Interact CardioVasc Thorac Surg 2007;6:661-664. doi:10.1510/icvts.2007.163386
© 2007 European Association of Cardio-Thoracic Surgery
Best evidence topic - Esophagus |
Does neoadjuvant chemotherapy improve survival in patients with resectable thoracic oesophageal cancer?
Shahzad G. Rajaa,*,
Kareem Salhiyyahb and
Kumaresan Nagarajana
a Department of Cardiothoracic Surgery (Level 9), Western Infirmary Glasgow, Dumbarton Road, Glasgow, G11 6NT, UK
b Department of Cardiac Surgery, Royal Hospital for Sick Children, Dalnair Street, Glasgow, G3 8SJ, UK
Received 14 July 2007;
accepted 17 July 2007
*Corresponding author. Fax: +441412111751.
E-mail address: drrajashahzad{at}hotmail.com (S.G. Raja).
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Abstract
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A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was whether neoadjuvant chemotherapy improves survival in patients with resectable oesophageal cancer. Altogether 685 papers were identified using the below mentioned search. Nine represented the best evidence to answer the clinical question. The author, journal, date and country of publication, patient group, relevant outcomes and weaknesses were tabulated. We conclude that combining neoadjuvant chemotherapy with surgery for resectable thoracic oesophageal cancer has theoretical appeal and may offer a modest survival advantage compared to surgery alone. The most recent meta-analysis and the largest randomised trial 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 randomised trial did not demonstrate a significant benefit.
Key Words: Chemotherapy; Oesophageal carcinoma; Survival; Neoadjuvant chemotherapy
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1. Introduction
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A best evidence topic was constructed according to a structured protocol. This protocol is fully described in the ICVTS [1].
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2. Clinical scenario
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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.
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3. Three-part question
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In [patients with resectable oesophageal carcinoma] does [neoadjuvant chemotherapy compared to surgery alone] improve [survival]?
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4. Search strategy
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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.
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5. Search outcome
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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 in Table 1.
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6. Discussion
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Gebski et al. [2] 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. [3] 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. [4] 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 [5].
Kaklamanos et al. [6] 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. [7] 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 [8] and 1998 [9], 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 [9] 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. [10] 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.
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7. Clinical bottom line
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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.
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References
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- 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.
- Malthaner RA, Wong RK, Rumble RB, Zuraw L. 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 and meta-analysis. BMC Med 2004; 2:35.[CrossRef][Medline]
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- 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.[CrossRef][Medline]
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- Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, Estes N, Haller DG, Ajani J, Kocha W, Minsky BD, Roth JA. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 1998; 339:1979–1984.[Abstract/Free Full Text]
- Bhansali MS, Vaidya JS, Bhatt RG, Patil PK, Badwe RA, Desai PB. 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.[Abstract/Free Full Text]
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Abstract
1. Introduction