Chemotherapy following complete resection of non-small-cell lung cancer is of small but significant benefit in terms of survival
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《血管的通路杂志》
a Department of Cardiothoracic Surgery, The Royal Hospital for Sick Children, Dalnair Street, Glasgow, G3 8SJ, UK
b Department of Cardiothoracic Surgery, The Western Infirmary, Glasgow, UK
c Department of Cardiothoracic Surgery, James Cook University Hospital, Middlesbrough, UK
Abstract
A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether patients benefit in terms of survival from chemotherapy following complete resection of non-small-cell lung cancer. Altogether 681 papers were found using the reported search, of which 14 represented the best evidence on this topic. The authour, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses were tabulated. We conclude that post-operative adjuvant chemotherapy carries a small survival benefit in those patients with complete resection of their lung cancer. This survival benefit is in the region of a 4% absolute survival advantage at 5 years. Thus, 25 patients require chemotherapy to save one life at 5 years. This should be discussed with all the patients following complete resection of non-small-cell lung cancer.
Key Words: Evidence based medicine; Lung neoplasms; Antineoplastic agents; Survival; Thoracic surgery
1. Introduction
A best evidence topic was constructed according to a structured protocol. This protocol is fully described in the ICVTS [1].
2. Clinical scenario
You are seeing a 60-year-old patient 5 days after a left lower lobectomy for a 4 cm squamous cell carcinoma. There were no obvious nodal involvement at operation. He is diabetic and an ex-smoker but otherwise relatively well and ready to go home. You tell him that he is ready to go, but that he will probably need chemotherapy in a few weeks time. He is alarmed at this and worried that the operation has, therefore, not been a success, and you enter into a long discussion about chemotherapy, the operation, and his likely prognosis. After this lengthy discussion you wonder, whether it is really worth referring these early stage patients for chemotherapy, and thus resolve to look up the evidence.
3. Three-part question
In patients with [fully resected non-small-cell lung cancer], does [chemotherapy] improve [5-year survival]
4. Search strategy
Medline 1966–April 2006, using the Ovid interface.
[exp antineoplastic agents] AND [lung resection.mp OR exp thoracic surgery, video assisted OR exp thoracic surgery OR exp video-assisted surgery OR lobectomy.mp OR resect$.mp] AND [exp lung neoplasms OR exp carcinoma, non-small-cell lung] Limit results to human studies.
5. Search outcome
The search produced 1081 potentially relevant abstracts. The UK MRC meta-analysis reported in 1995, which was used in an individual patient data methodology, was regarded as a definitive review of pre-1995 work [12]. Studies published prior to this date were, therefore, not individually included. This led to 681 studies published after 1995.
Fourteen published studies identified as being the best evidence are tabulated in Table 1.
6. Results
6.1. Platinum-based chemotherapy trials
The UK MRC meta-analysis of 1995 showed a trend towards improved survival with both platinum and UFT based adjuvant chemotherapy following complete resection compared with surgery alone [12]. Although this trend did not reach statistical significance, the findings stimulated large new randomised trials.
These trials differed in the pathological stages they recruited, and in the use of radiotherapy. The JBR-10 study and IALT studies demonstrated an overall benefit with chemotherapy. Both utilised a modern chemotherapy regime, although IALT recruited stage III and allowed radiotherapy, whereas JBR-10 did not. The three negative trials all allowed radiotherapy and later stage patients. Two meta-analyses [14,15] have shown moderate benefit with chemotherapy over surgery alone, with identical and significant hazard ratios of 0.89.
6.2. Uracil/Tegafur (UFT) Trials
Uracil-Tegafur or UFT (Taino Pharmaceuticals, Tokyo) has been studied in Japan. Tegafur is a prodrug of flourouracil, given with Uracil, which inhibits the breakdown of flourouracil. It is given orally, providing stable plasma levels over long periods. A heterogeneous study including stage I–III [11] showed an overall survival benefit, but this was not confirmed in further studies [8–10]. However, subgroup analyses of some of these trials found a survival benefit in early-stage disease [8,10], and the JLCRG stage I adenocarcinoma-only study showed an overall survival benefit. In the one study with both a platinum and a UFT arm there was no significant difference between the regimes [11]. Three recent meta-analyses have now confirmed a significant overall survival benefit for UFT over surgery alone, with Hazard ratios of 0.74 to 0.82 [14,15]. Currently, UFT is not available in the EU or US.
