Neoadjuvant long-course chemoradiation

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Background

Chemotherapy is routinely added to long-course radiation treatment. A 2012 Cochrane systematic review and meta-analysis of six relevant randomised controlled trials (RCTs) in stage III (node positive) rectal cancer found that chemoradiation was associated with a lower risk of local recurrence and improved disease-free survival, compared with radiation treatment alone.[1] However, no differences in sphincter preservation or overall survival were observed. A similar 2013 Cochrane meta-analysis of five trials (all of which were also included in the 2012 meta-analysis), including both stage II and III rectal cancer, made similar findings of improved pathological complete response rates and lower rates of local recurrence, with no difference in treatment for rates of sphincter preservation or overall survival.[2]

Neoadjuvant therapyA type of treatment given as a first step to shrink a tumour before main treatment (usually surgery) is given. is regarded as standard treatment for most stage II and III rectal cancers. The key demonstrated benefits of neoadjuvant therapy are reductions in the risk of local recurrence and its significant associated morbidity and of short-term and long-term toxicities. It has not been shown to improve disease-free survival or overall survival.

Neoadjuvant therapyA type of treatment given as a first step to shrink a tumour before main treatment (usually surgery) is given., rather than surgery followed by adjuvant therapy, has been the preferred approach world-wide since the 2004 publication of the seminal German CAO/ARO/AIO-94 study, which compared preoperative with postoperative chemoradiation in 823 patients.[3] At 5-year follow-up, the study reported equivalent disease-free and overall survival in both treatment groups, but more than halving of the rate of local relapse in the preoperative group (6% versus 13%, p = 0.006), corresponding to a relative risk of recurrence of 0.46 favouring preoperative therapy. The preoperative treatment group also showed a lower risk of grade 3–4 acute toxicity (27% versus 40%, p = 0.001) and grade 3–4 long-term toxicity (14% versus 24%, p = 0.01).[3] There were no differences between groups in the rates of postoperative complications.[3]

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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 surgery alone? (NEO1b)

A systematic review was undertaken to evaluate three strategies for managing rectal cancer:

  • neoadjuvant chemoradiation followed by resection
  • resection followed by postoperative chemoradiation
  • resection alone (no chemoradiation).

Four level II RCTs were identified that recruited patients with stage II and III rectal cancer:

  • The CAO/ARO/AIO-94 study[3] conducted in Germany compared preoperative with postoperative chemoradiation in 823 patients with clinical stage T3 or T4 or node-positive disease. Five-year[3] and 10-year follow-up data[4] have been published.
  • The US National Surgical Adjuvant Breast and Bowel Project R-03 (NSABP R-03) study[5] compared preoperative or postoperative chemoradiotherapy in 267 patients with clinical T3 or T4 or node-positive rectal cancer.
  • A single-institution trial conducted in Korea randomised 240 patients to chemoradiation (50Gy in 25 daily fractions with concurrent capecitabine) given preoperatively or postoperatively.[6] Adjuvant therapyA treatment given with or shortly after another treatment to make it more effective. This usually refers to surgery followed by chemotherapy or radiotherapy. in both arms was either capecitabine or bolus 5FU (driven by availability).
  • A single-institution trial conducted in China randomised patients to either total mesorectal excision surgery alone, or total mesorectal excision preceded by chemoradiation (with capecitabine and oxaliplatin which is not regarded as standard).[7] Both arms received postoperative adjuvant chemotherapy. Interim findings from only 184 randomised patients have been published.

Three of these four studies were underpowered, with patient recruitment substantially lower than anticipated. The NSABP R-03 study[5] accrued only 267 of a planned 900 patients. The Chinese study is an interim analysis of 184 of a planned 500 patients; this trial used a non-inferiority study design.[7] The Korean study did not reach accrual target.[6] Of a planned 432 patients, 240 were enrolled and their data analysed. Only the CAO/ARO/AIO-94 study accrued to target (planned 680, enrolled 823 patients anticipating 15% dropout).[3][4] Therefore, we accorded more weight to the data from this study.

Outcomes reported by these RCTs included local recurrence, disease-free survival, overall survival, distant metastases, and complications including perioperative and postoperative mortality. All of these studies all had an unclear (high) risk of bias, as outcome assessors were not blinded to intervention type and outcomes were not always clearly described in the study protocol.[5][7][4][6]

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.

Local recurrenceThe reappearance of cancer at a site that was previously treated and responded to therapy. was reported in all RCTs as 3-, 5- or 10-year local recurrence rates.

