'Watch and wait' approach after clinical complete response to neoadjuvant chemoradiation (NEO1a)

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Background

Rectal cancer surgery is associated with risks of significant morbidity, poor functional outcomes and permanent stomas. Patients who have a pathological remission and confirmed by surgery have an excellent oncological outcome. Therefore, a ‘watch and wait’ alternative has been proposed for patients who achieve a complete response to nonsurgical treatment with chemoradiation. As this approach is still investigational, it should ideally be subject to clearly defined protocols and managed by a multidisciplinary team, rather than applied ad hoc.

Note that this is not the same as non-operative management for other reasons after neoadjuvant CRT (e.g. patient refusal of surgery). The ‘watch and wait’ approach as described here only applies to patients who achieve a clinical complete response as determined by the treating team.

Approximately 10–20% of patients who receive neoadjuvant chemoradiation have a pathological complete response at the time of surgery.[1] These patients are expected to have an excellent prognosis. However, the critical issue is whether a clinical complete response after neoadjuvant treatment correlates well with a pathological complete response.

Traditionally, determination of response has relied on clinical and endoscopic examination by the surgeon. However, a mucosal clinical complete response may not correlate well with a pathological complete response at the primary site. Regional node status can only be monitored by radiological imaging, which is also imperfect in assessing a complete response in patients with nodal disease.[2]

MRI is not funded in Australia for this indication. Furthermore, even on MRI it may be difficult to distinguish between fibrosis and residual tumour plus micro-metastases may be missed at the nodal level.[3]

A high level of confidence in postoperative staging would be required in order to be confident not to proceed with surgery. Furthermore, careful surveillance would then be required in order to detect early recurrence. See Optimal approach to elective resection for rectal cancers for discussion of alternative, minimally invasive, surgical options for tumours with an excellent clinical response to neoadjuvant therapy.

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Systematic review evidence

For patients diagnosed with stage II-III rectal cancer, for which patients does neoadjuvant chemoradiation with surgery achieve equivalent or better outcomes than neoadjuvant chemoradiotherapy alone? (NEO1a)

A systematic review was undertaken to evaluate the benefits of definitive chemoradiation (clinical complete response) not followed by resection.

One systematic review and meta-analysis[4] and 12 cohort studies[5][6][7][8][9][10][11][12][13][14][15][16] were identified that compared outcomes for patients who underwent either surgery or observation after neoadjuvant chemoradiation.

The meta-analysis[4] included pooled data from nine of the cohort studies comparing patients with clinical complete response followed by a 'watch and wait' approach (n = 251), with those who had surgery (n = 334). This meta-analysis had a moderate risk of bias.

There was significant heterogeneity among the comparator characteristics of the cohort studies. Six[8][10][11][12][13][14] of the 12 studies compared patients who had a clinical complete response to neoadjuvant therapy who were then placed into a ‘watch and wait’ follow-up protocol to those that had incomplete clinical response to neoadjuvant treatment and then proceeded to surgery. One study[6] compared patients with a radiologic complete response across three treatment groups: radical surgery, local excision, or wait-and see and another study[15] compared patients who had a complete clinical response and underwent either radical resection or watch’-and-wait’ treatment. For the remainder of the studies, the comparison arm consisted of patients who had a pathological complete response to neoadjuvant treatment and proceeded to surgery[5][6][7][9]. There was variability between studies as to the timing of, and method/s by which cCR was determined, including several combinations of examination, endoscopic, CEACarcinoembryonic antigen. A protein that may be found in the blood of a person with colorectal cancer., MRI, CT and PET studies. This heterogeneity limits interpretation of results and does not permit easy comparisons between studies.

Seven of the cohort studies[5][6][7][8][9][10][16] had a high risk of bias, one study had a moderate risk of bias,[11] and four studies had a low risk of bias.[12][13][14][15]

Outcomes reported in observational studies included local recurrence, disease-free survival, overall survival, distant metastases, and perioperative complications including colostomy-free survival and incontinence.

The search strategy, inclusion and exclusion criteria, and quality assessment are described in detail in the Technical report.


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Local recurrenceThe reappearance of cancer at a site that was previously treated and responded to therapy.