6.3. United Kingdom Clinical Guidelines
The UK National Institute for Health and Clinical Excellence (NICE) and the Scottish Intercollegiate Guidelines Network both issued guidelines on the management of lung cancer in February 2005 (www.nice.org.uk and www.sign.ac.uk). NICE concluded, ‘Adjuvant chemotherapy should be offered to NSCLC patients who have had a complete resection, with discussion of the risks and benefits’. However, NICE further described surgery and chemotherapy as ‘suitable for some patients’ in stage I, II and IIIA, although surgery alone remained ‘first choice for eligible patients’ in stage I and II.
Similarly, the SIGN guideline states ‘adjuvant chemotherapy should be considered for resected NSCLC, but discussed fully given the small margin of benefit, risks of toxicity and uncertainty as to which group of patients are likely to benefit’.
6.4. Conclusions
Recent randomised trials of both platinum and UFT-based adjuvant chemotherapy have shown a survival benefit for both regimes compared to surgery alone. These findings have been confirmed in meta-analyses of several randomised controlled trials, and can be considered level 1 evidence for both regimes. No benefit of one regime over another has been demonstrated, and compliance rates for both are moderate.
The overall survival benefits are relatively small- single figures changes in five-year survival. Many trials have not reported quality of life analysis, which is particularly significant when the survival benefit is modest. For these reasons, some fully informed patients may not wish chemotherapy, and the decision merits careful discussion, tailored to an individual patient's circumstances. Whether the benefits seen apply to all pathological stages needs further clarification. The role, if any, of adjuvant radiotherapy and the use of biomarkers predicting response to chemotherapy remain subjects of active study. An updated individual patient data meta-analysis of recent trials is currently in preparation.
The role of neo-adjuvant chemotherapy is the subject of ongoing clinical trials, including the Bimodality Lung Oncology Trial (BLOT) and the UK MRC Lu-22 Trial.
7. Clinical bottom line
Post-operative adjuvant chemotherapy carries a small survival benefit in those patients with complete resection of their lung cancer. This survival benefit is in the region of a 4% absolute survival advantage at 5 years. Thus, 25 patients require chemotherapy to save one life at 5 years. This should be discussed with all the patients following complete resection of non-small-cell lung cancer.
References
Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact CardioVasc Thorac Surg 2003; 2:405–440.
Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, Fry W, Bethune D, Ayoub J, Ding K, Seymour L, Graham B, Tsao MS, Gandara D, Kesler K, Demmy T. Shepherd F for the JBR-10 Investigators. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005; 352:2589–2597.
Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. N Engl J Med 2004; 350:351–360.
Scagliotti GV, Fossati R, Torri V, Crino L, Giaccone G, Silvano G, Martelli M, Clerici M, Cognetti F, Tonato M. Adjuvant Lung Project Italy/European Organisation for Research Treatment of Cancer – Lung Cancer Cooperative Group Investigators. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or III A non-small-cell lung cancer. J Natl Cancer Inst 2003; 95:1453–1461.
Waller D, Peake MD, Stephens RJ, Gower NH, Milroy R, Parmar MK, Rudd RM, Spiro SG. Chemotherapy for patients with non-small cell lung cancer: the surgical setting of the big lung trial. Eur J Cardiothorac Surg 2004; 26:173–182.
Keller SM, Adak S, Wagner H, Herskovic H, Komaki R, Brooks BJ, Perry MC, Livingston RB, Johnson DH. for the Eastern Cooperative Oncology Group. A randomised trial of post-operative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. N Engl J Med 2000; 343:1217–1222.
Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, Watanabe Y, Wada H, Tsuboi M, Hamajima N. for the Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy. A randomised trial of adjuvant chemotherapy with Uracil-Tegafur for adenocarcinoma of the lung. N Engl J Med 2004; 350:1713–1721.