In the CAO/ARO/AIO-94 study[4], the preoperative chemoradiation group showed significantly lower 5-year and 10-year local recurrence, compared with the postoperative chemoradiation group: 5% versus 9.7% at 5 years and 7.1% versus 10.1% at 10 years (hazard ratio [HR] 0.6%, p = 0.048) on intention-to-treat analysis. The benefit of preoperative treatment over postoperative treatment was accentuated when comparing those who actually received their assigned treatments (6.8% versus 10.5%; HR 0.54, p = 0.02).[4]

The other studies reported no significant difference in local recurrence rates:

  • The NSABP R-03 study[5] reported similar local-regional recurrence risk (5-year cumulative incidence 10.7%) in the preoperative and postoperative chemoradiation groups (HR 0.86; 95% confidence interval [CI] 0.41 to 1.81, p = 0.693).
  • The Korean study[6] reported no significant differences in 5-year local recurrence between the preoperative and postoperative chemoradiation treatment groups (absolute difference 1%, p = 0.393).
  • The Chinese study[7] reported no difference in 3-year local recurrence between groups who received preoperative chemoradiation group and surgery alone (absolute difference 0.1%, p = 0.776).

Disease-free survival

Disease-free survival was reported in all four RCTs.[5][4][6][7]

The NSABP R-03 study[5] reported a higher 5-year disease-free survival rate in the preoperative chemoradiation group, compared with the postoperative chemoradiation group (64.7% versus 53.4%; HR 0.63 (95% CI 0.44 to 0.90, p = 0.011).

The other three studies[3][6][7] reported marginal, but not statistically significant increases in disease-free survival among the preoperative chemoradiation group compared with the postoperative chemoradiation or no chemoradiation (surgery only) group:

  • The CAO/ARO/AIO-94 study[4] reported no difference in disease-free survival for preoperative chemoradiation versus postoperative radiation at 10-year follow-up (p = 0.540).
  • The Korean study[6] reported no difference in disease-free survival for preoperative chemoradiation versus postoperative radiation at 5-year follow-up (p=0.866).
  • The Chinese study[7] reported no difference in disease-free survival for preoperative chemoradiation versus surgery alone (p=0.766).

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Overall survival

Overall survival was reported in all four RCTs.[4][5][6][7] None of the RCTs reported a statistically significant difference between groups in overall survival. The NSABP R-03 study[5] reported a nonsignificant overall survival benefit at 5-year follow-up favouring preoperative therapy (74.5% versus 65.5%; HR 0.693, 95% CI 0.468 to 1.026, p = 0.065).

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

Distant metastases were reported in all RCTs[4][5][6][7], with no significant differences observed.

Complications

Perioperative and postoperative complications reported in the RCTs included rates of perioperative mortality, anastomotic leakage, obstruction, wound infection, and fistula.

Perioperative mortality rates were reported in two RCTs. The CAO/ARO/AIO-94 study[3] reported in-hospital mortality rates of 0.7% in the preoperative chemoradiation group and 1.3% in the postoperative chemoradiation group (p = 0.41). The Chinese study[7] reported no perioperative mortality in either group.

The CAO/ARO/AIO-94 study 5-year follow-up data[3] showed significantly lower rates of perioperative and postoperative toxicity in the preoperative chemoradiation group, compared with the postoperative chemoradiation group: acute grade 3–4 toxicity 27% versus 40% (p = 0.001) and long-term toxicity 14% versus 24% (p = 0.01). Rates of postoperative complications were similar between groups (36% versus 34%, p = 0.68). There were no differences in rates of delayed wound healing, postoperative bleeding, ileus, or anastomotic leakage.

The other three RCTs reported no significant differences in complication rates between treatment groups. The NSABP R-03 study[5] reported similar rates of postoperative complications in the preoperative and postoperative chemoradiation groups (25% versus 22.6%). Neither the Korean[6] nor the Chinese[7] studies reported significant differences in complication rates, with low rates observed in each group.

