our findings provide convincing and consistent evidence that short-course preoperative radiotherapy is an effective treatment for patients with operable rectal cancer. Funding Medical Research Council (UK) and the National Cancer Institute of Canada.

Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial

Summary Background Local recurrence rates in operable rectal cancer are improved by radiotherapy (with or without chemotherapy) and surgical techniques such as total mesorectal excision. However, the contributions of surgery and radiotherapy to outcomes are unclear. We assessed the effect of the involvement of the circumferential resection margin and the plane of surgery achieved. Methods In this prospective study, the plane of surgery achieved and the involvement of the circumferential resection margin were assessed by local pathologists, using a standard pathological protocol in 1156 patients with operable rectal cancer from the CR07 and NCIC-CTG CO16 trial, which compared short-course (5 days) preoperative radiotherapy and selective postoperative chemoradiotherapy, between March, 1998, and August, 2005. All analyses were by intention to treat. This trial is registered, number ISRCTN 28785842. Findings 128 patients (11%) had involvement of the circumferential resection margin, and the plane of surgery achieved was classified as good (mesorectal) in 604 (52%), intermediate (intramesorectal) in 398 (34%), and poor (muscularis propria plane) in 154 (13%). We found that both a negative circumferential resection margin and a superior plane of surgery achieved were associated with low local recurrence rates. Hazard ratio (HR) was 0·32 (95% CI 0·16–0·63, p=0·0011) with 3-year local recurrence rates of 6% (5–8%) and 17% (10–26%) for patients who were negative and positive for circumferential resection margin, respectively. For plane of surgery achieved, HRs for mesorectal and intramesorectal groups compared with the muscularis propria group were 0·32 (0·16–0·64) and 0·48 (0·25–0·93), respectively. At 3 years, the estimated local recurrence rates were 4% (3–6%) for mesorectal, 7% (5–11%) for intramesorectal, and 13% (8–21%) for muscularis propria groups. The benefit of short-course preoperative radiotherapy did not differ in the three plane of surgery groups (p=0·30 for trend). Patients in the short-course preoperative radiotherapy group who had a resection in the mesorectal plane had a 3-year local recurrence rate of only 1%. Interpretation In rectal cancer, the plane of surgery achieved is an important prognostic factor for local recurrence. Short-course preoperative radiotherapy reduced the rate of local recurrence for all three plane of surgery groups, almost abolishing local recurrence in short-course preoperative radiotherapy patients who had a resection in the mesorectal plane. The plane of surgery achieved should therefore be assessed and reported routinely. Funding Medical Research Council (UK) and the National Cancer Institute of Canada.

The Modern Abdominoperineal Excision: The Next Challenge After Total Mesorectal Excision

Objectives:Examine the cause of local recurrence (LR) and patient survival (S) following abdominoperineal resection (APR) and anterior resection (AR) for rectal carcinoma and the effect of introduction of total mesorectal excision (TME) on APR. Methods:A total of 608 patients underwent surgery for rectal cancer in Leeds from 1986 to 1997. CRM status and follow-up data of local recurrence and patient survival were available for 561 patients, of whom 190 underwent APR (32.4%) and 371 AR (63.3%). Also, a retrospective study of pathologic images of 93 specimens of rectal carcinoma. Results:Patients undergoing APR had a higher LR and lower survival (LR, 22.3% versus 13.5%, P = 0.002; S, 52.3% versus 65.8%, P = 0.003) than AR. LR free rates were lower in the APR group and cancer specific survival was lowered (LR, 66% versus 77%, log rank P = 0.03; S, 48% versus 59%, log rank P = 0.02). Morphometry: total area of surgically removed tissue outside the muscularis propria was smaller in APR specimens (n = 27) than AR specimens (n = 66) (P < 0.0001). Linear dimensions of transverse slices of tissue containing tumor, median posterior, and lateral measurements were smaller (P < 0.05) in the APR than the AR group. APR specimens with histologically positive CRM (n = 11) had a smaller area of tissue outside the muscularis propria (P = 0.04) compared with the CRM-negative APR specimens (n = 16). Incidence of CRM involvement in the APR group (41%) was higher than in the AR group (12%) (P = 0.006) in the 1997 to 2000 cohort. Similar results (36% and 22%) were found in the 1986 to 1997 cohort (P = 0.002). Conclusions:Patients treated by APR have a higher rate of CRM involvement, a higher LR, and poorer prognosis than AR. The frequency of CRM involvement for APR has not diminished with TME. CRM involvement in the APR specimens is related to the removal of less tissue at the level of the tumor in an APR. Where possible, a more radical operation should be considered for all low rectal cancer tumors.