Nakagawa M, Tanaka F, Tsubota N, Ohta M, Takao M, Wada H. A randomised phase III trial of adjuvant chemotherapy with UFT for completely resected pathological stage I non-small-cell lung cancer: the West Japan Study Group for Lung Cancer Surgery (WJSG) – the 4th study. Ann Oncol 2005; 16:75–80.
Endo C, Saito Y, Iwanami H, Tsushima T, Imai T, Kawamura M, Kondo T, Koike K, Handa M, Kanno R, Fujimura S. A randomized trial of postoperative UFT therapy in p stage I, II non-small-cell lung cancer: North-east Japan Study Group for Lung Cancer Surgery. Lung Cancer 2003; 40:181–186.
Wada H, Miyahara R, Tanaka F, Hitomi S. Postoperative adjuvant chemotherapy with PVM (Cisplatin + Vindesine + Mitomycin C) and UFT (Uracil + Tegafur) in resected stage I-II NSCLC (non-small-cell lung cancer): a randomised clinical trial. West Japan Study Group for Lung Cancer Surgery (WJSG). Eur J Cardiothorac Surg 1999; 15:438–443.
Wada H, Hitomi S, Teramatsu T. Adjuvant chemotherapy after complete resection in non-small-cell lung cancer. West Japan Study Group for Lung Cancer Surgery. J Clin Oncol 1996; 14:1048–1054.
Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. Br Med J 1995; 311:7010899–909.
Sedrakyan A, Van Der Meulen J, O'Byrne K, Prendiville J, Hill J, Treasure T. Postoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis. J Thorac Cardiovasc Surg 2004; 128:414–419.
Hamada C, Tanaka F, Ohta M, Fujimura S, Kodama K, Imaizumi M, Wada H. Metaanalysis of postoperative adjuvant chemotherapy with tegafur-uracil in non-small-cell lung cancer. J Clin Oncol 2005; 23:4999–5006.
Hotta K, Matsuo K, Ueoka H, Kiura K, Tabata M, Tanimoto M. Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomised controlled trials J Clin Oncol 2004; 22:3860–3867.(Douglas West, Alan J.B. K)
b Department of Cardiothoracic Surgery, The Western Infirmary, Glasgow, UK
c Department of Cardiothoracic Surgery, James Cook University Hospital, Middlesbrough, UK
Abstract
A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether patients benefit in terms of survival from chemotherapy following complete resection of non-small-cell lung cancer. Altogether 681 papers were found using the reported search, of which 14 represented the best evidence on this topic. The authour, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses were tabulated. We conclude that post-operative adjuvant chemotherapy carries a small survival benefit in those patients with complete resection of their lung cancer. This survival benefit is in the region of a 4% absolute survival advantage at 5 years. Thus, 25 patients require chemotherapy to save one life at 5 years. This should be discussed with all the patients following complete resection of non-small-cell lung cancer.
Key Words: Evidence based medicine; Lung neoplasms; Antineoplastic agents; Survival; Thoracic surgery
1. Introduction
A best evidence topic was constructed according to a structured protocol. This protocol is fully described in the ICVTS [1].
2. Clinical scenario
You are seeing a 60-year-old patient 5 days after a left lower lobectomy for a 4 cm squamous cell carcinoma. There were no obvious nodal involvement at operation. He is diabetic and an ex-smoker but otherwise relatively well and ready to go home. You tell him that he is ready to go, but that he will probably need chemotherapy in a few weeks time. He is alarmed at this and worried that the operation has, therefore, not been a success, and you enter into a long discussion about chemotherapy, the operation, and his likely prognosis. After this lengthy discussion you wonder, whether it is really worth referring these early stage patients for chemotherapy, and thus resolve to look up the evidence.
3. Three-part question
In patients with [fully resected non-small-cell lung cancer], does [chemotherapy] improve [5-year survival]
4. Search strategy
Medline 1966–April 2006, using the Ovid interface.