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Evidence summary and recommendations

Evidence summary Level References
Patients with Stage II–III rectal cancer undergoing neoadjuvant chemoradiation have a reduced risk of local recurrence compared with those undergoing postoperative chemoradiation (evidence from one study). II [4], [5], [6], [7]
Preoperative chemoradiation has not been clearly demonstrated to improve disease-free survival, compared with postoperative chemoradiation or with surgery alone, in patients with Stage II–III rectal cancer. A significant improvement in disease-free survival favouring preoperative treatment was reported in one study that was underpowered for this outcome. II [4], [5], [6], [7]
Preoperative chemoradiation does not reduce the risk of distant metastases, compared with postoperative chemoradiation or with surgery alone, in patients with Stage II–III rectal cancer. II [4], [6], [7]
Patients receiving preoperative chemoradiation may have a lower incidence of perioperative and postoperative complications, compared with those receiving postoperative chemoradiation (evidence from one study). II [3]
Evidence-based recommendationA recommendation formulated after a systematic review of the evidence, indicating supporting references.Question mark transparent.png Grade
Consider neoadjuvant chemoradiation for patients with stage II-III rectal cancer where appropriate.
C
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

The current standard dose of neoadjuvant chemoradiation is 50–50.4 Gy (boost volume after 45 Gy) with either continuous infusional 5FU or capecitabine.

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

‘Early’ cT3N0 rectal cancer (<1mm extension) is considered potentially suitable for surgery without neoadjuvant treatment in some international guidelines; but requires a high level of confidence in staging investigations and interpretation.

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Considerations in making these recommendations

Neoadjuvant chemoradiation can be recommended for most patients with stage II–III rectal cancer with the aims of reducing the risk of local recurrence and for reducing rates of perioperative and postoperative complications, on the basis of limited evidence from one study.[3][4] However, it has not been shown to improve disease-free survival or overall survival rates.

Some international guidelines suggest that for ‘early’ T3 (stage II) rectal cancer (<1mm extension beyond muscularis propria) then surgery without neoadjuvant therapy is acceptable. This would need to be agreed upon in multidisciplinary team discussion, with a high level of confidence in MRI staging.

The absolute benefit of neoadjuvant chemoradiation in reducing risk of recurrence is small, compared with adjuvant chemoradiation (3% at 10 year follow up in the CAO/ARO/AIO-94 study[4]). Nevertheless, due to the significant morbidity associated with local recurrence, any modality that can reduce this risk is preferred as long as toxicities are acceptable.

Available evidence suggests that toxicity rates are reduced when using neoadjuvant chemoradiation rather than adjuvant chemoradiation.

Health system implications

Clinical practice

Neoadjuvant chemoradiation is currently standard practice in Australia, so the recommendation does not represent any change to current clinical practice.

Resourcing

No additional resourcing would be required to implement the recommendation, as neoadjuvant chemoradiation is currently regarded as standard practice in Australia.

Barriers to implementation

No barriers to implementation are anticipated, as neoadjuvant chemoradiation is currently regarded as standard practice in Australia.

Next section: 'watch and wait' approach after clinical complete response to neoadjuvant chemoradiation

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References

  1. McCarthy K, Pearson K, Fulton R, Hewitt J. Pre-operative chemoradiation for non-metastatic locally advanced rectal cancer. Cochrane Database Syst Rev 2012 Dec 12;12:CD008368 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23235660.
  2. De Caluwé L, Van Nieuwenhove Y, Ceelen WP. Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer. Cochrane Database Syst Rev 2013 Feb 28;(2):CD006041 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23450565.
  3. 3.003.013.023.033.043.053.063.073.083.093.10 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 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15496622.
  4. 4.004.014.024.034.044.054.064.074.084.094.104.114.124.13 Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol 2012 Jun 1;30(16):1926-33 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22529255.
  5. 5.005.015.025.035.045.055.065.075.085.095.105.11 Roh MS, Colangelo LH, O'Connell MJ, Yothers G, Deutsch M, Allegra CJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 2009 Nov 1;27(31):5124-30 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19770376.
  6. 6.006.016.026.036.046.056.066.076.086.096.106.116.12 Park JH, Yoon SM, Yu CS, Kim JH, Kim TW, Kim JC. Randomized phase 3 trial comparing preoperative and postoperative chemoradiotherapy with capecitabine for locally advanced rectal cancer. Cancer 2011 Aug 15;117(16):3703-12 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21328328.
  7. 7.007.017.027.037.047.057.067.077.087.097.107.117.127.13 Fan WH, Wang FL, Lu ZH, Pan ZZ, Li LR, Gao YH, et al. Surgery with versus without preoperative concurrent chemoradiotherapy for mid/low rectal cancer: an interim analysis of a prospective, randomized trial. Chin J Cancer 2015 Jun 10;34(9):394-403 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26111932.
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Appendices


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