The meta-analysis[4] reported that local recurrence risk was significantly higher at 1, 2, 3, and 5 years among patients with clinical complete response to neoadjuvant therapy who underwent ‘watch and wait’ than those who underwent surgery: relative risk (RR) at 5-year follow-up 5.69 (95% confidence interval [CI] 1.99 to 16.25, p = 0.001). Although most of the included individual studies reported non- significant differences in local recurrence favouring the surgical arm, pooled analysis showed a statistically significant difference at all time points analysed.[4]

Three cohort studies that were not included in the meta-analysis[10][8][15] reported local recurrence rates in patients who received chemoradiation with and without surgery.

A Danish prospective observational study compared watch-and-wait with surgical resection in patients with resectable, T2 or T3, N0-N1 rectal adenocarcinoma who underwent high-dose chemoradiation.[10] It reported local recurrence in 9 of 40 patients from the watch and wait (local recurrence risk of 26%) at a median follow-up of 2 years.[10]

A UK study (the OnCoRe project)[8] performed propensity-score matched cohort analysis for patients with rectal adenocarcinoma who received preoperative chemoradiotherapy (45 Gy in 25 daily fractions with concurrent fluoropyrimidine-based chemotherapy). Patients who had a clinical complete response were offered a watch-and-wait approach, while those who did not have a clinical complete response were offered surgical resection if eligible. The study reported a local recurrence rate of 38% in the watch-and-wait arm at 3 years.[8]

A Taiwanese retrospective cohort study of 44 patients with cCR, 18 of whom opted for watch-and-wait, with a mean follow-up time of approximately 4 years, reported two local recurrence in the watch-and-wait group; and none in the surgery group.[15]Back to top

Disease-free survival

The systematic review and meta-analysis[4] reported that there was no significant difference in disease-free survival at 1, 2, 3 and 5 years between patients who underwent watch-and-wait and those who underwent surgery: RR at 5-year follow-up 0.96 (95% CI 0.85 to 1.08).

Only one study[5] included in this systematic review and meta-analysis observed a significantly lower 5-year disease-free survival rate among patients with clinical complete response to neoadjuvant chemoradiation who underwent watch-and-wait than among those who underwent surgery (60.9% versus 82.8%; RR 0.79; 95% CI 0.65 to 0.98, p=0.011). All other cohort studies included in the systematic review and meta-analysis observed non-significant differences rates between groups in disease-free survival ranging from 0.2% to 12.5%.[4]

Of the three cohort studies that were not included in the meta-analysis,[10][8][15] the OnCoRe project}}[8] observed no difference in 3-year non-regrowth disease-free survival, and the Taiwanese retrospective study reported disease-free survival of 69.8 months ('watch and wait') and 89 months (surgery) (p=0.354)[15]. The Danish prospective observational study[10] did not formally report disease-free survival.


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Overall survival

The meta-analysis reported no significant difference in overall survival at 1, 2, 3 and 5 years between patients who underwent watch-and-wait and those who underwent surgery: RR at 5-year follow-up1.01; 95% CI 0.92 to 1.11).[4]

Of the three studies that were not included in the meta-analysis, none reported statistically significant between-group differences in overall survival.[10][8][15]Back to top

Distant metastasisCancer that has spread from the original (primary) tumour to distant organs or distant lymph nodes.

The meta-analysis reported no significant difference in the rate of distant metastases at 1, 2, 3 or 5 year: RR at 5-year follow-up 0.95; 95% CI 0.47 to 1.91, p=0.88).[4] Included individual studies mostly observed no significant differences between groups.[4]

Of the three studies not included in the meta-analysis,[10][8][15] the Danish prospective observational study[10] reported higher distant metastases rates in the surgery group (18.2%) compared with the definitive chemoradiation group (7.5%) at a median follow-up of 26.7 months. However, no statistical comparison was provided and samples sizes were small (n = 11 for chemoradiation followed by surgery and n = 40 for chemoradiation followed by observation). The surgery group consisted of all patients who did not have clinical complete response, so their results are not directly comparable with the group who did achieve clinical complete response to neoadjuvant treatment. The Taiwanese retrospective cohort study reported one distant metastasis in the surgery group and none in the watch-and-wait group at a mean follow-up of approximately 4 years.[15]Back to top