Preoperative high-resolution magnetic resonance imaging can identify good prognosis stage I, II, and III rectal cancer best managed by surgery alone: a prospective, multicenter, European study.

Objective:To assess local recurrence, disease-free survival, and overall survival in magnetic resonance imaging (MRI)–predicted good prognosis tumors treated by surgery alone. Background:The MERCURY study reported that high-resolution MRI can accurately stage rectal cancer. The routine policy in most centers involved in the MERCURY study was primary surgery alone in MRI-predicted stage II or less and in MRI “good prognosis” stage III with selective avoidance of neoadjuvant therapy. Patients and Methods:Data were collected prospectively on all patients included in the MERCURY study who were staged as MRI-defined “good” prognosis tumors. “Good” prognosis included MRI-predicted safe circumferential resection margins, with MRI-predicted T2/T3a/T3b (less than 5 mm spread from muscularis propria), regardless of MRI N stage. None received preoperative or postoperative radiotherapy. Overall survival, disease-free survival, and local recurrence were calculated. Results:Of 374 patients followed up in the MERCURY study, 122 (33%) were defined as “good prognosis” stage III or less on MRI. Overall and disease-free survival for all patients with MRI “good prognosis” stage I, II and III disease at 5 years was 68% and 85%, respectively. The local recurrence rate for this series of patients predicted to have a good prognosis tumor on MRI was 3%. Conclusions:The preoperative identification of good prognosis tumors using MRI will allow stratification of patients and better targeting of preoperative therapy. This study confirms the ability of MRI to select patients who are likely to have a good outcome with primary surgery alone.

Magnetic Resonance Imaging–Detected Tumor Response for Locally Advanced Rectal Cancer Predicts Survival Outcomes: MERCURY Experience

PURPOSE To assess magnetic resonance imaging (MRI) and pathologic staging after neoadjuvant therapy for rectal cancer in a prospectively enrolled, multicenter study. METHODS In a prospective cohort study, 111 patients who had rectal cancer treated by neoadjuvant therapy were assessed for response by MRI and pathology staging by T, N and circumferential resection margin (CRM) status. Tumor regression grade (TRG) was also assessed by MRI. Overall survival (OS) was estimated by using the Kaplan-Meier product-limit method, and Cox proportional hazards models were used to determine associations between staging of good and poor responders on MRI or pathology and survival outcomes after controlling for patient characteristics. RESULTS On multivariate analysis, the MRI-assessed TRG (mrTRG) hazard ratios (HRs) were independently significant for survival (HR, 4.40; 95% CI, 1.65 to 11.7) and disease-free survival (DFS; HR, 3.28; 95% CI, 1.22 to 8.80). Five-year survival for poor mrTRG was 27% versus 72% (P = .001), and DFS for poor mrTRG was 31% versus 64% (P = .007). Preoperative MRI-predicted CRM independently predicted local recurrence (LR; HR, 4.25; 95% CI, 1.45 to 12.51). Five-year survival for poor post-treatment pathologic T stage (ypT) was 39% versus 76% (P = .001); DFS for the same was 38% versus 84% (P = .001); and LR for the same was 27% versus 6% (P = .018). The 5-year survival for involved pCRM was 30% versus 59% (P = .001); DFS, 28 versus 62% (P = .02); and LR, 56% versus 10% (P = .001). Pathology node status did not predict outcomes. CONCLUSION MRI assessment of TRG and CRM are imaging markers that predict survival outcomes for good and poor responders and provide an opportunity for the multidisciplinary team to offer additional treatment options before planning definitive surgery. Postoperative histopathology assessment of ypT and CRM but not post-treatment N status were important postsurgical predictors of outcome.

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.

Preoperative Magnetic Resonance Imaging Assessment of Circumferential Resection Margin Predicts Disease-Free Survival and Local Recurrence: 5-Year Follow-Up Results of the MERCURY Study

