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Three Part Question

In [patients with resectable oesophageal carcinoma] does [neoadjuvant chemotherapy compared to surgery alone] improve [survival]?

Clinical Scenario

You are attending the thoracic multidisciplinary meeting. The case of a 44-year-old man with localised, resectable oesophageal carcinoma is discussed. One of the oncologists suggests neoadjuvant chemotherapy for this patient, however, the thoracic surgeon disagrees with his suggestion claiming that there is no benefit of this strategy and it would make surgery more difficult. You resolve to investigate this further.

Search Strategy

The English language scientific literature was reviewed primarily by searching Medline from 1950 through June 2007 using Ovid interface.
[Chemotherapy.mp OR exp antineoplastic agents/] AND [survival.mp OR mortality.mp] AND [Exp esophageal neoplasms/OR oesophageal carcinoma.mp OR oesophageal cancer.mp] AND [Exp surgery/OR surgery.mp].
The 'related articles' function was used to broaden the search and all abstracts, studies, and citations scanned were reviewed. The reference lists of articles found through these searches were also reviewed for relevant articles. In addition, Cochrane Database of Systematic Reviews and links on web sites CINAHL [Cumulative Index to Nursing and Allied Health Literature], DARE [Database of Abstracts of Reviews of Effectiveness], CANCERLIT and EMBASE containing published articles were searched for relevant information.

Search Outcome

A total of 685 papers were found using the search strategy. Nine papers were deemed to represent the best evidence on the topic and are summarised

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Gebski et al, 2007 Australia	8 studies comprising 1724 patients with local operable oesophageal carcinoma, published from 1982-1992 Neoadjuvant chemotherapy vs surgery alone Data also collected from 10 chemotherapy trials	Meta-analysis (level 1a)	Overall survival	Hazard ratio (HR) for neoadjuvant chemotherapy was 0.90 (0.81–1.00; P=0.05), at 2 years absolute survival benefit of 7% 2 year hazard ratio for chemoradiotherapy 0.81 (95% CI 0.70–0.93;P=0.002), corresponding to a 13% absolute survival benefit	Eight RCTs included. Publication bias. Different dose regimens in different trials. Included trials had patients with SCC, adenocarcinoma and mixed tumors. North American Intergroup trial and MRC trial included
			Squamous cell carcinoma survival	2 year hazard ratio 0.88 [0.75–1.03]; P=0.12
			Adenocarcinoma survival	2 year hazard ratio 0.78 [0.64–0.95]; P=0.014
Malthaner et al, 2006, Canada	8 studies comprising 1729 patients with local operable oesophageal carcinoma	Meta-analysis (level 1a)	Survival benefits of neoadjuvant chemotherapy vs surgery alone	12% reduction in risk of mortality for patients given preoperative chemotherapy when compared to surgery alone	North American Intergroup trial and MRC trial included. Marked clinical heterogeneity among two major trials (North American Intergroup trial and MRC trial) included in the meta-analysis. Random effects meta-analysis performed
Malthaner et al, 2004a BMC Med	1251 patients with local operable oesophageal carcinoma	Meta-analysis (level 1a)	Survival benefits of neoadjuvant chemotherapy vs surgery alone	No statistically significant differences in mortality for patients given preoperative chemotherapy when compared to surgery alone (RR, 1.00; 95% CI, 0.83 to 1.19; P=0.98)	6 of the 7 available trials included as one trial published as abstract. Marked clinical heterogeneity due to different chemotherapy protocols