Evidence summary and recommendations

Evidence summary Level References
Among patients with rectal cancer who have undergone chemoradiation, there is a higher risk of local recurrence with a ‘watch and wait’ approach compared with patients who have surgery, as evidenced by a meta-analysis observational of cohort studies. However, there was heterogeneity in the design of individual cohort studies. III-2 [4], [10], [5], [12], [13], [6], [14], [7], [11], [9], [16], [15]
Observed disease-free survival rates among patients with rectal cancer did not consistently differ between those who received chemoradiation alone and those who received chemoradiation followed by surgery, despite a higher risk of local recurrence when the ‘watch and wait’ strategy was used. III-2 [4], [5], [6], [7], [8], [9], [11], [12], [14], [15], [16], [17]
No significant differences in distant metastases or overall survival among patients with rectal cancer were observed between those who received chemoradiation alone and those who received chemoradiation followed by surgery. III-2 [10], [5], [12], [13], [6], [14], [4], [7], [8], [11], [9], [15], [16]
Evidence-based recommendationA recommendation formulated after a systematic review of the evidence, indicating supporting references.Question mark transparent.png Grade
For patients with rectal cancer who have had a clinical complete response to neoadjuvant chemoradiation, and planned resection according to the standard recommendation is either not possible or the patient declines it, a ‘watch and wait’ approach can be considered, provided that:
  • the risks and benefits have been discussed with the multidisciplinary team and the patient
  • the patient is monitored closely for local recurrence
  • the patient is offered an appropriate surgical resection procedure if local recurrence is detected.
D
Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

A ‘watch and wait’ approach for patients with clinical complete response following chemoradiation is not considered standard practice. Clinicians and patients who select this option must be aware of increased risk of recurrence necessitating surgical intervention, and the importance of close follow-up.

Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

Follow-up and surveillance guidelines for a ‘watch and wait’ approach, in particular the frequency of follow-up tests, are not established. Testing may include serial CEACarcinoembryonic antigen. A protein that may be found in the blood of a person with colorectal cancer. measurements, clinical examination, radiological surveillance, and sigmoidoscopy/colonoscopy.

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Considerations in making these recommendations

RCTs have not evaluated chemoradiation alone, compared with neoadjuvant chemoradiation followed by surgery, in patients with rectal cancer. Available evidence is from retrospective or prospective cohort studies in which patients with a clinical complete response underwent a watch-and-wait approach. These observational studies are challenging to interpret, as those patients who have a clinical complete response to chemoradiation may have an improved prognosis, whether or not they subsequently have surgery.

There is a higher risk of local recurrence with a watch-and-wait strategy. However, salvage surgery is appropriate and, based on available evidence, appears to achieve similar rates of disease-free survival and overall survival as immediate surgery.

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Health system implications

Clinical practice

Choosing observation alone, without surgery, in patients with clinical complete response after chemoradiation is not currently considered standard practice.

If observation without surgery is undertaken, the patient needs to understand this is not conventional treatment and compliance with close and strict surveillance is mandatory.

Resourcing

Strict surveillance would require resourcing for timely clinical review, imaging and examination ideally under anaesthetic.

Avoidance of surgery could result in lower costs, but these may be negated by intensive surveillance protocols.

Patients who are being followed with “watch and wait” should ideally be done so with a protocolised regimen of follow-up with prospective data collection.

Barriers to implementation

Lack of robust evidence may preclude uptake of this strategy.

Concern that patients may not adhere to strict follow up and surveillance, thus potentially rendering a curable early recurrence incurable if detected late.

No definitive recommendations available for optimum follow up strategy in this context.