PURPOSE The prognostic relevance of preoperative high-resolution magnetic resonance imaging (MRI) assessment of circumferential resection margin (CRM) involvement is unknown. This follow-up study of 374 patients with rectal cancer reports the relationship between preoperative MRI assessment of CRM staging, American Joint Committee on Cancer (AJCC) TNM stage, and clinical variables with overall survival (OS), disease-free survival (DFS), and time to local recurrence (LR). PATIENTS AND METHODS Patients underwent protocol high-resolution pelvic MRI. Tumor distance to the mesorectal fascia of ≤ 1 mm was recorded as an MRI-involved CRM. A Cox proportional hazards model was used in multivariate analysis to determine the relationship of MRI assessment of CRM to survivorship after adjusting for preoperative covariates. RESULTS Surviving patients were followed for a median of 62 months. The 5-year OS was 62.2% in patients with MRI-clear CRM compared with 42.2% in patients with MRI-involved CRM with a hazard ratio (HR) of 1.97 (95% CI, 1.27 to 3.04; P < .01). The 5-year DFS was 67.2% (95% CI, 61.4% to 73%) for MRI-clear CRM compared with 47.3% (95% CI, 33.7% to 60.9%) for MRI-involved CRM with an HR of 1.65 (95% CI, 1.01 to 2.69; P < .05). Local recurrence HR for MRI-involved CRM was 3.50 (95% CI, 1.53 to 8.00; P < .05). MRI-involved CRM was the only preoperative staging parameter that remained significant for OS, DFS, and LR on multivariate analysis. CONCLUSION High-resolution MRI preoperative assessment of CRM status is superior to AJCC TNM-based criteria for assessing risk of LR, DFS, and OS. Furthermore, MRI CRM involvement is significantly associated with distant metastatic disease; therefore, colorectal cancer teams could intensify treatment and follow-up accordingly to improve survival outcomes.

Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I)

Background:The first UKCCCR Anal Cancer Trial (1996) demonstrated the benefit of chemoradiation over radiotherapy (RT) alone for treating epidermoid anal cancer, and it became the standard treatment. Patients in this trial have now been followed up for a median of 13 years.Methods:A total of 577 patients were randomised to receive RT alone or combined modality therapy using 5-fluorouracil and mitomycin C. All patients were scheduled to receive 45 Gy by external beam irradiation. Patients who responded to treatment were recommended to have boost RT, with either an iridium implant or external beam irradiation. Data on relapse and deaths were obtained until October 2007.Results:Twelve years after treatment, for every 100 patients treated with chemoradiation, there are an expected 25.3 fewer patients with locoregional relapse (95% confidence interval (CI): 17.5–32.0 fewer) and 12.5 fewer anal cancer deaths (95% CI: 4.3–19.7 fewer), compared with 100 patients given RT alone. There was a 9.1% increase in non-anal cancer deaths in the first 5 years of chemoradiation (95% CI +3.6 to +14.6), which disappeared by 10 years.Conclusions:The clear benefit of chemoradiation outweighs an early excess risk of non-anal cancer deaths, and can still be seen 12 years after treatment. Only 11 patients suffered a locoregional relapse as a first event after 5 years, which may influence the choice of end points in future studies.

Surgery for locally recurrent rectal cancer.

PURPOSEResection of locally recurrent rectal cancer after curative resection represents a difficult clinical problem and a surgical challenge. The aim of this study was to assess the outcome of a series of patients who underwent resection of locally recurrent rectal cancer with curative intent.METHODSA retrospective review was performed of 64 patients who underwent surgical exploration with a view to cure for locally recurrent rectal cancer under the care of one surgeon between April 1997 and April 2004. Details were obtained on the primary tumor and the operation, the indication for investigation of recurrence, preoperative imaging, operative findings, morbidity and mortality, and histopathology.RESULTSThe median time interval between resection of primary tumor and surgery for locally recurrent disease was 31 (interquartile range, 21 to 48) months. Twenty-three patients had central disease, 10 patients had sacral involvement, 21 patients had pelvic sidewall involvement, and 10 patients had both sacral and sidewall involvement. Fifty-seven patients underwent resection of the tumor. Thirty-nine of the 57 patients underwent wide resection (abdominoperineal excision of rectum, anterior resection, or Hartmann’s procedure) whereas 18 patients (31.6 percent) required radical resection (pelvic exenteration or sacrectomy). Curative, negative resection margins were obtained in 21 of 57 patients who had tumor excision (36.8 percent). Perioperative mortality was 1.6 percent. Significant postoperative morbidity occurred in 40 percent of patients.CONCLUSIONSThis study has shown that a significant proportion of patients with locally recurrent rectal cancer can undergo resection with negative margins.

One millimetre is the safe cut-off for magnetic resonance imaging prediction of surgical margin status in rectal cancer

A pathologically involved margin in rectal cancer is defined as tumour within 1 mm of the surgical resection margin. There is no standard definition of a predicted safe margin on magnetic resonance imaging (MRI). The aim of this study was to assess which cut‐off (1, 2 or 5 mm) was the best predictor of local recurrence based on preoperative MRI assessment of the circumferential resection margin (CRM).