Malthaner et al, 2004b BMC Cancer	Patients with local operable oesophageal carcinoma	Guidelines (Level 1a)	Survival benefits of neoadjuvant chemotherapy vs surgery alone	Surgery alone (i.e. without neoadjuvant or adjuvant therapy) as the standard practice for adult patients with resectable thoracic oesophageal cancer for whom surgery is considered appropriate	Guideline formulated based on the findings of Malthaner(2004a) followed by external review, and subsequent Practice Guidelines Coordinating Committee revision suggestions and final approval
Kaklamanos et al, 2003 USA	1683 patients with local operable oesophageal carcinoma	Meta-analysis (level 1a)	Survival benefits of neoadjuvant chemotherapy vs surgery alone	Neoadjuvant chemotherapy modestly improved 2 year survival compared with surgery alone. The absolute difference was 4.4% (95% CI, 0.3–8.5%)	Marginal evidence of heterogeneity eliminated by restricting attention to the four most recent studies, which increased the estimate to 6.3% (95% CI, 1.8–10.7%)
Urschel et al, 2002 Canada	1976 patients with local operable oesophageal carcinoma	Meta-analysis (level 1a)	Survival benefits of neoadjuvant chemotherapy vs surgery alone	Odds ratio was 1.00 (0.76, 1.30; P=0.98) for 1 year survival, 0.88 (0.62, 1.24; P=0.45) for 2-year survival, 0.77 (0.37, 1.59; P=0.48) for 3-year survival	11 RCTs included. Many trials included in the meta-analysis were underpowered
MRCOCWG trial 2002 UK	802 patients with resectable oesophageal carcinoma	RCT (level 1b)	Overall survival	Overall survival was better in the chemotherapy group (HR 0.79; 95% CI 0.67–0.93; P=0.004). Median survival was 512 days (16.8 months) in the chemotherapy group compared with 405 days (13.3 months) in the surgery group (difference 107 days; 95% CI 30–196), and 2-year survival rates were 43% and 34% (difference 9%; 95% CI 3–14)	Adenocarcinoma predominant histological type. Three cycles of cisplatin and fluorouracil neoadjuvant chemotherapy. 9% patients in both groups received preoperative radiotherapy. Median time from randomisation to surgery was 63 days (IQR 55–75) in the group undergoing chemotherapy before surgery and 16 days (9–27) in the surgery group. Intention-to-treat survival analysis. 42 European centres recruited patients
Kelsen et al, 1998 USA	440 patients with local operable oesophageal carcinoma	RCT (level 1b)	Overall survival	No significant difference in median duration of survival, survival at 1 year or survival at 2 year	Adenocarcinoma predominant histological type. Three cycles of cisplatin and fluorouracil neoadjuvant chemotherapy. 71% patients received all three cycles of chemotherapy. 52% of the 133 patients who had potentially curative resections also received at least one cycle of postoperative chemotherapy. The median time from registration to operation was 9 days for the group undergoing only surgery and 93 days for the group undergoing chemotherapy before surgery. Intention-to-treat survival analysis. 123 North American centres recruited patients
Bhansali et al, 1996	1443 patients with local operable oesophageal carcinoma	Meta-analysis (level 1a)	Survival benefits of neoadjuvant chemotherapy vs surgery alone	Relative reduction in odds of death for the chemotherapy group of 4.2±23.7% (OR=0.96, 95% CI 0.75–1.22)	12 RCTs included. 4 of the 12 trials included additional radiotherapy. Only 1 trial included pure adenocarcinoma patients. 2 RCTs included patients with inoperable carcinoma. 1 trial included adjuvant chemotherapy