Next section: neoadjuvant chemotherapy regimen

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References

  1. Maas M, Nelemans PJ, Valentini V, Das P, Rödel C, Kuo LJ, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 2010 Sep;11(9):835-44 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20692872.
  2. Smith FM, Wiland H, Mace A, Pai RK, Kalady MF. Clinical criteria underestimate complete pathological response in rectal cancer treated with neoadjuvant chemoradiotherapy. Dis ColonThe main part of the large bowel, which absorbs water and electrolytes from undigested food (solid waste). Its four parts are the ascending colon, transverse colon, descending colon and sigmoid colon. RectumThe final section of the large bowel, ending at the anus. 2014 Mar;57(3):311-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24509452.
  3. Hanly AM, Ryan EM, Rogers AC, McNamara DA, Madoff RD, Winter DC, et al. Multicenter Evaluation of Rectal cancer ReImaging pOst Neoadjuvant (MERRION) Therapy. Ann Surg 2014 Apr;259(4):723-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23744576.
  4. 4.004.014.024.034.044.054.064.074.084.094.104.11 Li J, Li L, Yang L, Yuan J, Lv B, Yao Y, et al. Wait-and-see treatment strategies for rectal cancer patients with clinical complete response after neoadjuvant chemoradiotherapy: a systematic review and meta-analysis. Oncotarget 2016 Apr 6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27070085.
  5. 5.05.15.25.35.45.55.6 Araujo RO, Valadão M, Borges D, Linhares E, de Jesus JP, Ferreira CG, et al. Nonoperative management of rectal cancer after chemoradiation opposed to resection after complete clinical response. A comparative study. Eur J Surg Oncol 2015 Nov;41(11):1456-63 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26362228.
  6. 6.06.16.26.36.46.56.6 Lee SY, Kim CH, Kim YJ, Kim HR. Oncologic Outcomes according to the Treatment Strategy in Radiologic Complete Responders after Neoadjuvant Chemoradiation for Rectal Cancer. Oncology 2015;89(6):311-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26426305.
  7. 7.07.17.27.37.47.5 Maas M, Beets-Tan RG, Lambregts DM, Lammering G, Nelemans PJ, Engelen SM, et al. Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol 2011 Dec 10;29(35):4633-40 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22067400.
  8. 8.008.018.028.038.048.058.068.078.088.098.108.11 Renehan AG, Malcomson L, Emsley R, Gollins S, Maw A, Myint AS, et al. Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis. Lancet Oncol 2016 Feb;17(2):174-83 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26705854.
  9. 9.09.19.29.39.49.5 Smith JD, Ruby JA, Goodman KA, Saltz LB, Guillem JG, Weiser MR, et al. Nonoperative management of rectal cancer with complete clinical response after neoadjuvant therapy. Ann Surg 2012 Dec;256(6):965-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23154394.
  10. 10.0010.0110.0210.0310.0410.0510.0610.0710.0810.0910.1010.1110.12 Appelt AL, Pløen J, Harling H, Jensen FS, Jensen LH, Jørgensen JC, et al. High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study. Lancet Oncol 2015 Aug;16(8):919-27 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26156652.
  11. 11.011.111.211.311.411.5 Ayloor Seshadri R, Kondaveeti SS, Jayanand SB, John A, Rajendranath R, Arumugam V, et al. Complete clinical response to neoadjuvant chemoradiation in rectal cancers: can surgery be avoided? Hepatogastroenterology 2013 May;60(123):410-4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23635444.
  12. 12.012.112.212.312.412.5 Dalton RS, Velineni R, Osborne ME, Thomas R, Harries S, Gee AS, et al. A single-centre experience of chemoradiotherapy for rectal cancer: is there potential for nonoperative management? ColorectalReferring to the large bowel, comprising the colon and rectum. Dis 2012 May;14(5):567-71 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21831177.
  13. 13.013.113.213.313.4 Habr-Gama A, Perez RO. The surgical significance of residual mucosal abnormalities in rectal cancer following neoadjuvant chemoradiotherapy (Br J Surg 2012; 99: 993-1001). Br J Surg 2012 Nov;99(11):1601; author reply 1601-2 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23027080.
  14. 14.014.114.214.314.414.5 Li J, Liu H, Yin J, Liu S, Hu J, Du F, et al. Wait-and-see or radical surgery for rectal cancer patients with a clinical complete response after neoadjuvant chemoradiotherapy: a cohort study. Oncotarget 2015 Dec 8;6(39):42354-61 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26472284.
  15. 15.0015.0115.0215.0315.0415.0515.0615.0715.0815.0915.1015.1115.12 Lai CL, Lai MJ, Wu CC, Jao SW, Hsiao CW. Rectal cancer with complete clinical response after neoadjuvant chemoradiotherapy, surgery, or "watch and wait". Int J ColorectalReferring to the large bowel, comprising the colon and rectum. Dis 2016 Feb;31(2):413-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26607907.
  16. 16.016.116.216.316.4 Smith RK, Fry RD, Mahmoud NN, Paulson EC. Surveillance after neoadjuvant therapy in advanced rectal cancer with complete clinical response can have comparable outcomes to total mesorectal excision. Int J ColorectalReferring to the large bowel, comprising the colon and rectum. Dis 2015 Jun;30(6):769-74 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25787162.
  17. Habr-Gama A, Perez RO, Nadalin W, Sabbaga J, Ribeiro U Jr, Silva e Sousa AH Jr, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 2004 Oct;240(4):711-7; discussion 717-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15383798.
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Appendices


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