[exp antineoplastic agents] AND [lung resection.mp OR exp thoracic surgery, video assisted OR exp thoracic surgery OR exp video-assisted surgery OR lobectomy.mp OR resect$.mp] AND [exp lung neoplasms OR exp carcinoma, non-small-cell lung] Limit results to human studies.
5. Search outcome
The search produced 1081 potentially relevant abstracts. The UK MRC meta-analysis reported in 1995, which was used in an individual patient data methodology, was regarded as a definitive review of pre-1995 work [12]. Studies published prior to this date were, therefore, not individually included. This led to 681 studies published after 1995.
Fourteen published studies identified as being the best evidence are tabulated in Table 1.
6. Results
6.1. Platinum-based chemotherapy trials
The UK MRC meta-analysis of 1995 showed a trend towards improved survival with both platinum and UFT based adjuvant chemotherapy following complete resection compared with surgery alone [12]. Although this trend did not reach statistical significance, the findings stimulated large new randomised trials.
These trials differed in the pathological stages they recruited, and in the use of radiotherapy. The JBR-10 study and IALT studies demonstrated an overall benefit with chemotherapy. Both utilised a modern chemotherapy regime, although IALT recruited stage III and allowed radiotherapy, whereas JBR-10 did not. The three negative trials all allowed radiotherapy and later stage patients. Two meta-analyses [14,15] have shown moderate benefit with chemotherapy over surgery alone, with identical and significant hazard ratios of 0.89.
6.2. Uracil/Tegafur (UFT) Trials
Uracil-Tegafur or UFT (Taino Pharmaceuticals, Tokyo) has been studied in Japan. Tegafur is a prodrug of flourouracil, given with Uracil, which inhibits the breakdown of flourouracil. It is given orally, providing stable plasma levels over long periods. A heterogeneous study including stage I–III [11] showed an overall survival benefit, but this was not confirmed in further studies [8–10]. However, subgroup analyses of some of these trials found a survival benefit in early-stage disease [8,10], and the JLCRG stage I adenocarcinoma-only study showed an overall survival benefit. In the one study with both a platinum and a UFT arm there was no significant difference between the regimes [11]. Three recent meta-analyses have now confirmed a significant overall survival benefit for UFT over surgery alone, with Hazard ratios of 0.74 to 0.82 [14,15]. Currently, UFT is not available in the EU or US.
6.3. United Kingdom Clinical Guidelines
The UK National Institute for Health and Clinical Excellence (NICE) and the Scottish Intercollegiate Guidelines Network both issued guidelines on the management of lung cancer in February 2005 (www.nice.org.uk and www.sign.ac.uk). NICE concluded, ‘Adjuvant chemotherapy should be offered to NSCLC patients who have had a complete resection, with discussion of the risks and benefits’. However, NICE further described surgery and chemotherapy as ‘suitable for some patients’ in stage I, II and IIIA, although surgery alone remained ‘first choice for eligible patients’ in stage I and II.
Similarly, the SIGN guideline states ‘adjuvant chemotherapy should be considered for resected NSCLC, but discussed fully given the small margin of benefit, risks of toxicity and uncertainty as to which group of patients are likely to benefit’.
6.4. Conclusions
Recent randomised trials of both platinum and UFT-based adjuvant chemotherapy have shown a survival benefit for both regimes compared to surgery alone. These findings have been confirmed in meta-analyses of several randomised controlled trials, and can be considered level 1 evidence for both regimes. No benefit of one regime over another has been demonstrated, and compliance rates for both are moderate.
The overall survival benefits are relatively small- single figures changes in five-year survival. Many trials have not reported quality of life analysis, which is particularly significant when the survival benefit is modest. For these reasons, some fully informed patients may not wish chemotherapy, and the decision merits careful discussion, tailored to an individual patient's circumstances. Whether the benefits seen apply to all pathological stages needs further clarification. The role, if any, of adjuvant radiotherapy and the use of biomarkers predicting response to chemotherapy remain subjects of active study. An updated individual patient data meta-analysis of recent trials is currently in preparation.
The role of neo-adjuvant chemotherapy is the subject of ongoing clinical trials, including the Bimodality Lung Oncology Trial (BLOT) and the UK MRC Lu-22 Trial.