Comment(s)

Gebski et al. in 2007 published a meta-analysis of eight randomised controlled trials (RCTs) of neoadjuvant chemotherapy vs. surgery alone (n=1724) in patients with local operable oesophageal carcinoma demonstrated that the hazard ratio (HR) for neoadjuvant chemotherapy was 0.90 (0.81–1.00; P=0.05), which indicates a 2-year absolute survival benefit of 7%. There was no significant effect on all-cause mortality of chemotherapy for patients with squamous cell carcinoma (HR 0.88 [0.75–1.03]; P=0.12), although there was a significant benefit for those with adenocarcinoma (HR 0.78 [0.64–0.95]; P=0.014). Malthaner et al. in a 2006 Cochrane systematic review included 11 trials of 2051 patients. Their meta-analysis showed a 12% reduction in risk of mortality for patients given preoperative chemotherapy when compared to surgery alone. However, the evidence for a treatment effect was inconclusive (HR 0.88; 95% confidence interval [CI] 0.75–1.04; P=0.15). Malthaner et al. in 2004, in an earlier systematic review and meta-analysis pooling one-year mortality from six randomised trials, detected no statistically significant differences in mortality for patients given preoperative chemotherapy when compared to surgery alone. Based on the findings of this systematic review followed by external review, and subsequent Practice Guidelines Coordinating Committee revision suggestions, and final approval, the Gastrointestinal Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence-based Care recommended surgery alone (i.e. without neoadjuvant or adjuvant therapy) as the standard practice for adult patients with resectable thoracic oesophageal cancer for whom surgery is considered appropriate. Kaklamanos et al. in their meta-analysis of seven studies that investigated preoperative chemotherapy, and enrolled a total of 1683 patients, showed that neoadjuvant chemotherapy modestly improved 2-year survival compared with surgery alone. The absolute difference was 4.4% (95% CI, 0.3–8.5%). They eliminated marginal evidence of heterogeneity by restricting attention to the four most recent studies, which increased the estimate to 6.3% (95% CI, 1.8–10.7%). Treatment-related mortality increased by 1.7% with neoadjuvant chemotherapy (95% CI, –0.9–4.3%). Urschel et al. in their meta-analysis of eleven RCTs, which included 1976 patients, showed that odds ratio (95% CI; P-value), expressed as chemotherapy and surgery vs. surgery alone (treatment vs. control; values <1 favor chemotherapy–surgery arm), was 1.00 (0.76, 1.30; P=0.98) for 1-year survival, 0.88 (0.62, 1.24; P=0.45) for 2-year survival, 0.77 (0.37, 1.59; P=0.48) for 3-year survival, 1.71 (1.22, 2.40; P=0.002) for rate of resection, 0.71 (0.58, 0.87; P=0.001) for rate of complete resection, 0.94 (0.66, 1.35; P=0.76) for operative mortality, 1.08 (0.45, 2.60; P=0.87) for anastomotic leaks, 1.31 (0.77, 2.23; P=0.32) for postoperative pulmonary complications, 1.36 (0.83, 2.25; P=0.22) for all treatment mortality, 0.71 (0.36, 1.42; P=0.33) for local-regional cancer recurrence, 0.79 (0.57, 1.10; P=0.16) for distant cancer recurrence, and 0.63 (0.28, 1.41; P=0.26) for all cancer recurrence. A clinical response to chemotherapy was observed in 31% of patients and 5% had a complete pathological response. Chemotherapy mortality (before surgery) was 1.6%. Two large RCTs with conflicting results have been published in 2002 [MRCP] and 1998 [Kelsen], respectively. The MRCOCWG trial [8] recruiting 802 patients with resectable oesophageal cancer reported better overall survival (HR 0.79; 95% CI 0.67–0.93; P=0.004) in the chemotherapy group contrary to the North American Intergroup trial [Kelsen] recruiting 440 patients which reported that preoperative neoadjuvant chemotherapy did not improve overall survival among patients with oesophageal cancer. Marked clinical heterogeneity due to different chemotherapy protocols, use of postoperative chemotherapy and longer delay before surgery as well as fewer patients in the chemotherapy group undergoing surgery in the Intergroup trial may explain the different outcomes. Bhansali et al. in their meta-analysis of 12 RCTs, comparing adjuvant/neoadjuvant chemotherapy with surgery alone, showed a relative reduction in odds of death for the chemotherapy group of 4.2±23.7% (OR=0.96, 95% CI 0.75–1.22). In this meta-analysis all but one of the RCTs compared neoadjuvant chemotherapy with no chemotherapy.

Clinical Bottom Line

We conclude that combining neoadjuvant chemotherapy with surgery for resectable thoracic esophageal cancer has theoretical appeal and may offer a modest survival advantage compared to surgery alone. The most recent meta-analysis, and the largest RCT of 804 patients, demonstrated an absolute survival advantage of around 7–9% at two years which just reached statistical significance. Benefit was less clear for squamous cell carcinoma than adenocarcinoma and the second largest RCT did not demonstrate a significant benefit.

References

1. Gebski V, Burmeister B, Smithers BM et al. Australasian Gastro-Intestinal Trials Group. Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis. Lancet Oncol 2007; 8:226–234.
2. Malthaner RA, Collin S, Fenlon D. Preoperative chemotherapy for resectable thoracic esophageal cancer. Cochrane Database Syst Rev 2006, Issue 3. Art. No.: CD001556. DOI: 10.1002/14651858. CD001556.pub2.
3. Malthaner RA, Wong RK, Rumble RB et al. Members of the Gastrointestinal Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence-based Care Neoadjuvant or adjuvant therapy for resectable esophageal cancer: a systematic review. BMC 2004; 2:35.
4. Malthaner RA, Wong RK, Rumble RB et al. Gastrointestinal Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence-based Care Neoadjuvant or adjuvant therapy for resectable esophageal cancer: a clinical practice guideline. BMC Cancer 2004; 4:67.
5. Kaklamanos IG, Walker GR, Ferry K et al. Neoadjuvant treatment for resectable cancer of the esophagus and the gastroesophageal junction: a meta-analysis of randomized clinical trials. Ann Surg Oncol 2003; 10:754–761.
6. Urschel JD, Vasan H, Blewett CJ. A meta-analysis of randomized controlled trials that compared neoadjuvant chemotherapy and surgery to surgery alone for resectable esophageal cancer. Am J Surg 2002; 183:274–279.
7. Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomized controlled trial. Lancet 2002; 359:1727–1733.
8. Kelsen DP, Ginsberg R, Pajak TF et al. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 1998; 339:1979–1984.
9. Bhansali MS, Vaidya JS, Bhatt RG et al. Chemotherapy for carcinoma of the esophagus: a comparison of evidence from meta-analyses of randomized trials and of historical control studies. Ann Oncol 1996; 7:355–359.