Optimal timing surgery after neoadjuvant therapy
Traditionally, surgery is timed to occur 6-8 weeks after completion of neoadjuvant long-course chemoradiation. This is to allow enough time for pathological downstaging as well as patient recovery from neoadjuvant treatment. On the other hand, waiting too long could possibly increase the risk of tumour regrowth, metastatic potential, or the development of fibrosis making surgery more challenging.
An interval of at least 6 weeks between chemoradiation and surgery is favoured, based on the 1999 Lyon R90-01 study comparing intervals of less than 2 weeks and 68 weeks from radiation treatment completion to surgery. It found that the 6- to 8-week period improved tumour downstaging rates, compared with a shorter period. A 6-week wait was also the schedule used in the seminal German CAO/ARO/AIO-94 study rectal cancer study.
Overview of evidence (non-systematic literature review)[edit source]
No systematic reviews were undertaken for this topic. Practice points were based on selected published evidence. See Guidelines development process.
A 2016 meta-analysis included 13 prospective or retrospective studies investigating intervals between chemoradiation and surgery that were either longer or shorter than the ‘traditional’ 6- to 8-week period (over 3500 patients in total). It found that waiting longer than 8 weeks was associated with an increased pathological complete response rate: risk ratio (RR) 1.42 (95% CI 1.19 to 1.68, p < 0.0001). There were no differences in survival outcomes, R0 resection or sphincter preservation rates, or complications. However, this meta-analysis did not include any randomised controlled trials (RCT) and is largely based on retrospective data.
Three phase III RCTs have directly addressed this question:
- In the Lyon R90-01 study, 210 patients who received radiation treatment (39Gy in 13 daily fractions) were randomised to surgery within 2 weeks or at 6–8 weeks from completion of radiation treatment. A higher rate of pathological complete response was noted in the longer wait group, but no difference in overall survival was seen. However, the results of this study are difficult to interpret because it used a hypo-fractionated schedule, compared with standard schedules.
- In the GRECCAR-6 study, 265 patients were randomised to undergo surgery 7 versus 11 weeks post completion of chemoradiation. There was no difference in in the rates of pathological complete response or sphincter preservation between arms. Of some concern, the 11-week arm had a non-significantly higher rate of conversion to open surgery (15% versus 10%, p = 0.26) and more postoperative complications, including perineal healing complications if abdominoperineal resection was required.
- The UK NCT 01037049 trial, reported in abstract form and not yet published, randomised 237 patients with high risk features to surgery at either 6 weeks or 12 weeks after CRT. Patients in the 12-week arm were more frequently downstaged (58% versus 43%, p=0.019) and had a higher pCR rate (20% versus 9%,P<0.05). No significant difference was seen in surgical morbidity.
A retrospective cohort study using the National Cancer Database, published in 2016, included 6397 patients who had neoadjuvant therapy followed by surgery. Of those patients who had pathological complete response, 76.2% had surgery within 60 days. Delaying surgery more than 60 days in this cohort study was associated with a higher risk of positive surgical margins and decreased likelihood of sphincter preservation, as well as shorted overall survival (hazard ratio [HR] 1.3; 95% CI 1.19 to 1.45 p < 0.001). This is retrospective data and thus should be interpreted with caution.
Interim results from the Stockholm III trial are available. This study randomised 657 patients between 1998 and 2010 to one of three arms: short-course radiation treatment with immediate surgery, short-course radiation treatment with surgery after 4–8 weeks, or long-course radiation treatment with surgery after 4–8 weeks. A pre-planned interim analysis reported that patients who had short-course radiation treatment with delayed (4–8 weeks) surgery showed better outcomes, compared with those who had immediate surgery, including higher rates of tumour downstaging, pathologic complete regression (11.8% versus 1.7%), and tumour regression. It remains to be seen whether this translates to improved recurrence-free or overall survival. It was also observed that patients receiving short-course radiotherapy followed by surgery in between 11 and 17 days after the start of radiotherapy had the highest complication rate. Surgery should be avoided in this time window.
Available data for the optimal timing between completion of neoadjuvant C-RT and surgery indicate that surgery at least 6 weeks but by 12 weeks appears to be appropriate, until results from further studies become available.
Waiting longer within the 6-12 week time frame to allow optimal pathological downstaging may be selected preferentially, for example for patients with T4 tumours, where maximal downstaging is desirable.
- Francois Y, Nemoz CJ, Baulieux J, Vignal J, Grandjean JP, Partensky C, et al. Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: the Lyon R90-01 randomized trial. J Clin Oncol 1999 Aug;17(8):2396 Available from: http://www.ncbi.nlm.nih.gov/pubmed/10561302.
- Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004 Oct 21;351(17):1731-40 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15496622.
- Petrelli F, Sgroi G, Sarti E, Barni S. Increasing the Interval Between Neoadjuvant Chemoradiotherapy and Surgery in Rectal Cancer: A Meta-analysis of Published Studies. Ann Surg 2016 Mar;263(3):458-64 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24263329.
- Lefevre JH, Mineur L, Kotti S, Rullier E, Rouanet P, de Chaisemartin C, et al. Effect of Interval (7 or 11 weeks) Between Neoadjuvant Radiochemotherapy and Surgery on Complete Pathologic Response in Rectal Cancer: A Multicenter, Randomized, Controlled Trial (GRECCAR-6). J Clin Oncol 2016 Jul 18 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27432930.
- Evans, J; Bhoday, J; Sizer, B; Tekkis, B; Swift, R; Perez, R; et al. Results of a prospective randomised control 6 vs 12 trial: Is greater tumour downstaging observed on post treatment MRI if surgery is delayed to 12-weeks versus 6-weeks after completion of neoadjuvant chemoradiotherapy? Ann Oncol (2016) 27 (suppl 6): doi: 10.1093/annonc/mdw370.01 [cited 2016 Dec 28] Available from: http://annonc.oxfordjournals.org/content/27/suppl_6/452O.full.
- Huntington CR, Boselli D, Symanowski J, Hill JS, Crimaldi A, Salo JC. Optimal Timing of Surgical Resection After Radiation in Locally Advanced Rectal Adenocarcinoma: An Analysis of the National Cancer Database. Ann Surg Oncol 2016 Mar;23(3):877-87 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26514119.
- Pettersson D, Lörinc E, Holm T, Iversen H, Cedermark B, Glimelius B, et al. Tumour regression in the randomized Stockholm III Trial of radiotherapy regimens for rectal cancer. Br J Surg 2015 Jul;102(8):972-8; discussion 978 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26095256.