7. Clinical bottom line
Post-operative adjuvant chemotherapy carries a small survival benefit in those patients with complete resection of their lung cancer. This survival benefit is in the region of a 4% absolute survival advantage at 5 years. Thus, 25 patients require chemotherapy to save one life at 5 years. This should be discussed with all the patients following complete resection of non-small-cell lung cancer.
References
Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact CardioVasc Thorac Surg 2003; 2:405–440.
Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, Fry W, Bethune D, Ayoub J, Ding K, Seymour L, Graham B, Tsao MS, Gandara D, Kesler K, Demmy T. Shepherd F for the JBR-10 Investigators. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005; 352:2589–2597.
Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. N Engl J Med 2004; 350:351–360.
Scagliotti GV, Fossati R, Torri V, Crino L, Giaccone G, Silvano G, Martelli M, Clerici M, Cognetti F, Tonato M. Adjuvant Lung Project Italy/European Organisation for Research Treatment of Cancer – Lung Cancer Cooperative Group Investigators. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or III A non-small-cell lung cancer. J Natl Cancer Inst 2003; 95:1453–1461.
Waller D, Peake MD, Stephens RJ, Gower NH, Milroy R, Parmar MK, Rudd RM, Spiro SG. Chemotherapy for patients with non-small cell lung cancer: the surgical setting of the big lung trial. Eur J Cardiothorac Surg 2004; 26:173–182.
Keller SM, Adak S, Wagner H, Herskovic H, Komaki R, Brooks BJ, Perry MC, Livingston RB, Johnson DH. for the Eastern Cooperative Oncology Group. A randomised trial of post-operative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. N Engl J Med 2000; 343:1217–1222.
Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, Watanabe Y, Wada H, Tsuboi M, Hamajima N. for the Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy. A randomised trial of adjuvant chemotherapy with Uracil-Tegafur for adenocarcinoma of the lung. N Engl J Med 2004; 350:1713–1721.
Nakagawa M, Tanaka F, Tsubota N, Ohta M, Takao M, Wada H. A randomised phase III trial of adjuvant chemotherapy with UFT for completely resected pathological stage I non-small-cell lung cancer: the West Japan Study Group for Lung Cancer Surgery (WJSG) – the 4th study. Ann Oncol 2005; 16:75–80.
Endo C, Saito Y, Iwanami H, Tsushima T, Imai T, Kawamura M, Kondo T, Koike K, Handa M, Kanno R, Fujimura S. A randomized trial of postoperative UFT therapy in p stage I, II non-small-cell lung cancer: North-east Japan Study Group for Lung Cancer Surgery. Lung Cancer 2003; 40:181–186.
Wada H, Miyahara R, Tanaka F, Hitomi S. Postoperative adjuvant chemotherapy with PVM (Cisplatin + Vindesine + Mitomycin C) and UFT (Uracil + Tegafur) in resected stage I-II NSCLC (non-small-cell lung cancer): a randomised clinical trial. West Japan Study Group for Lung Cancer Surgery (WJSG). Eur J Cardiothorac Surg 1999; 15:438–443.
Wada H, Hitomi S, Teramatsu T. Adjuvant chemotherapy after complete resection in non-small-cell lung cancer. West Japan Study Group for Lung Cancer Surgery. J Clin Oncol 1996; 14:1048–1054.
Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. Br Med J 1995; 311:7010899–909.
Sedrakyan A, Van Der Meulen J, O'Byrne K, Prendiville J, Hill J, Treasure T. Postoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis. J Thorac Cardiovasc Surg 2004; 128:414–419.
Hamada C, Tanaka F, Ohta M, Fujimura S, Kodama K, Imaizumi M, Wada H. Metaanalysis of postoperative adjuvant chemotherapy with tegafur-uracil in non-small-cell lung cancer. J Clin Oncol 2005; 23:4999–5006.
Hotta K, Matsuo K, Ueoka H, Kiura K, Tabata M, Tanimoto M. Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomised controlled trials J Clin Oncol 2004; 22:3860–3867.(Douglas West, Alan J.B. K)